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Credentials

Education ?

Medical School
Tulane University (1977)

Awards & Distinctions ?

Awards  
One of America's Leading Experts on:
Gene Therapy
Lung Cancer (Lung Neoplasm)
Lung Cancer (Non-Small-Cell Lung Carcinoma)
Lung Cancer (Pleural Neoplasms)
Lung Transplantation
Mediastinum Cancer (Mediastinal Neoplasm)
Mesothelioma (Asbestos-related Cancer)
Pneumonectomy
Pulmonary Emphysema (COPD)
Thoracoscopy
Thymectomy
Thymus Tumor (Thymoma)
Video-Assisted Thoracic Surgery
Castle Connolly America's Top Doctors® (2002 - 2015)
Castle Connolly America's Top Doctors® for Cancer (2005 - 2007, 2009 - 2012, 2014 - 2015)
Patients' Choice Award (2014)
Associations
American Board of Thoracic Surgery
Society of Thoracic Surgeons
American Board of Surgery
American Society of Clinical Oncology
Foundation for Thymic Cancer Research
Cardiothoracic Surgery Network

Affiliations ?

Dr. Kaiser is affiliated with 7 hospitals.

Hospital Affiliations

Score

Rankings

  • University of PA Medical Center/Presbyterian
    Thoracic Surgery (Cardiothoracic Vascular Surgery)
    51 N 39th St, Philadelphia, PA 19104
    •  
    Top 25%
  • Pennsylvania Hospital University PA Health System
    Thoracic Surgery (Cardiothoracic Vascular Surgery)
    800 Spruce St, Philadelphia, PA 19107
    •  
    Top 50%
  • Hospital of the University of PA
    Thoracic Surgery (Cardiothoracic Vascular Surgery)
    3400 Spruce St, Philadelphia, PA 19104
    •  
    Top 50%
  • University Of Pennsylvania Medical Center
  • Temple University Hospital - Episcopal Campus
    100 E Lehigh Ave, Philadelphia, PA 19125
  • Hchd
  • University of Penn Med Center-Presb Med Group
  • Publications & Research

    Dr. Kaiser has contributed to 246 publications.
    Title Should Asymptomatic Enlarged Thymus Glands Be Resected?
    Date November 2010
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    Patients frequently have an "enlarged thymus" incidentally identified on imaging. We sought to determine whether thymectomy is appropriate in patients with diffusely enlarged thymus glands.

    Title Prevention of Surgical Resident Attrition by a Novel Selection Strategy.
    Date September 2010
    Journal Annals of Surgery
    Excerpt

    We modified the resident selection strategy in an attempt to reduce resident attrition (RA).

    Title National Emphysema Treatment Trial Redux: Accentuating the Positive.
    Date September 2010
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    Under the Freedom of Information Act, we obtained the follow-up data of the National Emphysema Treatment Trial (NETT) to determine the long-term outcome for "a heterogeneous distribution of emphysema with upper lobe predominance," postulated by the NETT hypothesis to be optimal candidates for lung volume reduction surgery.

    Title In Situ Hybridization for Coccidioides Immitis 5.8s Ribosomal Rna Sequences in Formalin-fixed, Paraffin-embedded Pulmonary Specimens Using a Locked Nucleic Acid Probe: a Rapid Means for Identification in Tissue Sections.
    Date August 2010
    Journal Diagnostic Molecular Pathology : the American Journal of Surgical Pathology, Part B
    Excerpt

    Coccidioides immitis/Coccidioides posadasii are common causes of pulmonary infection in certain geographic areas, and are highly infectious when working with culture isolates in the laboratory. Rapid techniques to accurately identify this pathogen in tissues may be of benefit for diagnosis and in limiting the exposure of laboratory personnel to this agent. Locked nucleic acids (LNA) are modified nucleotides in which a ribonucleoside is linked between the 2'-oxygen and the 4'-carbon atoms with a methylene unit. LNA oligonucleotides exhibit increased thermal stability and make excellent probes for in situ hybridization (ISH). In this study, ISH utilizing a biotin-labeled LNA probe targeting Coccidioides sp. ribosomal RNA sequences in 6 formalin-fixed, paraffin-embedded pulmonary tissue specimens from 6 patients with culture positive or histologic findings suggestive of Coccidioides sp. infection is described. The cultures of the pulmonary specimens confirmed C. immitis in 3 of 6 patients. The ISH procedure with the LNA probe was positive in all 6 cases, although the number of organisms that were highlighted varied from rare to numerous. ISH with a biotin-labeled DNA probe of the same sequence was positive in 4 of the 6 cases and the signal intensity and number of organisms was much less than that observed with the LNA probe. Negative control tissues containing a variety of different fungal pathogens including Aspergillus sp., Fusarium sp., Blastomyces dermatitidis, Candida sp, Histoplasma capsulatum, and Zygomyces did not hybridize with the LNA and DNA probes. ISH with an LNA oligonucleotide probe targeting Coccidioides sp. ribosomal RNA is useful for rapid ISH. ISH could be rapidly performed when fungal pathogens are observed in tissue but cultures are negative or have not been performed.

    Title Nonoperative Thoracic Duct Embolization for Traumatic Thoracic Duct Leak: Experience in 109 Patients.
    Date March 2010
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    To demonstrate the efficacy of a minimally invasive, nonoperative, catheter-based approach to the treatment of traumatic chyle leak.

    Title The State of General Surgery Training: a Different Perspective.
    Date March 2009
    Journal Journal of Surgical Education
    Excerpt

    Much has been written about the influences of Accreditation Council for Graduate Medical Education (ACGME) work restrictions, the litigious climate in American medicine, and the proliferation of subspecialty fellowships on general surgery training. Few previous studies have addressed general surgical residents' perceptions of surgical training on a national level.

    Title Academic Medicine Amenities Unit: Developing a Model to Integrate Academic Medical Care with Luxury Hotel Services.
    Date February 2009
    Journal Academic Medicine : Journal of the Association of American Medical Colleges
    Excerpt

    The interface between established values of academic medicine and the trend toward inpatient amenities units requires close examination. Opinions of such units can be polarized, reflecting traditional reservations about the ethical dilemma of offering exclusive services only to an elite patient group. An amenities unit was developed at the University of Pennsylvania Health System in 2007, using an approach that integrated academic medicine values with the benefits of philanthropy and service excellence to make amenities unit services available to all patients. Given inherent internal political concerns, a broadly based steering committee of academic and hospital leadership was developed. An academically appropriate model was conceived, anchored by four principles: (1) integration of academic values, (2) interdisciplinary senior leadership, (3) service excellence, and (4) recalibrated occupancy expectations based on multiple revenue streams. Foremost is ensuring the same health care is afforded all patients throughout the hospital, thereby overcoming ethical challenges and optimizing teaching experiences. Service excellence frames the service ethic for all staff, and this, in addition to luxury hotel-style amenities, differentiates the style and feel of the unit from others in the hospital. Recalibrated occupancy creates program viability given revenue streams redefined to encompass gifts and patient revenue, including both reimbursement and self-pay. The medical-surgical amenities patient-care unit has enjoyed a successful first year and a growing stream of returning patients and admitting physicians. Implications for other academic medical centers include opportunities to extrapolate service excellence throughout the hospital and to cultivate philanthropy to benefit services throughout the medical center.

    Title Systemic Blockade of Transforming Growth Factor-beta Signaling Augments the Efficacy of Immunogene Therapy.
    Date January 2009
    Journal Cancer Research
    Excerpt

    Locally produced transforming growth factor-beta (TGF-beta) promotes tumor-induced immunosuppression and contributes to resistance to immunotherapy. This article explores the potential for increased efficacy when combining immunotherapies with TGF-beta suppression using the TGF-beta type I receptor kinase inhibitor SM16. Adenovirus expressing IFN-beta (Ad.IFN-beta) was injected intratumorally once in established s.c. AB12 (mesothelioma) and LKR (lung cancer) tumors or intratracheally in a Kras orthotopic lung tumor model. Mice bearing TC1 (lung cancer) tumors were vaccinated with two injections of adenovirus expressing human papillomavirus-E7 (HPV-E7; Ad.E7). SM16 was administered orally in formulated chow. Tumor growth was assessed and cytokine expression and cell populations were measured in tumors and spleens by real-time PCR and flow cytometry. SM16 potentiated the efficacy of both immunotherapies in each of the models and caused changes in the tumor microenvironment. The combination of SM16 and Ad.IFN-beta increased the number of intratumoral leukocytes (including macrophages, natural killer cells, and CD8(+) cells) and increased the percentage of T cells expressing the activation marker CD25. SM16 also augmented the antitumor effects of Ad.E7 in the TC1 flank tumor model. The combination did not increase HPV-E7 tetramer-positive CD8(+) T cells in the spleens but did induce a marked increase in the tumors. Tumors from SM16-treated mice showed increased mRNA and protein for immunostimulatory cytokines and chemokines, as well as endothelial adhesion molecules, suggesting a mechanism for the increased intratumoral leukocyte trafficking. Blockade of the TGF-beta signaling pathway augments the antitumor effects of Ad.IFN-beta immune-activating or Ad.E7 vaccination therapy. The addition of TGF-beta blocking agents in clinical trials of immunotherapies may increase efficacy.

    Title Transforming Growth Factor-beta Receptor Blockade Augments the Effectiveness of Adoptive T-cell Therapy of Established Solid Cancers.
    Date September 2008
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: Adoptive cellular immunotherapy is a promising approach to eradicate established tumors. However, a significant hurdle in the success of cellular immunotherapy involves recently identified mechanisms of immune suppression on cytotoxic T cells at the effector phase. Transforming growth factor-beta (TGF-beta) is one of the most important of these immunosuppressive factors because it affects both T-cell and macrophage functions. We thus hypothesized that systemic blockade of TGF-beta signaling combined with adoptive T-cell transfer would enhance the effectiveness of the therapy. EXPERIMENTAL DESIGN: Flank tumors were generated in mice using the chicken ovalbumin-expressing thymoma cell line, EG7. Splenocytes from transgenic OT-1 mice (whose CD8 T cells recognize an immunodominant peptide in chicken ovalbumin) were activated in vitro and adoptively transferred into mice bearing large tumors in the presence or absence of an orally available TGF-beta receptor-I kinase blocker (SM16). RESULTS: We observed markedly smaller tumors in the group receiving the combination of SM16 chow and adoptive transfer. Additional investigation revealed that TGF-beta receptor blockade increased the persistence of adoptively transferred T cells in the spleen and lymph nodes, increased numbers of adoptively transferred T cells within tumors, increased activation of these infiltrating T cells, and altered the tumor microenvironment with a significant increase in tumor necrosis factor-alpha and decrease in arginase mRNA expression. CONCLUSIONS: We found that systemic blockade of TGF-beta receptor activity augmented the antitumor activity of adoptively transferred T cells and may thus be a useful adjunct in future clinical trials.

    Title Extended Transcervical Thymectomy in the Treatment of Myasthenia Gravis.
    Date September 2008
    Journal Annals of the New York Academy of Sciences
    Excerpt

    The ideal operative technique for thymectomy in myasthenia gravis remains controversial. Most surgeons perform thymectomy via median sternotomy, some supplementing this with an even more extensive mediastinal and cervical dissection designed to remove all areas of possible ectopic thymic tissue. We and others have advocated a transcervical approach that is less morbid and costly than sternotomy approaches. The transcervical approach allows a complete extracapsular thymic resection, but it does not address all areas of potential ectopic thymic tissue. We have published our experience with 151 extended transcervical thymectomies (TCT). At mean follow-up of 53 months (complete follow-up in 97%), Kaplan-Meier estimates of complete stable remission were 33% and 35% at 3 and 6 years. If one includes patients who became asymptomatic but remained on low dose, single-drug immunosuppression as complete remissions (CRs), then the CR rates were 43% and 45% at 3 and 6 years. Longer term (mean 83 months) follow-up of the earliest 84 patients in the series showed preserved CR rates. On multivariate analysis, only preoperative Osserman Class (group mean 2.3) was significantly associated with improved CR rate. These results were obtained with a major operative complication rate of 0.7% and minor complication rate of 6.6%, and nearly every operation was performed without the need for overnight hospital admission. We believe that these response rates following TCT are sufficiently similar to those following transsternal techniques of thymectomy to allow us to recommend this less morbid and less costly operation as an eminently reasonable choice in the surgical treatment of myasthenia gravis.

    Title Surgical Treatment of Thymic Epithelial Neoplasms.
    Date August 2008
    Journal Hematology/oncology Clinics of North America
    Excerpt

    Resection continues to be the mainstay of treatment for epithelial lesions of the thymus. This has never been in doubt for encapsulated stage I and II lesions, but we recently have come to a greater appreciation of the role of preoperative therapy for locally advanced lesions, particularly stage III disease. For any lesion that presents in the anterior mediastinum and on CT scan does not appear to be eminently resectable, a biopsy should be performed to rule out lymphoma after serum germ cell markers have been obtained to rule out the rare primary mediastinal or metastatic germ cell tumor.

    Title Postoperative Mortality After Esophagectomy for Cancer: Development of a Preoperative Risk Prediction Model.
    Date June 2008
    Journal Annals of Surgical Oncology
    Excerpt

    BACKGROUND: Surgical resection for the treatment of esophageal cancer remains a high-risk procedure. To develop a model to predict risk of postoperative death, we sought to identify factors associated with postoperative mortality for Medicare patients undergoing esophagectomy for cancer. METHODS: We evaluated patients in the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare database who underwent esophagectomy for esophageal cancer from 1997 to 2003. Variables evaluated were patient age, race, marital status, sex, tumor stage, Charlson score, and hospital volume. Hospital volume was evaluated in tertiles of even volume groups (low, < .67 cases a year; medium, .68 to 2.33 cases a year; high, > 2.33 cases a year). The primary outcome measure was postoperative mortality, defined as death within 30 days of esophagectomy or death during the hospitalization in which the primary surgical procedure was performed. In-hospital deaths more than 30 days after esophagectomy were included in the outcomes to more accurately estimate the true mortality of this procedure. Multivariable logistic regression analyses were performed to evaluate the relationship between patient and provider characteristics and postoperative mortality. Finally, characteristics identified by the regression analysis were used to generate a simplified, clinically applicable model predicting risk of postoperative mortality in the Medicare population. RESULTS: A total of 1172 patients underwent esophageal cancer surgery during this study period. Overall postoperative mortality was 14%. Multivariable logistic regression demonstrated that age, Charlson score, and hospital volume were statistically significant predictors of postoperative mortality. The other variables such as race, martial status, sex, and disease stage were not found to be significant. The odds of postoperative mortality at low-volume hospitals were almost twice those at a high-volume hospital. Age greater than 80 increased odds of mortality almost twofold. Similarly, Charlson scores of > or = 2 resulted in more than a 1.5-fold risk of postoperative mortality. Our prediction model using these variables accurately stratified postoperative mortality for this population. CONCLUSIONS: Postoperative mortality (30-day and in-hospital) remains high after esophagectomy. Age, Charlson score, and hospital volume were identified as independent predictors of postoperative mortality. A simple risk prediction model that uses preoperative clinical data accurately predicted patient postoperative mortality for this SEER-Medicare population.

    Title What's New in Acs Surgery: Principles and Practice.
    Date May 2008
    Journal Bulletin of the American College of Surgeons
    Title Rapid Disuse Atrophy of Diaphragm Fibers in Mechanically Ventilated Humans.
    Date March 2008
    Journal The New England Journal of Medicine
    Excerpt

    BACKGROUND: The combination of complete diaphragm inactivity and mechanical ventilation (for more than 18 hours) elicits disuse atrophy of myofibers in animals. We hypothesized that the same may also occur in the human diaphragm. METHODS: We obtained biopsy specimens from the costal diaphragms of 14 brain-dead organ donors before organ harvest (case subjects) and compared them with intraoperative biopsy specimens from the diaphragms of 8 patients who were undergoing surgery for either benign lesions or localized lung cancer (control subjects). Case subjects had diaphragmatic inactivity and underwent mechanical ventilation for 18 to 69 hours; among control subjects diaphragmatic inactivity and mechanical ventilation were limited to 2 to 3 hours. We carried out histologic, biochemical, and gene-expression studies on these specimens. RESULTS: As compared with diaphragm-biopsy specimens from controls, specimens from case subjects showed decreased cross-sectional areas of slow-twitch and fast-twitch fibers of 57% (P=0.001) and 53% (P=0.01), respectively, decreased glutathione concentration of 23% (P=0.01), increased active caspase-3 expression of 100% (P=0.05), a 200% higher ratio of atrogin-1 messenger RNA (mRNA) transcripts to MBD4 (a housekeeping gene) (P=0.002), and a 590% higher ratio of MuRF-1 mRNA transcripts to MBD4 (P=0.001). CONCLUSIONS: The combination of 18 to 69 hours of complete diaphragmatic inactivity and mechanical ventilation results in marked atrophy of human diaphragm myofibers. These findings are consistent with increased diaphragmatic proteolysis during inactivity.

    Title Sleep and Quality of Life in Long-term Lung Cancer Survivors.
    Date February 2008
    Journal Lung Cancer (amsterdam, Netherlands)
    Excerpt

    BACKGROUND: Sleep problems are common in lung cancer survivors, yet little is known about the prevalence, determinants, and effects on quality of life (QoL) of these sleep problems in long-term lung cancer survivors. METHODS: A case-control study design comparing 76 elderly lung cancer survivors (LCS, >5 years post diagnosis with mean survival time of 8 years+/-2.1 years) and 78 elderly non-cancer controls (NCC). Measurements included a standardized questionnaire for sleep (Pittsburgh Sleep Quality Index-PSQI), and analogue scales for dyspnea, pain, and other comorbid symptoms, as well as demographic factors and cancer history. RESULTS: Overall, 56.6% of LCS had poor sleep (PSQI global score >5) as compared to only 29.5% of NCC (p<0.001), and 49.2% of LCS who did not have sleep difficulties prior to their lung cancer diagnosis ultimately developed them. There was also evidence of significant impairments in sleep efficiency in LCS (78.3%) relative to NCC (89.6%, p<0.001), predominantly due to increased nocturnal awakenings. A single-item analogue scale for sleep quality was not as effective in identifying sleep problems as more specific questions about sleep duration and sleep efficiency. Poor sleep quality was significantly correlated with impairments in quality of life, even when controlling for other factors, such as dyspnea. CONCLUSIONS: Even 8 years after diagnosis, LCS continue to have significant sleep difficulties. By asking specific questions about sleep medication use, nocturnal awakenings and sleep efficiency, health care providers can identify sleep problems that could be treated and potentially improve the quality of life of their patients.

    Title A Phase I Clinical Trial of Single-dose Intrapleural Ifn-beta Gene Transfer for Malignant Pleural Mesothelioma and Metastatic Pleural Effusions: High Rate of Antitumor Immune Responses.
    Date October 2007
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-beta gene transfer using an adenoviral vector (Ad.IFN-beta) in patients with malignant pleural mesothelioma (MPM) and metastatic pleural effusions (MPE). EXPERIMENTAL DESIGN: Ad.IFN-beta was administered through an indwelling pleural catheter in doses ranging from 9 x 10(11) to 3 x 10(12) viral particles (vp) in two cohorts of patients with MPM (7 patients) and MPE (3 patients). Subjects were evaluated for (a) toxicity, (b) gene transfer, (c) humoral, cellular, and cytokine-mediated immune responses, and (d) tumor responses via 18-fluorodeoxyglucose-positron emission tomography scans and chest computed tomography scans. RESULTS: Intrapleural Ad.IFN-beta was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 x 10(11) vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 x 10(12) vp. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space. Intrapleural levels of cytokines were highly variable at baseline and after response to gene transfer. Gene transfer was documented in 7 of the 10 patients by demonstration of IFN-beta message or protein. Antitumor immune responses were elicited in 7 of the 10 patients and included the detection of cytotoxic T cells (1 patient), activation of circulating natural killer cells (2 patients), and humoral responses to known (Simian virus 40 large T antigen and mesothelin) and unknown tumor antigens (7 patients). Four of 10 patients showed meaningful clinical responses defined as disease stability and/or regression on 18-fluorodeoxyglucose-positron emission tomography and computed tomography scans at day 60 after vector infusion. CONCLUSIONS: Intrapleural instillation of Ad.IFN-beta is a potentially useful approach for the generation of antitumor immune responses in MPM and MPE patients and should be investigated further for overall clinical efficacy.

    Title Tumor Suppressor Functions of Arlts1 in Lung Cancers.
    Date October 2007
    Journal Cancer Research
    Excerpt

    ARLTS1 is a newly characterized tumor suppressor gene located at chromosome 13q14.3 and involved in the pathogenesis of various types of tumors: two single-nucleotide polymorphisms, one of them responsible for protein truncation, were found statistically associated with familial malignancies, whereas DNA hypermethylation and genomic deletions have been identified as a mechanism of ARLTS1 down-regulation in sporadic cancers. We found that in a large portion of lung carcinomas (37%) and in all analyzed lung cancer cell lines, ARLTS1 is strongly down-regulated due to DNA methylation in its promoter region. After its restoration by adenoviral transduction, ARLTS1-negative A549 and H1299 cells underwent apoptosis and inhibition of cell growth. Furthermore, ARLTS1 reexpression significantly reduced the ability of A549 and H1299 to form tumors in nude mice. Finally, we identified approximately 650 transcripts differentially expressed after restoration of ARLTS1 expression in A549 cells, suggesting that various pathways involved in cell survival, proliferation, signaling, and development mediate the effects of wild-type ARLTS1 in a lung cancer system.

    Title The Patient Safety Leadership Academy at the University of Pennsylvania: the First Cohort's Learning Experience.
    Date September 2007
    Journal Quality Management in Health Care
    Excerpt

    BACKGROUND: We based the Patient Safety Leadership Academy (PSLA) on the premise that improving management skills could improve patient safety and employee satisfaction. STUDY DESIGN: Fellows completed baseline surveys on leadership skills knowledge, patient safety knowledge, and program goals. They completed the same surveys 7 months later at the final PSLA session. The fellows also completed a survey assessing how PSLA improved expertise and comparing PSLA to other patient safety learning opportunities. Matched pairs t tests were used to compare baseline and postprogram results. RESULTS: Baseline scores indicated appropriateness of focusing on leadership, with average leadership knowledge (2.48) significantly lower than patient safety knowledge (3.22). For patient safety, postprogram results were significant for 8 of 10 questions. All results were significant for leadership. Fellows also rated skills covered by the curriculum on a scale of 1 to 10. For all areas, the median score for knowledge gained was 7. When compared with other patient safety learning experiences, participants rated PSLA as 4 or 5, where 1 indicated the other experience much more valuable and 5 much more valuable. CONCLUSIONS: PSLA demonstrates that leadership skills are perceived as important by physicians and managers in surgical areas. This study demonstrated that a leadership skills approach to patient safety training could improve knowledge in specific leadership areas and general patient safety.

    Title A 10-gene Classifier for Distinguishing Head and Neck Squamous Cell Carcinoma and Lung Squamous Cell Carcinoma.
    Date August 2007
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: The risk of developing metastatic squamous cell carcinoma for patients with head and neck squamous cell carcinoma (HNSCC) is very high. Because these patients are often heavy tobacco users, they are also at risk for developing a second primary cancer, with squamous cell carcinoma of the lung (LSCC) being the most common. The distinction between a lung metastasis and a primary LSCC is currently based on certain clinical and histologic criteria, although the accuracy of this approach remains in question. EXPERIMENTAL DESIGN: Gene expression patterns derived from 28 patients with HNSCC or LSCC from a single center were analyzed using penalized discriminant analysis. Validation was done on previously published data for 134 total subjects from four independent Affymetrix data sets. RESULTS: We identified a panel of 10 genes (CXCL13, COL6A2, SFTPB, KRT14, TSPYL5, TMP3, KLK10, MMP1, GAS1, and MYH2) that accurately distinguished these two tumor types. This 10-gene classifier was validated on 122 subjects derived from four independent data sets and an average accuracy of 96% was shown. Gene expression values were validated by quantitative reverse transcription-PCR derived on 12 independent samples (seven HNSCC and five LSCC). The 10-gene classifier was also used to determine the site of origin of 12 lung lesions from patients with prior HNSCC. CONCLUSIONS: The results suggest that penalized discriminant analysis using these 10 genes will be highly accurate in determining the origin of squamous cell carcinomas in the lungs of patients with previous head and neck malignancies.

    Title It's Not Always Just About the "bottom Line".
    Date July 2007
    Journal Annals of Surgery
    Title Phase I Study of Paclitaxel Given by Seven-week Continuous Infusion Concurrent with Radiation Therapy for Locally Advanced Non-small Cell Lung Cancer.
    Date May 2007
    Journal Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
    Excerpt

    BACKGROUND: Paclitaxel is active in non-small-cell lung cancer (NSCLC) and is a radiosensitizer with a dose-response relationship that depends more on duration of exposure than peak concentration. A continuous infusion prolongs exposure and may maximize the drug-radiation interaction. The goal of this National Cancer Institute-sponsored phase I study was to determine the feasibility and toxicity of a continuous infusion paclitaxel (24 hours/day, 7 days/week, 7 weeks total) concurrent with standard radiation therapy (RT) for locally advanced NSCLC. METHODS: Eligible patients had locally advanced (T4, N1-3, M0 or Tany, N2-3, M0) NSCLC, performance status less than or equal to 2, and adequate hematological, hepatic, renal, and pulmonary function. RT was given to a total dose of 64.8 Gy at 1.8 Gy/day. Paclitaxel was delivered by infusion beginning 48 hours before and then continuously throughout the 7 weeks of RT. The paclitaxel concentration was escalated in sequential dose cohorts ranging from 0.5 to 17 mg/m/d, and each contained at least three patients in a standard phase I design. RESULTS: Twenty-nine patients were enrolled. Significant grade 3+ toxicity was observed in one patient, who experienced grade 3 pneumonitis at the 6.5-mg/m/day dose level. This cohort was expanded, but none of four additional patients experienced significant toxicity. Three patients completed the 15-mg/m/day dose level without serious or dose-limiting toxicity. The two patients entered at the 17-mg/m/day dose level had grade 4 neutropenia requiring a delay in therapy of more than 1 week. The median survival of all patients was 12 months; however, 4 of 27 patients (15%) survived longer than 60 months (mean 63.4 months). CONCLUSION: The maximally tolerated and recommended phase II paclitaxel dose delivered by protracted continuous infusion is 15 mg/m/day when combined with thoracic RT. This schedule allows for the delivery of more total paclitaxel than other published regimens and may have less esophagitis than weekly paclitaxel regimens. This regimen has the potential to achieve a radiosensitizing serum concentration of paclitaxel continuously for 7 weeks without exceeding levels associated with neutropenia or neurotoxicity. There were four long-term survivors in this phase I study. These data suggest that continuous paclitaxel infusion with concurrent RT is safe and should be of interest to explore in combination with other cytotoxic or targeted therapies.

    Title Complications of Video-assisted Thoracoscopic Lung Biopsy in Patients with Interstitial Lung Disease.
    Date March 2007
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Current guidelines recommend surgical lung biopsy for diagnosis of interstitial lung diseases (ILDs) in selected patients. To shed light on the risk-benefit ratio for this recommendation, we examined the morbidity and mortality associated with video-assisted thoracoscopic surgical (VATS) lung biopsy in a group of outpatients. METHODS: A retrospective cohort study was conducted of 68 consecutive ambulatory patients with radiographically apparent interstitial lung disease (ILD) referred for VATS biopsy during a 6-year period. Incidence of postoperative mortality, prolonged air leaks, pneumonias, and re-admissions were calculated. Risk factors for complications of surgery were examined. RESULTS: Three deaths occurred within 60 days after biopsy for a mortality rate of 4.4% (95% confidence interval [CI], 1% to 12%), and 19.1% (95% CI, 11% to 31%) experienced one or more complications of surgery. Risk factors for morbidity included preoperative dependence on oxygen therapy and pulmonary hypertension. The three patients who died had usual interstitial pneumonia on their biopsy specimen and were reintubated postoperatively for acute lung injury. Aggregation of articles published over the past 10 years reporting on surgical lung biopsy for the diagnosis of ILD yielded a postoperative mortality rate of 2% to 4.5%. CONCLUSIONS: VATS lung biopsy for diagnosis of ILD, even in ambulatory patients, is not an entirely benign procedure. Biopsy rarely may trigger an acute exacerbation of usual interstitial pneumonitis. The risk of postoperative complications appears to be greatest in those dependent on oxygen and those who have pulmonary hypertension. This information may be used in weighing the risk-benefit ratio of biopsy in individual patients.

    Title Patterns and Predictions of Resident Misbehavior--a 10-year Retrospective Look.
    Date February 2007
    Journal Current Surgery
    Excerpt

    BACKGROUND: Surgical educators are charged with ensuring that their trainees conduct themselves in a professional manner. The authors retrospectively reviewed a 10-year experience of incident reports on surgical housestaff to determine patterns and predictors of behavior. METHODS: A retrospective review of all letters, e-mails, and incident reports was conducted for general surgery residents from 1995 to 2005. Descriptive variables were selected for binary categorization (not mutually exclusive): poor professional conduct, protocol violation, administrative deficiency, verbal mistreatment, physical boundary issues, mistreatment of superiors, and deficient medical student interaction. Resident status was defined as current, graduate, and attrition. RESULTS: Of 110 residents [90 [82%] categorical, 23 [21%] undesignated preliminary (3 overlapped both groups); 87 [79%] male, 23 [21%] female] who trained at the University of Pennsylvania during this period, 66 complaints were generated about 29 individuals. Overall, 50 of the 66 complaints (76%) were directed toward men and the remaining 16 (24%) toward women; 24% of all men and 35% of all women received 1 or more complaints. A total of 76% of complaints concerned categorical residents and 24% undesignated preliminary residents. And 26% of all categorical residents and 26% of all preliminary residents received at least 1 complaint. The most common complaints concerned professional conduct (83%), protocol violation (33%), verbal mistreatment (23%), deficiencies of administrative duties (8%), violations of physical boundaries (5%), deficient medical student interaction (5%), and mistreatment of attendings by residents (3%). Recipients of verbal mistreatment included staff nurses (27%), radiology technicians (13%), medical students (13%), environmental services employees (7%), security guards (7%), patients (7%), surgery attendings (7%), anesthesia attendings (7%), internal medicine chief residents (7%), and pharmacists (7%). A total of 31% of the complaints were regarding residents who involuntarily departed and 7% regarding residents who left voluntarily before completion. The mean PGY level at first complaint was 2.2 years. Of the 29 residents receiving complaints, 16 had recurrent offenses (range 2 to 7 total complaints, positive predictive value [PPV] 53%). CONCLUSION: Resident misbehavior manifests early and recurs often. Furthermore, it is frequently directed toward perceived subordinates. Nondesignated preliminary status, premature departure from the program, and the eventual selection of specific subspecialty fellowships seems to increase the risk for resident misbehavior. Identified residents require close surveillance and remediation.

    Title Cytokine Response is Lower After Lung Volume Reduction Through Bilateral Thoracoscopy Versus Sternotomy.
    Date January 2007
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Lung volume reduction surgery performed through bilateral video-assisted thoracoscopy (BVATS) was associated in the National Emphysema Treatment Trial with a statistically significant reduction in intensive care unit days, failure to wean, hospital stay, and cost, and earlier recovery compared with median sternotomy. Studies comparing other minimally invasive techniques with "open" procedures, including pulmonary lobectomy, have demonstrated reduced serum proinflammatory mediators postoperatively. We measured these levels after lung volume reduction surgery through BVATS and sternotomy. METHODS: Serum cytokine levels were measured by radioimmunoassay in 9 consecutive, steroid-free patients undergoing sternotomy and lung volume reduction surgery and 6 undergoing BVATS and lung volume reduction surgery. The groups were not statistically different with respect to age, partial pressure of arterial carbon dioxide, percent forced expiratory volume in 1 second, percent residual volume, percent total lung capacity, diffusion capacity of the lung for carbon monoxide, 6-minute walk, or apical perfusion fraction. Proinflammatory interleukin 6 and interleukin 8 and antiinflammatory interleukin 10 were evaluated preoperatively and postoperatively on days 1, 4, and 5. Clinical data were prospectively collected. RESULTS: There were no major postoperative complications or deaths. Interleukin 6 levels were lower in the BVATS than the sternotomy group (p = 0.016 by repeated measures analysis of variance). Interleukin 8 levels were lower in the BVATS group at most postoperative time points, but there were no significant differences in interleukin 8 or interleukin 10 levels between the sternotomy and BVATS groups at any individual time point or by analysis of variance. CONCLUSIONS: Use of a BVATS approach to lung volume reduction surgery is associated with reduced postoperative release of proinflammatory cytokines compared with a sternotomy approach. This may account for the reduction in recovery time and some measures of postoperative morbidity seen with the BVATS approach.

    Title Parasternal Intercostal Muscle Remodeling in Severe Chronic Obstructive Pulmonary Disease.
    Date November 2006
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    Studies in experimental animals indicate that chronic increases in neural drive to limb muscles elicit a fast-to-slow transformation of fiber-type proportions and myofibrillar proteins. Since neural drive to the parasternal intercostal muscles (parasternals) is chronically increased in patients with severe chronic obstructive pulmonary diseases (COPDs), we carried out the present study to test the hypothesis that the parasternals of COPD patients exhibit an increase in the proportions of both slow fibers and slow myosin heavy chains (MHCs). Accordingly, we obtained full thickness parasternal muscle biopsies from the third interspace of seven COPD patients (mean +/- SE age: 59 +/- 4 yr) and seven age-matched controls (AMCs). Fiber typing was done by immunohistochemistry, and MHC proportions were determined by SDS-PAGE followed by densitometry. COPD patients exhibited higher proportions of slow fibers than AMCs (73 +/- 4 vs. 51 +/- 3%; P < 0.01). Additionally, COPD patients exhibited higher proportions of slow MHC than AMCs (56 +/- 4 vs. 46 +/- 4%, P < 0.04). We conclude that the parasternal muscles of patients with severe COPD exhibit a fast-to-slow transformation in both fiber-type and MHC proportions. Previous workers have demonstrated that remodeling of the external intercostals, another rib cage inspiratory muscle, elicited by severe COPD is characterized by a slow-to-fast transformation in both fiber types and MHC isoform proportions. The physiological significance of this difference in remodeling between these two inspiratory rib cage muscles remains to be elucidated.

    Title Interferon Beta Adenoviral Gene Therapy in a Patient with Ovarian Cancer.
    Date November 2006
    Journal Nature Clinical Practice. Oncology
    Excerpt

    Background A 47-year-old woman with a history of ovarian cancer and a 6-year disease-free remission presented with dyspnea and increased abdominal girth. The patient was found to have ascites and a large left pleural effusion, both of which contained malignant cells consistent with recurrent ovarian cancer. Her disease progressed despite treatment with chemotherapeutic and hormonal agents. She was then enrolled in a phase I clinical trial of adenoviral-mediated interferon beta gene therapy.Investigations Abdominal and chest CT scans, 2-[(18)F]fluoro-2-deoxyglucose PET scan, viral cultures, interferon cytokine analysis, immunophenotyping, and tumor cytotoxicity analyses.Diagnosis Stage IV ovarian cancer with malignant ascites and pleural effusion.Management Tunneled pleural catheter and intrapleural adenoviral-mediated interferon beta gene therapy.

    Title Outcomes After 151 Extended Transcervical Thymectomies for Myasthenia Gravis.
    Date November 2006
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: The ideal operative technique for thymectomy in myasthenia gravis (MG) remains controversial. We present the largest series of extended transcervical thymectomy to provide outcomes data to compare with transsternal procedures. METHODS: A retrospective chart review/interview was made of 164 patients operated upon from 1992 to 2004. Complete remission (CR) was defined as asymptomatic off medication for 6 months or asymptomatic on low-dose single-drug therapy (< or = 10 mg/d prednisone or < or = 150 mg/d azathioprine). A modified Osserman classification based upon the Myasthenia Gravis Foundation of America quantitative disease severity score was employed. RESULTS: The overall complication rate was 7.3%, and nearly all procedures were outpatient. Mean age at surgery was 43 years, and mean preoperative Osserman class was 2.3 (21% class 1; 39% class 2; 28% class 3; 12% class 4). Mean length of follow-up was 53 months. Mean postoperative Osserman class was 1.0. Nineteen percent of patients failed to improve. The crude cumulative CR rate was 37% (n = 58). Kaplan-Meier estimates of CR were 43% and 45% at 3 and 6 years, respectively. On multivariate analysis, only preoperative disease severity was significantly (inversely) associated with Kaplan-Meier CR rates. Longer-term follow-up (83 months) of only the earlier patients shows preserved CR rates (46%). CONCLUSIONS: This largest series of extended transcervical thymectomy for MG confirms that the 5-year Kaplan-Meier CR rate is comparable with that obtained after transsternal procedures. Patients with less severe disease have higher CR rates. Complete responses are durable, as the CR rate remains stable with extended follow-up.

    Title Wilms' Tumor Arising Within a Mediastinal Teratoma.
    Date September 2006
    Journal Journal of Pediatric Surgery
    Excerpt

    The majority of Wilms' tumors present in young children as an intraabdominal mass of renal origin. The use of multimodal treatment protocols according to internationally recognized treatment guidelines has resulted in extremely high cure rates even in the setting of advanced disease. By comparison, Wilms' tumors in older patients or Wilms' tumors located entirely outside the kidney are extremely rare. Because of the rarity of these tumors and the lack of established treatment guidelines specific to these lesions, older patients with atypical Wilms' tumors are at risk for under treatment and poorer outcomes. We report the case of an 18-year-old man with a Wilms' tumor arising within a mediastinal teratoma and discuss the management of this extremely rare lesion.

    Title Familial Massive Leiomyoma with Esophageal Leiomyomatosis: an Unusual Presentation in a Father and His 2 Daughters.
    Date August 2006
    Journal Journal of Pediatric Surgery
    Excerpt

    Esophageal leiomyomatosis and leiomyoma are benign neoplastic lesions composed of proliferating smooth muscle cells. Although rare, these 2 conditions may occur simultaneously in an individual patient. Symptomatic patients often require surgical management. We describe the first reported cases of family members presenting with esophageal leiomyomatosis and concomitant massive esophageal leiomyoma.

    Title Anterior Surgical Approaches to the Thoracic Outlet.
    Date July 2006
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    OBJECTIVES: The anatomy of the thoracic outlet is complex, and the optimum surgical approach to pathologic disease at this location is controversial. Although the Dartevelle approach to the apex seems to be a safer and more direct approach, this technique has not been widely adopted in the United States. We have used this approach for pathologic disease at the thoracic outlet and modified it. Our experience is described in this article. METHODS: A retrospective review was performed on all patients who underwent an anterior approach between December 1997 and May 2003. RESULTS: There were 42 patients who underwent anterior approaches to pathologic disease at the level of the outlet. Diagnosis included apical non-small cell lung cancers (20 patients), osteosarcoma (2 patients), spinal cord compression (5 patients), solitary metastasis (4 patients), and benign lesions (11 patients). There were 22 female and 20 male patients with ages ranging from 26 to 82 years (mean age, 54.6 years). There were 25 complications in 14 patients and 1 in-hospital death. A transmanubrial approach was used in 14 patients, the standard Dartevelle technique was used in 8 patients, and a transclavicular approach with reapproximation of the clavicle was used in 20 patients. Reapproximation failed in 5 patients (3/3 patients who underwent fixation with mini-plates and 2/17 patients with sternal wires). CONCLUSIONS: The anterior approach is a useful adjunct to a thoracic surgeon's armamentarium. When a transclavicular approach is optimal, division and reapproximation of the clavicle are feasible. In our experience, reapproximation with wires is superior to plates and screws.

    Title Multiple Variables Affecting Blood Usage in Lung Transplantation.
    Date July 2006
    Journal The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation
    Excerpt

    BACKGROUND: A few publications have reported on the role of variables affecting blood component usage during lung transplantation. METHODS: Transfusion records for lung transplantation patients at the Hospital of the University of Pennsylvania (November 1991 to July 2004) were reviewed. Bivariate analyses and regression models were used to correlate usage of packed red blood cells (RBC), fresh-frozen plasma (FFP) and platelets (PLT) with variables such as disease, number of pulmonary lobes (1 or 2), cardiopulmonary bypass (CPB) status and time on bypass. RESULTS: Among 376 patients examined during the study period, blood product usage (in units) was significantly higher in double- than in single-lung recipients (RBC, 5.76 vs 1.21; FFP, 5.55 vs 1.10; PLT, 1.15 vs 0.16; p < 0.001). Patients on CPB also used significantly more units (RBC, 8.28 vs 1.45; FFP, 9.70 vs 0.73; PLT, 1.86 vs 0.14; p < 0.001), correlating with time on bypass. Patients transplanted for Eisenmenger syndrome (ES) and cystic fibrosis (CF) received significantly more blood products than those transplanted for other diseases (RBC, ES = 17.91 vs CF = 7.31 vs all others <2.00; FFP, ES = 19.18 vs CF = 5.72 vs others <2.00; PLT, ES = 4.73 vs CF = 1.22 vs others <0.40; p < 0.001). A regression model identified variables predictive of blood product usage, including the number of lungs transplanted, CPB status, disease and patient age. CONCLUSIONS: Patients receiving double-lung transplantations, on CPB, or transplanted for ES and CF exhibited a very highly statistically significant demand (p < 0.001) for more blood products. Additional selected variables differentially predicted usage. These data will help transplant surgeons and transfusion medicine specialists better anticipate and prepare blood products for use in lung transplantation.

    Title Blockade of Tnf-alpha Decreases Both Inflammation and Efficacy of Intrapulmonary Ad.ifnbeta Immunotherapy in an Orthotopic Model of Bronchogenic Lung Cancer.
    Date June 2006
    Journal Molecular Therapy : the Journal of the American Society of Gene Therapy
    Excerpt

    Adenoviral immuno-gene therapy using interferon-beta has been effective in an orthotopic model of lung cancer. However, pulmonary inflammation induced by adenoviral (Ad) vectors will almost certainly limit the maximally tolerated dose. On the other hand, the strong innate immune response generated by the vector may be helpful in initiating the adaptive immune response required for efficacy. The goals of this study were to develop an effective approach to inhibit Ad.IFNbeta-mediated acute pulmonary inflammation and to determine whether this reduction of Ad-mediated inflammation decreased the therapeutic efficacy of Ad.IFNbeta in a mouse model of bronchioloalveolar cancer. Our data show that anti-TNF-alpha antibodies can blunt the innate pulmonary immune response induced by Ad vectors, even in sensitized animals. However, this effect also inhibited the ability of the animal to generate anti-tumor immune responses and reduced survival in an orthotopic lung cancer model responsive to Ad.IFNbeta treatment. Interestingly, in a flank model of tumor using a cell line derived from the lung tumor, TNF-alpha blockade did not inhibit efficacy. These data suggest that the innate immune response to adenovirus in the lung may be important in immuno-gene therapy of lung cancer. Therapeutic application of anti-inflammatory therapy in immuno-gene therapy strategies should thus be undertaken with caution.

    Title Activation of Tumor-associated Macrophages by the Vascular Disrupting Agent 5,6-dimethylxanthenone-4-acetic Acid Induces an Effective Cd8+ T-cell-mediated Antitumor Immune Response in Murine Models of Lung Cancer and Mesothelioma.
    Date February 2006
    Journal Cancer Research
    Excerpt

    5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity thought to be due to ability to induce high local levels of tumor necrosis factor (TNF)-alpha that disrupt established blood vessels within tumors. The drug has completed phase 1 testing in humans and is currently in phase 2 trials in combination with chemotherapy. Although characterized as a "vascular disrupting agent," there are some studies suggesting that DMXAA also has effects on the immune system that are important for its efficacy. The goal of this study was to carefully define the immune effects of DMXAA in a series of murine lung cancer and mesothelioma cell lines with varying immunologic characteristics. We show that DMXAA efficiently activated tumor-associated macrophages to release a variety of immunostimulatory cytokines and chemokines, including TNF-alpha; IFN-inducible protein-10; interleukin-6; macrophage inflammatory protein-2; monocyte chemotactic protein-1; and regulated on activation, normal T-cell expressed, and secreted. DMXAA treatment was highly effective in both small and large flank tumors. Animals cured of tumors by DMXAA generated a systemic memory response and were resistant to tumor cell rechallenge. DMXAA treatment led to initial tumor infiltration with macrophages that was followed by an influx of CD8(+) T cells. These CD8(+) T cells were required for antitumor efficacy because tumor inhibitory activity was lost in nude mice, mice depleted of CD8(+) T cells, and perforin knockout mice, but not in CD4(+) T-cell-depleted mice. These data show that activation of tumor-associated macrophages by DMXAA is an efficient way to generate a CD8(+) T-cell-dependent antitumor immune response even in animals with relatively nonimmunogenic tumors. Given these properties, DMXAA might also be useful in boosting other forms of immunotherapy.

    Title Long-term Follow-up of Patients with Malignant Pleural Mesothelioma Receiving High-dose Adenovirus Herpes Simplex Thymidine Kinase/ganciclovir Suicide Gene Therapy.
    Date February 2006
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: Delineation of the long-term follow-up data on a series of patients with malignant mesothelioma, who received a single intrapleural dose of a nonreplicative adenoviral (Ad) vector encoding the herpes simplex virus thymidine kinase "suicide gene" (Ad.HSVtk) in combination with systemic ganciclovir. EXPERIMENTAL DESIGN: This report focuses on the 21 patients receiving "high-dose" therapy, defined by an intrapleural dose of vector (> or =1.6 x 10(13) viral particles), where transgene-encoded tk protein was reliably identified on immunohistochemical staining. In 13 patients, the vector was deleted in the E1 and E3 regions of the Ad; in the other eight patients, the vector had deletions in the Ad genes E1 and E4. Safety, immunologic responses, transgene expression, and clinical responses were evaluated. RESULTS: Both the E1/E3-deleted vector and the E1/E4-deleted vector were well tolerated and safe, although production of the E1/E4 vector was more difficult. Posttreatment antibody responses against the tumors were consistently seen. Interestingly, we observed a number of clinical responses in our patients, including two long-term (>6.5 year) survivors, both of whom were treated with the E1/E4-deleted vector. CONCLUSIONS: Intrapleural Ad.HSVtk/ganciclovir is safe and well tolerated in mesothelioma patients and resulted in long-term durable responses in two patients. Given the limited amount of gene transfer observed, we postulate that Ad.HSVtk may have been effective due to induction of antitumor immune responses. We hypothesize that approaches aiming to augment the immune effects of Ad gene transfer (i.e., with the use of cytokines) may lead to increased numbers of therapeutic responses in otherwise untreatable pleural malignancies.

    Title Comparative Study of Subxiphoid Versus Video-thoracoscopic Pericardial "window".
    Date December 2005
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: It remains undefined whether surgical subxiphoid drainage or thoracoscopic pericardial "window" is the optimal operative approach to pericardial effusion. We hypothesized that the true window into the pleural space created by the latter might improve the duration of freedom from recurrent effusion. METHODS: We conducted a retrospective chart review of indications, preoperative and intraoperative variables, morbidity, recurrence, and survival. RESULTS: Fifty-six patients underwent the subxiphoid procedure and 15 underwent the thoracoscopic procedure. Echocardiographic evidence of tamponade was present before 8 of 10 thoracoscopic procedures (80%) and 43 of 56 subxiphoid procedures (81%) for which descriptions of hemodynamics were available. In addition, non-pericardial procedures were performed in 10 (67%) and 18 (32%) patients, respectively (p = 0.020). Anesthesia time was longer at thoracoscopy (117.1 +/- 32.4 vs 81.1 +/- 25.5 minutes; p < 0.001). Procedural morbidity was higher after thoracoscopy (4 [27%] vs 1 [2%]; p = 0.006), but was generally minor. Hospital mortality tended to be higher after the subxiphoid procedure (7 [13%] vs 0 [0%]; p = 0.332), but none of the deaths was procedure-related. Follow-up was complete for 65 patients (92%). Recurrence occurred in 1 thoracoscopy patient (8%) and 5 subxiphoid patients (10%) (p = 1.000). Mean time to recurrence by Kaplan-Meier analysis trends were longer after thoracoscopy (36.1 vs 11.4 months; p = 0.16), and multivariate analysis identified the thoracoscopic approach as an independent predictor of freedom from recurrence (relative risk, 0.41; p = 0.014). CONCLUSIONS: Operative time and minor procedural morbidity are higher with thoracoscopic pericardial window, but long-term control of effusion seemed to be better than after subxiphoid surgical drainage.

    Title Intrapulmonary Ifn-beta Gene Therapy Using an Adenoviral Vector is Highly Effective in a Murine Orthotopic Model of Bronchogenic Adenocarcinoma of the Lung.
    Date November 2005
    Journal Cancer Research
    Excerpt

    Given previous work showing that an adenoviral vector expressing IFN-beta (Ad.IFNbeta) was highly effective in eradicating i.p. mesothelioma tumors, the antitumor efficacy of this agent was evaluated in an orthotopic model of bronchogenic adenocarcinoma of the lung. These transgenic mice have a conditionally expressed, oncogenic K-rasG12D allele that can be activated by intratracheal administration of an adenovirus expressing Cre recombinase (Ad.Cre). K-rasG12D mutant mice were given Ad.Cre intranasally to activate the oncogene. Mice were then given 10(9) plaque-forming units of a control vector (Ad.LacZ) or Ad.IFNbeta intranasally 3 and 4 weeks later, a time when lung tumors had been established. Cells derived from K-ras-mutated lung tumors were also grown in the flanks of mice to study mechanisms of therapeutic responses. In two separate experiments, untreated tumor-bearing mice all died by day 57 (median survival, 49 days). Ad.LacZ-treated mice all died by day 71 (median survival, 65 days). In contrast, 90% to 100% of mice treated with Ad.IFNbeta were long-term survivors (>120 days; P < 0.001). In addition, immunity to re-challenge with tumor cells was induced. In vitro and flank tumor studies showed that Ad.IFNbeta induced direct tumor cell killing and that depleting natural killer or CD8+ T cells, but not CD4+ T cells, with antibodies attenuated the effect of Ad.IFNbeta. These studies, showing remarkable antitumor activity in this orthotopic lung cancer model, provide strong preclinical support for a trial of Ad.IFNbeta to treat human non-small cell lung cancer.

    Title Pain and Physical Function Are Similar Following Axillary, Muscle-sparing Vs Posterolateral Thoracotomy.
    Date November 2005
    Journal Chest
    Excerpt

    STUDY OBJECTIVES: We set out to determine whether there is a difference in postoperative pain and recovery after the patient undergoes the axillary muscle-sparing incision (ie, muscle-sparing thoracotomy [MT]) vs the modified posterolateral incision (ie, posterolateral thoracotomy [PT]). DESIGN: Analysis of a database originally collected to determine the effect of the timing of epidural analgesia on long-term outcome after thoracotomy. SETTING: The Hospital of the University of Pennsylvania. PATIENTS: Patients presenting for lobectomy, segmentectomy, or bilobectomy. MEASUREMENTS: Pain, physical activity, and the extent that pain interfered with activities following major thoracotomy were prospectively assessed with standard questionnaires (ie, the brief pain inventory and the Medical Outcomes Study 36-item short form) on postoperative days 1 to 5, and at postoperative weeks 4, 8, 12, 24, 36, and 48 by a blinded research assistant. Perioperative care was standardized and included patient-controlled thoracic epidural analgesia until thoracostomy tube removal. RESULTS: Eighty-two subjects underwent MT and 38 subjects underwent PT during the 16-month accrual period. There were no significant differences in demographics. Pain reported during hospitalization and after hospital discharge did not differ with respect to incision type (p > or = 0.17). Postoperative physical activity levels were significantly less than those reported preoperatively, with a trend toward better functioning in the MT groups after 8 weeks. Incision type did not predict complications, morbidity, or mortality. CONCLUSIONS: When comparing patients who had undergone vertical, axillary, wholly MT to those who had undergone modified serratus muscle-sparing PT, postoperative differences in pain were not apparent. One should not anticipate reduced pain or more rapid overall recovery following MT, at least when epidural analgesia is used aggressively for perioperative pain control.

    Title Gemcitabine Selectively Eliminates Splenic Gr-1+/cd11b+ Myeloid Suppressor Cells in Tumor-bearing Animals and Enhances Antitumor Immune Activity.
    Date November 2005
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: Myeloid suppressor (Gr-1(+)/CD11b(+)) cells accumulate in the spleens of tumor-bearing mice where they contribute to immunosuppression by inhibiting the function of CD8(+) T cells and by promoting tumor angiogenesis. Elimination of these myeloid suppressor cells may thus significantly improve antitumor responses and enhance effects of cancer immunotherapy, although to date few practical options exist. EXPERIMENTAL DESIGN: The effect of the chemotherapy drug gemcitabine on the number of (Gr-1(+)/CD11b(+)) cells in the spleens of animals bearing large tumors derived from five cancer lines grown in both C57Bl/6 and BALB/c mice was analyzed. Suppressive activity of splenocytes from gemcitabine-treated and control animals was measured in natural killer (NK) cell lysis and Winn assays. The impact of myeloid suppressor cell activity was determined in an immunogene therapy model using an adenovirus expressing IFN-beta. RESULTS: This study shows that the chemotherapeutic drug gemcitabine, given at a dose similar to the equivalent dose used in patients, was able to dramatically and specifically reduce the number of myeloid suppressor cells found in the spleens of animals bearing large tumors with no significant reductions in CD4(+) T cells, CD8(+) T cells, NK cells, macrophages, or B cells. The loss of myeloid suppressor cells was accompanied by an increase in the antitumor activity of CD8(+) T cells and activated NK cells. Combining gemcitabine with cytokine immunogene therapy using IFN-beta markedly enhanced antitumor efficacy. CONCLUSIONS: These results suggest that gemcitabine may be a practical strategy for the reduction of myeloid suppressor cells and should be evaluated in conjunction with a variety of immunotherapy approaches.

    Title Surgeon Contribution to Hospital Bottom Line: Not All Are Created Equal.
    Date November 2005
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: We hypothesized that surgeon productivity is directly related to hospital operating margin, but significant variation in margin contribution exists between specialties. SUMMARY BACKGROUND DATA: As the independent practitioner becomes an endangered species, it is critical to better understand the surgeon's importance to a hospital's bottom line. An appreciation of surgeon contribution to hospital profitability may prove useful in negotiations relating to full-time employment or other models. METHODS: Surgeon total relative value units (RVUs), a measure of productivity, were collected from operating room (OR) logs. Annual hospital margin per specialty was provided by hospital finance. Hospital margin data were normalized by dividing by a constant such that the highest relative hospital margin (RHM) in fiscal year 2004 expressed as margin units (mu) was 1 million mu. For each specialty, data analyzed included RHM/OR HR, RHM/case, and RHM/RVU. RESULTS: Thoracic (34.55 mu/RVU) and transplant (25.13 mu/RVU) were the biggest contributors to hospital margin. Plastics (-0.57 mu/RVU), maxillofacial (1.41 mu/RVU), and gynecology (1.66 mu/RVU) contributed least to hospital margin. Relative hospital margin per OR HR for transplant slightly exceeded thoracic (275.74 mu vs 233.94 mu) at the top and plastics and maxillofacial contributed the least (-3.83 mu/OR HR vs 9.36 mu/OR HR). CONCLUSIONS: Surgeons contribute significantly to hospital margin with certain specialties being more profitable than others. Payer mix, the penetration of managed care, and negotiated contracts as well as a number of other factors all have an impact on an individual hospital's margin. Surgeons should be fully cognizant of their significant influence in the marketplace.

    Title Radical Lobectomy, Esophagectomy, and Mediastinal Dissections for Intrathoracic Malignancy.
    Date August 2005
    Journal Surgical Oncology Clinics of North America
    Title Prognostic Implications of Cell Cycle, Apoptosis, and Angiogenesis Biomarkers in Non-small Cell Lung Cancer: a Review.
    Date August 2005
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    Lung cancer is the leading cause of cancer death in the U.S. with survival restricted to a subset of those patients able to undergo surgical resection. However, even with surgery, recurrence rates range from 30% to 60%, depending on the pathologic stage. With the advent of partially effective, but potentially toxic adjuvant chemotherapy, it has become increasingly important to discover biomarkers that will identify those patients who have the highest likelihood of recurrence and who thus might benefit most from adjuvant chemotherapy. Hundreds of papers have appeared over the past several decades proposing a variety of molecular markers or proteins that may have prognostic significance in non-small cell lung cancer. This review analyzes the largest and most rigorous of these studies with the aim of compiling the most important prognostic markers in early stage non-small cell lung cancer. In this review, we focused on biomarkers primarily involved in one of three major pathways: cell cycle regulation, apoptosis, and angiogenesis. Although no single marker has yet been shown to be perfect in predicting patient outcome, a profile based on the best of these markers may prove useful in directing patient therapy. The markers with the strongest evidence as independent predictors of patient outcome include cyclin E, cyclin B1, p21, p27, p16, survivin, collagen XVIII, and vascular endothelial cell growth factor.

    Title Effect of Chronic Obstructive Pulmonary Disease on Calcium Pump Atpase Expression in Human Diaphragm.
    Date August 2005
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    We have previously demonstrated that human diaphragm remodeling elicited by severe chronic obstructive pulmonary disease (COPD) is characterized by a fast-to-slow myosin heavy chain isoform transformation. To test the hypothesis that COPD-induced diaphragm remodeling also elicits a fast-to-slow isoform shift in the sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA), the other major ATPase in skeletal muscle, we obtained intraoperative biopsies of the costal diaphragm from 10 severe COPD patients and 10 control subjects. We then used isoform-specific monoclonal antibodies to characterize diaphragm fibers with respect to the expression of SERCA isoforms. Compared with control diaphragms, COPD diaphragms exhibited a 63% decrease in fibers expressing only fast SERCA (i.e., SERCA1; P < 0.001), a 190% increase in fibers containing both fast and slow SERCA isoforms (P < 0.01), and a 19% increase (P < 0.05) in fibers expressing only the slow SERCA isoform (i.e., SERCA2). Additionally, immunoblot experiments carried out on diaphragm homogenates indicated that COPD diaphragms expressed only one-third the SERCA1 content noted in control diaphragms; in contrast, COPD and control diaphragms did not differ with respect to SERCA2 content. The combination of these histological and immunoblot results is consistent with the hypothesis that diaphragm remodeling elicited by severe COPD is characterized by a fast-to-slow SERCA isoform transformation. Moreover, the combination of these SERCA data and our previously reported myosin heavy chain isoform data (Levine S, Nguyen T, Kaiser LR, Rubinstein NA, Maislin G, Gregory C, Rome LC, Dudley GA, Sieck GC, and Shrager JB. Am J Respir Crit Care Med 168: 706-713, 2003) suggests that diaphragm remodeling elicited by severe COPD should decrease ATP utilization by the diaphragm.

    Title Argatroban As a Heparin Substitute in Cases of Heparin-induced Thrombocytopenia.
    Date July 2005
    Journal The Annals of Thoracic Surgery
    Title Catamenial Pneumothorax: Optimal Hormonal and Surgical Management.
    Date June 2005
    Journal European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery
    Excerpt

    OBJECTIVE: To provide further information addressing the etiology, optimal hormonal management and surgical management in catamenial pneumothorax (CP). METHODS: We retrospectively analyzed records of all female patients operated on for spontaneous pneumothorax at a university hospital between January 1993 and March 2002. RESULTS: In eight of 24 patients, pneumothoraces were timed with menses. In all, the right side was involved. Seven patients were on hormonal medications pre-operatively and six post-operatively. All six patients taking estrogen/progesterone replacement had recurrences pre-operatively and two of three had recurrences post-operatively while on these medications. No patient suffered a pneumothorax either pre- or post-operatively while taking a gonadotropin releasing hormone agonist (two and three patients, respectively). Intraoperative findings included diaphragmatic implants [5] diaphragmatic fenestrations [4], apical blebs [2] and visceral pleural implants [2]. All pathology was specifically addressed at the time of surgery. Pleural space management included mechanical pleurodesis in seven and pleurectomy with talc insufflation in 1. Follow-up ranged from 27 to 63 months with a mean of 48 months. Three patients developed post-operative recurrences. One was managed without intervention and two required additional procedures. CONCLUSION: Catamenial pneumothorax is under appreciated, representing up to one-third of women with spontaneous pneumothorax. Hormonal agents that allow for menses are ineffective. Gonadotropin releasing hormone agonists should be considered as part of the pre-operative or post-operative management in high risk patients. Our findings suggest that an additional intervention to augment pleural symphysis at the level of the diaphragm should be performed.

    Title Treatment of Lung Cancer Using Clinically Relevant Oral Doses of the Cyclooxygenase-2 Inhibitor Rofecoxib: Potential Value As Adjuvant Therapy After Surgery.
    Date March 2005
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: To investigate the uses and limitations of cyclooxygenase- (COX) 2 inhibition using clinically relevant doses of oral rofecoxib in the treatment of murine models of non-small-cell lung cancer (NSCLC). SUMMARY BACKGROUND DATA: Overexpression of COX-2 has been reported in lung cancer. Several studies have demonstrated that high doses of COX-2 inhibitors could inhibit the growth of rodent and human lung cancer cell lines. The potential uses and limitations of COX-2 inhibition at doses equivalent to those currently approved for use in humans have not been well studied. METHODS: Three murine NSCLC cell lines were injected into the flanks of mice to establish tumor xenografts. Mice were treated orally with low doses of a COX-2 inhibitor (rofecoxib chow, 0.0075%). Mechanisms were evaluated by analysis of tumor-infiltrating lymphocytes. To study rofecoxib as adjuvant therapy, large established tumors (14-18 days after tumor inoculation) were surgically debulked and animals were treated with rofecoxib starting 3 days before surgery. Recurrence of the tumor after debulking was monitored. RESULTS: Rofecoxib significantly slowed the growth of small (0-120 mm) tumors (P < 0.01-0.05) in all 3 cell lines, with higher efficacy in the more immunogenic tumors. Minimal responses were noted in larger tumors. Rofecoxib appeared to augment CD8 T cell infiltration in immunogenic tumors. Rofecoxib significantly reduced the recurrence rate after debulking (P < 0.01). CONCLUSIONS: Clinically relevant doses of the COX-2 inhibitor rofecoxib given orally were effective in inhibiting the growth of small (but not large) tumors in 3 murine NSCLC cell lines tested and in preventing recurrences after surgical debulking. Depending on the immunogenicity of human tumors, COX-2 inhibition might be useful as adjuvant therapy for surgically resectable NSCLC.

    Title Soluble Type Ii Transforming Growth Factor-beta Receptor Inhibits Established Murine Malignant Mesothelioma Tumor Growth by Augmenting Host Antitumor Immunity.
    Date February 2005
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: Transforming growth factor (TGF)-beta blockade has been proposed as an anticancer therapy; however, understanding which tumor patients might benefit most from such therapy is crucial. An ideal target of such inhibitory therapy might be malignant mesothelioma (MM), a highly lethal, treatment-resistant malignancy of mesothelial cells of the pleura and peritoneum that produces large amounts of TGF-beta. The purpose of this study was to explore the possible therapeutic utility of TGF-beta blockade on MM. EXPERIMENTAL DESIGN: To evaluate this hypothesis, we tested the effects of a soluble TGF-beta type II receptor (sTGF-beta R) that specifically inhibits TGF-beta1 and TGF-beta 3 in three different murine MM tumor models, AB12 and AC29 (which produce large amounts of TGF-beta) and AB1 (which does not produce TGF-beta). RESULTS: Tumor growth of both established AB12 and AC29 tumors was inhibited by sTGF-beta R. In contrast, AB1 tumors showed little response to sTGF-beta R. The mechanism of these antitumor effects was evaluated and determined to be primarily dependent on immune-mediated responses because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice or mice depleted of CD8(+) T cells and (b) CD8(+) T cells isolated from spleens of mice treated with sTGF-beta R showed strong antitumor cytolytic effects, whereas CD8(+) T cells isolated from spleens of tumor-bearing mice treated with of control IgG2a showed no antitumor cytolytic effects. CONCLUSIONS: Our data suggest that TGF-beta blockade of established TGF-beta-secreting MM should be explored as a promising strategy to treat patients with MM and other tumors that produce TGF-beta.

    Title Surgical Education in the New Millennium: the University Perspective.
    Date February 2005
    Journal The Surgical Clinics of North America
    Title Alterations of the Tumor Suppressor Gene Parkin in Non-small Cell Lung Cancer.
    Date December 2004
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: Parkin, a gene mutated in autosomal recessive juvenile Parkinsonism and mapped to the common fragile site FRA6E on human chromosome 6q25-q27, is associated with a frequent loss of heterozygosity and altered expression in breast and ovarian carcinomas. In addition, homozygous deletions of exon 2 creating deleterious truncations of the Parkin transcript were observed in the lung adenocarcinoma cell lines Calu-3 and H-1573, suggesting that the loss of this locus and the resulting changes in its expression are involved in the development of these tumors. EXPERIMENTAL DESIGN: We examined 20 paired normal and non-small cell lung cancer samples for the presence of Parkin alterations in the coding sequence and changes in gene expression. We also restored gene expression in the Parkin-deficient lung carcinoma cell line H460 by use of a recombinant lentivirus containing the wild-type Parkin cDNA. RESULTS: Loss of heterozygosity analysis identified a common region of loss in the Parkin/FRA6E locus with the highest frequency for the intragenic marker D6S1599 (45%), and semi-quantitative reverse transcription-PCR revealed reduced expression in 3 of 9 (33%) lung tumors. Although we did not observe any in vitro changes in cell proliferation or cell cycle, ectopic Parkin expression had the ability to reduce in vivo tumorigenicity in nude mice. CONCLUSION: These data suggest that Parkin is a tumor suppressor gene whose inactivation may play an important role in non-small cell lung cancer tumorigenesis.

    Title Lung Cancer in Transplant Recipients: a Single-institution Experience.
    Date September 2004
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    HYPOTHESIS: That aggressive surgical treatment of lung cancer (LC) is justified by stage-based outcome in immunosuppressed solid organ transplant recipients. DESIGN: Case series. SETTING: University hospital. PATIENTS: Lung cancer developed in 15 patients (0.28%) among a solid organ transplant recipient population of 5400 accrued at our institution over a 25-year period. MAIN OUTCOME MEASURES: Smoking prevalence, subtypes and stages of LC represented, operative morbidity, and survival. RESULTS: The mean time from transplantation to the diagnosis of LC was 76 months (range, 9-192 months). Eight patients received kidneys; 3, lungs; and 4, hearts. Only 11 patients (73%) had a smoking history (mean, 66 pack-years). The following carcinomas developed in our patient population: adenocarcinoma, 6 patients; squamous cell, 5; large cell undifferentiated, 2; bronchoalveolar, 1; and small cell, 1. Eight patients (53%) presented with inoperable stage IIIB or IV disease. The remaining patients presented in stages IA (n = 2), IB (n = 1), IIB (n = 2), and IIIA (n = 2); all underwent resection. No major postoperative complications occurred. All patients with stage IIIB or greater disease with or without treatment died quickly (mean survival, 1.4 months; range, 0.33-3.0 months). All patients with stage IIB or less remain alive a mean of 37 months after resection. Patients with stage IIIA survived only a mean of 6.0 months despite resection. CONCLUSIONS: Regarding LCs in transplant recipients compared with LCs in the nontransplant population, we find that (1) there is an increased incidence among nonsmokers; (2) death occurs rapidly in unresected patients; (3) resection carries a low morbidity rate; and (4) resection seems to offer a high chance of cure in those with cancers staged IIB or less.

    Title Microarray Data Simulator for Improved Selection of Differentially Expressed Genes.
    Date June 2004
    Journal Cancer Biology & Therapy
    Excerpt

    The development of microarray technology has allowed researchers to measure expression levels of thousands of genes simultaneously. Analysis of these data requires the best normalization and statistical approaches to account for the biological and technical variability inherent in the technique. To approach this problem we have developed a publicly available simulator of microarray hybridization experiments that can be used to help assess the accuracy of bioinformatic tools in discovering significant genes. After analyzing microarray hybridization experiments from over 50 samples, an estimate of various degrees of technical and biological variability was obtained. This information was used to develop a simulator of microarray hybridization data which modeled "normal tissue samples" and "diseased tissue samples" with known, defined, changes in gene expression (a "gold standard"). The data derived from the simulator were then used to evaluate the true positive and false negative rates of several normalization procedures and gene selection techniques. We found that the type of normalization approach used was an important aspect of data analysis. Global normalization was the least accurate approach. Evaluation of gene selection techniques showed that "Significance analysis of microarrays" (SAM) and "Patterns of Gene Expression" (PaGE) were more accurate than simple t-test analysis. We provide access to the microarray hybridization simulator as a public resource for biologists to further test new emerging genomic bioinfomatic tools.

    Title Gene Expression Profiling of Malignant Mesothelioma.
    Date June 2004
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: Malignant mesothelioma is a uniformly fatal cancer of the pleural and peritoneal spaces. Several challenging clinical problems include poor understanding of the pathophysiology, inaccurate diagnosis from tissue samples, and unsuccessful treatment strategies. The purpose of this study was to use microarray analysis to identify specific gene expression changes in mesothelioma compared with normal mesothelium. Experimental Design: We performed gene expression analysis on mesothelioma tissue specimens from 16 patients and compared these to 4 control pleural tissue samples using cDNA microarray filters with 4132 clones. Multiple normalization and analysis approaches were used. Quantitative reverse transcription-PCR and immunohistochemistry were used to validate results. RESULTS: Genes (166) were significantly up-regulated, and 26 were down-regulated. Validation of 18 genes using real-time PCR confirmed array predictions in every case. Analysis revealed activation of several key pathways including genes involved in glucose metabolism, mRNA translation, and cytoskeletal remodeling. Expression profiling identified processes likely responsible for 18-fluoro-2-deoxy-glucose uptake and tumor localization by positron emission tomography, and a role for hypoxia-inducible factor-1 was suggested. Potentially important up-regulated genes included gp96, lung resistance-related protein, galectin-3 binding protein, the M(r) 67,000 laminin receptor (on tumor vessels), and voltage-dependent anion channels. Prospective testing using reverse transcription-PCR confirmed up-regulation of these novel markers. CONCLUSIONS: Expression profiling revealed marked up-regulation of energy, protein translation, and cytoskeletal remodeling pathways in mesothelioma. Additional genes that could be important in our understanding of the pathogenesis of mesothelioma, aiding in diagnosis, or improving targets for therapy were also identified.

    Title Simple Technique for Maximal Thoracic Muscle Harvest.
    Date May 2004
    Journal The Annals of Thoracic Surgery
    Excerpt

    We present a modification of technique for standard muscle flap harvest, the placement of cutaneous traction sutures. This technique allows for maximal dissection of the thoracic muscles even through minimal incisions. Through improved exposure and traction, complete dissection of the muscle bed can be performed and the tissue obtained maximized. Because more muscle bulk is obtained with this technique, the need for a second muscle may be prevented.

    Title Evolving Options in the Management of Esophageal Perforation.
    Date May 2004
    Journal The Annals of Thoracic Surgery
    Excerpt

    Esophageal perforation remains a devastating event that is difficult to diagnose and manage. The majority of injuries are iatrogenic and the increasing use of endoscopic procedures can be expected to lead to an even higher incidence of esophageal perforation in coming years. Accurate diagnosis and effective treatment depend on early recognition of clinical features and accurate interpretation of diagnostic imaging. Outcome is determined by the cause and location of the injury, the presence of concomitant esophageal disease, and the interval between perforation and initiation of therapy. The overall mortality associated with esophageal perforation can approach 20%, and delay in treatment of more than 24 hours after perforation can result in a doubling of mortality. Surgical primary repair, with or without reinforcement, is the most successful treatment option in the management of esophageal perforation and reduces mortality by 50% to 70% compared with other interventional therapies.

    Title Adenovirus-mediated Gene Transfer of Enhanced Herpes Simplex Virus Thymidine Kinase Mutants Improves Prodrug-mediated Tumor Cell Killing.
    Date April 2004
    Journal Cancer Gene Therapy
    Excerpt

    The Herpes simplex virus 1 (HSV) thymidine kinase (tk) suicide gene together with ganciclovir (GCV) have been successfully used for the in vivo treatment of various solid tumors and for the ablation of unwanted transfused stem cells in recent clinical trials. With the aim of improving this therapeutic system, we compared the potential efficacy of adenoviral (Ad) vectors expressing enhanced tk mutants in vitro and in vivo. The previously created HSV-tk mutants dm30 and sr39, created by random sequence mutagenesis, were inserted into a standard Ad.RSV E1(-)E3(-) backbone using homologous recombination. GCV killing of Ad.HSV-tk, Ad.dm30-tk and Ad.sr39-tk was assessed in various tumor cell lines with a cell proliferation assay. Cells expressing the two TK mutants were two-to-five-fold more sensitive to GCV when compared with Ad.HSV-tk transduced cells in all cell lines tested (five human mesotheliomas, one human lung cancer, a human cervical carcinoma, a mouse fibrosarcoma, and a rat glioma line) at equal TK expression levels. Flank tumor models, including cell-mixing studies, assessed the in vivo efficacy of the engineered viruses in BALB/C and SCID mice. In all animal studies, Ad.dm30-tk and Ad.sr39-tk showed more tumor growth inhibition than Ad.HSV-tk when GCV was administered. The use of adenovirus-mediated gene transfer of both tk mutants dm30-tk and sr39-tk for cancer suicide gene therapy should provide a more effective and safer alternative to wild-type HSV-tk.

    Title Suramin Inhibits the Growth of Malignant Mesothelioma in Vitro, and in Vivo, in Murine Flank and Intraperitoneal Models.
    Date April 2004
    Journal Lung Cancer (amsterdam, Netherlands)
    Excerpt

    Surgical debulking of malignant mesothelioma (MM) ultimately fails due to local recurrence. Suramin, an inhibitor of extracellular growth factors (ECGFs), has demonstrated efficacy in the treatment of malignant mesothelioma in a small case series. Our goal was to study survival benefits and disease progression in several MM animal models treated with suramin as a potential agent for adjuvant therapy. In vitro growth of human (REN, I-45), rat (II-45) and murine (AB12) mesothelioma cell lines were measured with or without suramin exposure. Human and murine MM tumors were implanted subcutaneously into murine flanks or injected intraperitoneally (i.p.) into murine abdominal cavities. Dose and treatment schedules were optimized to reduce the rate of tumor progression and to improve survival curves. Suramin inhibited the in vitro growth of all cell lines, reaching statistical significance (P<0.01) three doubling cycles after suramin administration, with a maximum inhibition of 10-25% of control growth. A significant time- and dose-dependent effect was observed. In vivo, suramin inhibited the growth of MM in the xenogeneic model (55% of control growth, P<0.01), and in the syngeneic model at both the low and high loading doses (46 and 36% of control growth, respectively, P<0.01). Suramin treatment inhibited in vivo growth in the REN intraperitoneal model shown grossly by necropsy of same day deaths comparing treatment and control animals. Tumor inhibition with the higher dose was also reflected by the lower mean tumor burden scores (control: 4.0 and high dose: 3.4). Suramin inhibits the growth of human, murine, and rat MM in vitro, in a time- and dose-dependent manner. Suramin also inhibits the growth of human MM flank and intraperitoneal xenografts in vivo in an immunodeficient host, as well as the growth of syngeneic murine flank tumors in an immunocompetent host. These studies demonstrate that suramin may have the potential to provide effective therapy for MM, and that further studies are necessary to elucidate the survival advantage of suramin mediated MM growth inhibition.

    Title Differentially Expressed Apoptotic Genes in Early Stage Lung Adenocarcinoma Predicted by Expression Profiling.
    Date March 2004
    Journal Cancer Biology & Therapy
    Excerpt

    OBJECTIVE: In undiseased lung epithelial cells, apoptosis is an evolutionarily conserved and genetically regulated form of cell suicide which plays an important role in development and in the maintenance of tissue homeostasis. Neoplastic lung cells develop the ability to deregulate growth by alterations in these genes which control apoptosis. Genomic profiling was used to compare gene expression levels in early stage lung adenocarcinomas and nonneoplastic pulmonary tissue in order to comprehensively identify alterations in the process of apoptosis. METHODS: RNA extracted from node negative, poorly differentiated lung adenocarcinomas (15 patients) and nonneoplastic pulmonary tissue (5 patients) was hybridized to oligonucleotide microarray filters containing 44,363 genes. Ontological classification was used to extract genes involved with apoptosis. Further analysis discovered a subset of differentially expressed genes for further study. RESULTS: Of the 308 apoptotic genes on the microarray filters, 24 genes were predicted to be differentially expressed in lung adenocarcinomas. Alterations in several genes (i.e., Akt, BcL-xL, PTEN, FAS) are consistent with the literature. We also identified 10 novel genes that have not been described in nonsmall cell lung cancer (i.e., RIP, Caspase 1, PDK-1). CONCLUSIONS: These results identified several potential apoptotic genes altered in lung cancer.

    Title Two Commonly Used Neoadjuvant Chemoradiotherapy Regimens for Locally Advanced Stage Iii Non-small Cell Lung Carcinoma: Long-term Results and Associations with Pathologic Response.
    Date March 2004
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    BACKGROUND: We performed this study to determine the outcomes (pathologic response, survival, local-regional control, and toxicity) in patients treated with neoadjuvant chemoradiotherapy and planned operation for stage IIIA non-small cell lung carcinoma. METHODS: Patients treated from 1993 to 2000 with neoadjuvant chemoradiotherapy and a predetermined plan for subsequent surgical resection for stage III non-small cell lung carcinoma were analyzed. All patients underwent pretreatment evaluation at the university's Multidisciplinary Lung Cancer Center. Most patients (87%) had complete mediastinoscopy staging, and all were believed to be poor candidates for up-front operation because of bulky extent of disease. The radiotherapy program used conventional, 2-dimensionally planned treatment to 45 to 54 Gy in 1.8- to 2-Gy fraction size. Concurrent chemotherapy consisted of etoposide/cisplatin or carboplatin/paclitaxel. Study end points included resectability, pathologic response, local-regional control, survival, and toxicity. An exploratory comparison between pathologic response and long-term survival was performed. An exploratory comparison between older chemotherapy (etoposide/cisplatin) and third-generation chemotherapy (carboplatin/paclitaxel) was also performed. RESULTS: Of 53 patients, 45 (85%) were deemed surgical candidates after induction therapy. Twenty-two (42% of the initial cohort) patients had a major pathologic response to stage 0, I, or II disease. The 5-year actuarial survival was 31%. Major pathologic response was associated with improved survival (48% vs 24%; P =.027). The overall rate of early death potentially related to therapy in this series was 9%; this mostly occurred in patients who underwent right pneumonectomy. There was no difference in efficacy or mortality between etoposide/cisplatin and radiotherapy versus carboplatin/paclitaxel and radiotherapy, although the latter regimen was associated with less grade 3 or higher acute toxicity necessitating interruption or hospitalization during neoadjuvant treatment (P =.02). In-field local control was achieved in 83% of all patients (90% of the patients who underwent resection). Brain metastases as the first site of treatment failure occurred in 23% of all patients. CONCLUSIONS: Neoadjuvant concurrent chemoradiation delivers high resectability, major pathologic response rate, and excellent local-regional control, with encouraging long-term survival considering the patient population studied. Major pathologic response correlates with long-term survival. Neoadjuvant carboplatin/paclitaxel and radiotherapy is an appropriate framework on which to add new therapies.

    Title Immuno-gene Therapy with Interferon-beta Before Surgical Debulking Delays Recurrence and Improves Survival in a Murine Model of Malignant Mesothelioma.
    Date March 2004
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    OBJECTIVES: Immuno-gene therapy of mesothelioma with an adenovirus encoding interferon-beta mediated strong antitumor responses in murine models with low but not high tumor burden. Our goals were to determine the mechanisms responsible for this loss of efficacy and to test the hypothesis that the combination of preoperative adenovirus encoding interferon-beta and surgical resection would be effective in treating bulky tumors. METHODS: Flank tumors of a mouse mesothelioma cell line were treated with adenovirus encoding interferon-beta or adenoviral vector encoding the bacterial protein beta-galactosidase. Cytotoxic T lymphocytes and tumor infiltration by T lymphocytes were measured. Tumors were surgically excised 72 hours later and tumor cells were injected in the contralateral flank to create a model of a metastatic focus. Tumor-free survival and distant metastatic disease were assessed. RESULTS: Immuno-gene therapy effectively treated small tumors (<200 mm(3)) but did not reduce the size of large (>800 mm(3)) flank tumors. Although treatment with adenovirus encoding interferon-beta resulted in the generation of tumor-neutralizing splenocytes in large tumors, the number of T cells visualized within the tumors was minimal. Tumors treated with adenovirus encoding interferon-beta (versus adenoviral vector encoding the bacterial protein beta-galactosidase or phosphate-buffered saline solution) prior to debulking increased long-term tumor-free survival and resulted in two- to sixfold smaller foci of implanted tumor cells at 2 weeks postoperatively. CONCLUSIONS: The use of adenovirus encoding interferon-beta or surgical debulking alone is ineffective in treating large tumors, but combining preoperative adenovirus encoding interferon-beta and surgical debulking significantly reduces tumor recurrence and improves long-term tumor-free survival. We postulate that adenovirus encoding interferon-beta amplifies the cytotoxic T-lymphocyte antitumor response, allowing elimination of residual tumor cells.

    Title Giant Bullous Lung Disease: Evaluation, Selection, Techniques, and Outcomes.
    Date February 2004
    Journal Chest Surgery Clinics of North America
    Excerpt

    Patient selection remains one of the most important aspects of successful surgery for bullous disease. Operation is indicated for patients who have incapacitating dyspnea with large bullae that fill more than 30% of the hemithorax and result in the compression of healthy adjacent lung tissue. Operation is also indicated for patients who have complications related to bullous disease such as infection or pneumothorax. Patients who have bullous disease in the presence of diffuse lung disease (emphysematous or nonemphysematous) should be evaluated on an individual basis and surgery should be performed on patients in whom even a small increase in pulmonary function might be of major benefit. Smoking cessation and outpatient pulmonary rehabilitation are required of all patients preoperatively. Patients should undergo PFTs including lung volumes by whole body plethysmography, spirometry, diffusion capacity, and arterial blood gas. CT remains the most important preoperative evaluation because it is useful assessing the extent of bullous disease and the quality of the surrounding lung tissue. The authors favor a minimally invasive technique through VATS whenever possible because it might allow for a quicker recovery and might be associated with less pain than is seen following thoracotomy. Modified Monaldi-type drainage procedures are also effective, especially in high-risk patients who cannot tolerate excisional procedures. Special care must be taken to avoid sacrifice of any potentially functional lung tissue. Lobectomies should be avoided whenever possible. The best results are seen in limited resections of large bullae that spare all surrounding functional pulmonary parenchyma. Postoperative complications are minimized through aggressive tracheobronchial toilet and vigorous chest physiotherapy. Adequate pain control in maintained throughout the postoperative period, initially by way of epidural infusion of morphine or fentanyl and later through oral opioids. Early ambulation and pulmonary rehabilitation also help minimize complications.

    Title Use of Cyclooxygenase-2 Inhibition to Enhance the Efficacy of Immunotherapy.
    Date February 2004
    Journal Cancer Research
    Excerpt

    Antitumor effects of cyclooxygenase-2 (COX-2) inhibition have been reported in a wide variety of tumor models and in human cancers, both as chemoprevention and therapy. Human mesothelioma tumors have been shown to overexpress COX-2 and high levels of COX-2 protein have been demonstrated to be a prognostic factor, indicating poor outcome in this tumor. In this study, we determined that inhibition of COX-2 by oral administration of Rofecoxib significantly slowed but did not cure the growth of small tumors in mesothelioma-bearing mice. Large tumors were unaffected. This effect was dependent on the presence of CD8+ T cells and was associated with increased tumor-infiltrating lymphocytes. Because these activities are consistent with a mechanism that results in a decrease in the immunosuppressive environment of the tumor, we additionally examined the effect of COX-2 blockade combined with Ad.IFN-beta therapy, a treatment that we have previously demonstrated results in expansion of antitumor CD8+ CTLs and cures a high percentage of small mesothelioma tumors in mice. Ad.IFN-beta therapy combined with COX-2 inhibition was associated with an increased number of T cells within tumors and resulted in cures of small tumors, significant inhibition of the growth of large established tumors, and inhibition of the growth of metastatic tumor foci after surgical debulking. The additive effects of these modes of treatment suggests that it would be rational to combine COX-2 inhibition with immuno- and immunogene therapy approaches (perhaps in conjunction with surgical debulking) in human clinical trials of treatment of mesothelioma and other tumors.

    Title Is Surgical Science Dead? The Excelsior Society Lecture.
    Date January 2004
    Journal Journal of the American College of Surgeons
    Title Current Management of Esophageal Leiomyoma.
    Date January 2004
    Journal Journal of the American College of Surgeons
    Title Trance- and Cd40 Ligand-matured Dendritic Cells Reveal Mhc Class I-restricted T Cells Specific for Autologous Tumor in Late-stage Ovarian Cancer Patients.
    Date January 2004
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: The use of mature dendritic cells (DCs) presenting tumor-associated antigens (TAAs) to trigger tumor-specific T cells in vivo or in vitro represents a promising approach for cancer immunotherapy. We hypothesized that tumor antigens, mostly unidentified, are present on ovarian tumor cells and that mature DCs could be used to generate tumor-specific responses in unprimed patients. We also sought to measure preexisting antitumor immunity in patients with advanced ovarian cancer. EXPERIMENTAL DESIGN: Autologous DCs from 10 patients with ovarian cancer were pulsed with killed autologous primary tumors as a source of TAAs. DCs were then cultured in the presence of tumor necrosis factor alpha + TRANCE (tumor necrosis factor-related activation-induced cytokine) to induce maturation. Mature TAA-pulsed DCs were used in vitro to stimulate tumor-specific peripheral blood T cells. RESULTS: TRANCE and CD40 ligand were effective at maturing DCs. T-cell lines were generated in vitro that were capable of secreting IFN-gamma in response to autologous tumor. These tumor-specific T cells were MHC class I restricted. The frequency of tumor-specific T cells in uncultured cells from malignant ascites fluid and peripheral blood was measured in the same patients. CONCLUSIONS: IFN-gamma-secreting tumor-specific T cells were demonstrated at baseline in uncultured T cells from some unvaccinated ovarian cancer patients; however, the T cells could not kill autologous tumor. These data demonstrate that mature DCs presenting tumor antigens from engulfed autologous tumors can be used to augment antitumor immunity in vitro in patients with epithelial ovarian cancer. The results support the feasibility of therapeutic vaccination of ovarian cancer patients.

    Title Bronchial Sleeve Resection for Posttransplant Stricture.
    Date January 2004
    Journal The Annals of Thoracic Surgery
    Excerpt

    Nonanastomotic bronchial stenosis is a rare complication of lung transplantation. We report a case of a bilateral lung transplant recipient who experienced recalcitrant stenosis of the bronchus intermedius. All attempts at conservative management failed, and the stricture was successfully treated by a parenchymal-sparing segmental sleeve resection. Although rare, this is an important technique in the management of this difficult problem.

    Title Comparison of Stages I-ii Thymoma Treated by Complete Resection with or Without Adjuvant Radiation.
    Date December 2003
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Adjuvant radiation after resection of Masaoka stage II thymoma is widely advocated, but the evidence supporting it is controversial. Studies addressing this issue generally report few patients and lump all patients beyond stage I together in the analysis. METHODS: We retrospectively compared outcomes of stage I and II thymomas treated by resection alone with thymomas treated by resection plus radiation. Histology was re-reviewed to confirm pathologic staging and resection margin status. RESULTS: Between February 1992 and 2002, we performed 167 resections for thymoma. Of these, 70 patients were believed to have tumors in stage IIb or less intraoperatively, and all of these patients underwent complete resection. We reviewed the histopathology of 62 of 70 patients. Thirty thymomas demonstrated less than complete transcapsular microscopic invasion (stage I) and 40 thymomas demonstrated microscopic transcapsular invasion or macroscopic invasion into surrounding fatty tissue (stage II). Forty-seven patients underwent surgery without postoperative mediastinal radiotherapy. Dosages in the 23 radiated patients (3 stage I and 20 stage II) consisted of 45 to 55 Gy. Median follow-up was 70.3 months. Stage II patients who were radiated (n = 20) and those who were not radiated (n = 20) consisted of identical proportions in stages IIa and IIb. Two patients recurred (1 unradiated stage I patient and 1 radiated stage IIb patient). Overall 5-year survival rate was 91%. All who died were free of recurrence at time of death. Log-rank test showed no difference in Kaplan Meier survival curves (p = 0.32) between the radiated and unradiated groups. CONCLUSIONS: These data support the contention that margin-negative surgical resection alone is sufficient treatment for both stages I and II thymoma.

    Title Alterations in Cell Cycle Genes in Early Stage Lung Adenocarcinoma Identified by Expression Profiling.
    Date December 2003
    Journal Cancer Biology & Therapy
    Excerpt

    In normal lung epithelial cells, cellular division is an ordered, tightly regulated process involving multiple checkpoints that assess extracellular growth signals, cell size, and DNA integrity. In contrast, neoplastic lung cells develop the ability to bypass several of these checkpoints, particularly at the G1/S and G2/M boundaries. We used genomic profiling to compare gene expression levels in early stage lung adenocarcinomas and non-neoplastic pulmonary tissue in order to comprehensively identify alterations in the process of cell cycling. RNA extracted from node negative, poorly differentiated lung adenocarcinomas (15 patients) and non-neoplastic pulmonary tissue (5 patients) was hybridized to oligonu-cleotide microarray filters containing 44,363 genes. Ontological classification was used to extract genes involved with cell cycle progression. Further analysis discovered a subset of differentially expressed genes for further study. Of the 624 cell cycle genes on the microarray filters, 40 genes were predicted to be differentially expressed in lung adeno-carcinomas. Alterations in several genes (i.e., cyclin B1, cyclin D1, p21, MDM2) are consistent with published data in the literature. We also identified 19 novel genes that have neither been described in non-small cell lung cancer (i.e., cdc2, cullin 4A, ZAC, p57, DP-1, GADD45, PISSLRE, cdc20) nor in any other tumors (i.e., cyclin F, cullin 5, p34). These results identified several potential cell cycle genes altered in lung cancer.

    Title Weerda Diverticuloscope: Novel Use to Remove Embedded Esophageal Foreign Bodies.
    Date November 2003
    Journal The Annals of Thoracic Surgery
    Excerpt

    Embedded sharp foreign bodies of the cervical esophagus represent a clinical challenge. Initial attempts at removal are usually undertaken by nonsurgical endoscopists who are often successful with blunt objects. Unsuccessful attempts with sharp objects, however, can result in distal migration, mucosal damage, and frank perforation. Thoracic surgeons are often called on for cervical esophagotomy after endoscopic attempts have failed. This report describes the novel use of a Weerda diverticuloscope for removal of a dental appliance with metallic hooks embedded in the cervical esophagus.

    Title Human Diaphragm Remodeling Associated with Chronic Obstructive Pulmonary Disease: Clinical Implications.
    Date October 2003
    Journal American Journal of Respiratory and Critical Care Medicine
    Excerpt

    Diaphragm remodeling associated with chronic obstructive pulmonary disease (COPD) consists of a fast-to-slow fiber type transformation as well as adaptations within each fiber type. To try to explain disparate findings in the literature regarding the relationship between fiber type proportions and FEV1, we obtained costal diaphragm biopsies on 40 subjects whose FEV1 ranged from 118 to 16% of the predicted normal value. First, we noted that our exponential regression model indicated that changes in FEV1 can account for 72% of the variation in the proportion of Type I fibers. Second, to assess the impact of COPD on diaphragm force generation, we measured maximal specific force generated by single permeabilized fibers prepared from the diaphragms of two patients with normal pulmonary function tests and two patients with severe COPD. We noted that fibers prepared from the diaphragms of severe COPD patients generated a lower specific force than control fibers (p < 0.001) and Type I fibers generated a lower specific force than Type II fibers (p < 0.001). Our finding of an exponential relationship between the proportion of Type I fibers and FEV1 accounts for discrepancies in the literature. Moreover, our single-fiber results suggest that COPD-associated diaphragm remodeling decreases diaphragmatic force generation by adaptations within each fiber type as well as by fiber type transformations.

    Title Allelic Loss on Chromosome 3p21.3 and Promoter Hypermethylation of Semaphorin 3b in Non-small Cell Lung Cancer.
    Date July 2003
    Journal Cancer Research
    Excerpt

    The aim of this study was to evaluate the promoter methylation status and loss of heterozygosity (LOH) of the SEMA3B in non-small cell lung cancers (NSCLCs). We analyzed the methylation status of semaphorin 3B (SEMA3B) promoter and LOH at 3p21.3 in eight NSCLC cell lines and 27 primary tumors. Hypermethylation of SEMA3B was found in 50% of the cell lines and 41% of the primary tumors studied. The presence of hypermethylation was statistically associated with loss of SEMA3B expression in both cell lines (P = 0.02) and primary tumors (P < 0.01). There was no correlation between SEMA3B and tumor stage. On the other hand, the correlation between SEMA3B methylation status and LOH at 3p21.3 was significant (P = 0.02). Notably, 7 of 8 tumors with both hypermethylation and LOH of SEMA3B showed the absence of the expression. Treatment with 5-AZAC restored SEMA3B expression in NSCLC cell line. These results indicate that SEMA3B gene alterations may play a important role in the malignant transformation of NSCLC via a two-hit mechanism, including epigenetic changes and allelic loss, for tumor suppressor gene inactivation.

    Title Management of Unremitting Chylothorax by Percutaneous Embolization and Blockage of Retroperitoneal Lymphatic Vessels in 42 Patients.
    Date June 2003
    Journal Journal of Vascular and Interventional Radiology : Jvir
    Excerpt

    PURPOSE: To demonstrate the applicability, technique, and efficacy of percutaneous transabdominal catheter embolization or needle disruption of retroperitoneal lymphatic vessels in the treatment of high-output or unremitting chylothorax. MATERIALS AND METHODS: Forty-two patients (21 men, 21 women; mean age, 56 y; range, 19-80 y) who had chylothorax with various etiologies were referred from the thoracic surgery department for treatment as soon as chylothorax was documented. The thoracic duct was punctured and catheterized via a peritoneal cannula to facilitate embolization with use of microcoils, particles, or glue; if there were no lymph trunks that could be catheterized, attempts were made to disrupt lymph collaterals with use of needles. RESULTS: The thoracic duct was catheterized in 29 patients and embolized in 26 patients. In patients with lymph trunks that could be catheterized, treatment resulted in cure within 7 days in 16 patients and partial response with cure within 3 weeks in six patients. In the patients with lymph trunks that could not be catheterized (n = 16), disruption with use of needles resulted in cure in five patients and partial response in two patients. Cure and partial response rates after thoracic duct embolization and needle disruption were 73.8%, with no morbidity. Surgical thoracic duct ligation was performed in seven patients. The nonprocedural mortality rate was 19%. Follow-up was 3 months or longer. CONCLUSIONS: Effective percutaneous treatment of high-output or medically uncontrollable chylothorax was performed promptly and safely in more than 70% of referred cases. This procedure should be attempted, especially if patients are very ill, before riskier surgical thoracic duct ligation is considered.

    Title Ww Domain Containing Oxidoreductase Gene Expression is Altered in Non-small Cell Lung Cancer.
    Date March 2003
    Journal Cancer Research
    Excerpt

    WWOX (WW domain containing oxidoreductase), a putative tumor suppressor gene that maps to the common fragile site FRA16D on chromosome 16q23.3-24.1, is altered in breast, esophageal, and ovarian cancer. Because the FRA3B/FHIT locus at 3p14.2 is a preferential target for genetic changes caused by tobacco smoke, we intended to evaluate the status of the FRA16D/WWOX gene in non-small cell lung cancer; we have analyzed 27 paired normal and tumor lung tissues and 8 lung cancer cell lines for WWOX alterations by reverse transcriptase-PCR, loss of heterozygosity, and mutation analysis. Transcripts missing WWOX exons were detected in 7 primary tumors (7 of 27; 25.9%) and 5 of 8 cell lines. In addition, loss of heterozygosity at the WWOX locus was observed in 10 primary tumors (10 of 27; 37.0%). We conclude that WWOX alterations occur in a significant fraction of lung cancers and may contribute to the pathogenesis of non-small cell lung cancer.

    Title Pathological Response to Preoperative Chemoradiation Worsens with Anemia in Non-small Cell Lung Cancer Patients.
    Date February 2003
    Journal Cancer Journal (sudbury, Mass.)
    Excerpt

    PURPOSE: Positive links between hemoglobin level and therapeutic tumor response are well documented in carcinoma of the cervix and the head and neck, but little evidence of such a link exists for lung cancer. We analyzed our series of patients treated with preoperative chemoradiation for stage IIIA non-small cell lung carcinoma. PATIENTS AND METHODS: Between June 1992 and February 2000, 41 consecutive patients with clinical stage IIIA (N2, documented by mediastinoscopy or another invasive procedure) non-small cell lung carcinoma received preoperative-intent chemoradiation. The median preoperative radiation dose was 48.6 Gy, and all patients received cisplatin- or paclitaxel-based chemotherapy. Response was graded on a four point scale: (1) progressive disease before surgery and/or technically inoperable; (2) stable disease with resection performed, but specimen containing > 50% viable tumor; (3) partial response with specimen containing < 50% tumor; and (4) complete response or near-complete response: RO resection with no residual carcinoma or pT1NO with only microscopic residual foci. Pretreatment hemoglobin values were correlated with pathological outcome using ANOVA and the non-parametric test for trend across ordered groups. RESULTS: The mean hemoglobin level for groups 1 through 4 was 11.8, 12.1, 12.5, and 13.2 respectively, and the association was statistically significant. If the analysis was limited to patients actually undergoing surgery (eliminating group 1), the association remained significant. The nonparametric test for trend across ordered groups was also significant with and without group 1. DISCUSSION: Our analysis supports the hypothesis that response to chemoradiation of non-small cell lung carcinoma improves with increasing hemoglobin levels.

    Title Evaluating Respiratory Muscle Adaptations: a New Approach.
    Date January 2003
    Journal American Journal of Respiratory and Critical Care Medicine
    Title Benign Expectoration of a Surgical Clip Through a Pneumonectomy Stump.
    Date January 2003
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Title Malignant Mesothelioma: Options for Management.
    Date December 2002
    Journal The Surgical Clinics of North America
    Excerpt

    In the past, there has been a tendency to think of diffuse malignant pleural mesothelioma as one disease in therapeutic terms, regardless of histological type and tumor stage. This does not happen with other tumors, yet it is equally illogical and inappropriate in mesothelioma. As with other tumors, early diagnosis-while the disease is still in stage I, or even at an in situ stage-must be the goal so that therapy can be maximized, particularly if immunotherapy or gene therapy is to be used. Patients with pure epithelial mesothelioma have a better prognosis and respond better to trimodality therapy. Stage I patients who meet fitness criteria should be offered the option of radical surgery in combination with chemotherapy and radiotherapy. Further research is required to determine the optimum neoadjuvant and adjuvant modalities, particularly the timing of individual drugs, use of hyperthermia, and route of administration. The place of immunotherapy and gene therapy as adjunctive treatments also remains to be defined. For example, it may be possible to reduce tumor bulk and perhaps downstage the disease with immunotherapy before radical surgery, if treatment is started early enough. Gene therapy may have a role either preoperatively or in destroying the microscopic disease that remains after radical surgery. These and other combinations of treatment need to be tested in well-designed clinical trials, probably on a multicenter basis (to enroll a sufficient number of patients). Finding the means to improve treatment for sarcomatous and mixed histology mesothelioma remains a challenge. At present, radical surgery does not seem worthwhile for these patients when combined with currently employed chemotherapy and radiotherapy; however, chemotherapy combinations used for treating other sarcomas need to be evaluated as adjunctive therapy before radical surgery is abandoned altogether as a mode of treatment. A collaborative approach involving thoracic surgeons, basic scientists and oncologists, and physicians with experience in treating mesothelioma is essential. Despite its increasing frequency, mesothelioma is still a relatively rare tumor, so treatment should be concentrated in relatively few supraregional centers to maximize expertise and allow innovative treatment combinations to be implemented with the greatest chance of success. Evaluation of new therapeutic approaches will be achieved more rapidly if these supraregional centers collaborate in multicenter trials. The nihilistic approach of simply waiting until the mesothelioma epidemic eventually begins to decline spontaneously in 20 or 30 years is untenable in view of the hundreds of thousands of deaths that will result if no effective treatment is found.

    Title Validating a Dipstick Method for Detecting Recent Smoking.
    Date December 2002
    Journal Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
    Excerpt

    This report evaluates the validity of a new method for verifying self-reported smoking status in patients presenting for pulmonary medicine treatment. A prospective comparison was made between self-reports of smoking status and a new semiquantitative, enzyme-linked, immunosorbent assay-based method testing for the presence of a prime nicotine metabolite, cotinine. Results were validated by gas chromatography/mass spectrometry. Data were collected in an urban, academic, tertiary health care setting. The study included 76 consecutive new patients presenting to participating clinical practices at the Pulmonology or Thoracic Surgery Services. Before taking a smoking history, patients were informed that their urine would be tested onsite for the presence of nicotine using a new method, the NicoMeter, for determining tobacco product exposure, followed by more standard laboratory testing. The level of agreement between the biochemical measurement types was excellent, kappa = 0.777. The new biochemical measurement type used was easy to use. Self-reported smoking status corresponded closely to biochemical testing. However, there was a 5.3-9.5% misclassification of smoking status among the group studied, depending upon the measurement type used. Among 32 lung cancer patients, 15.6%, most likely misrepresented their current smoking status. The NicoMeter appears to be a valid and useful method for confirming self-reported smoking status. Lung cancer patients had a higher rate of inaccurate nonsmoking compared with patients with nonmalignant pulmonary disease. The findings have implications for investigators who accept self-reported smoking status without biochemical verification.

    Title Long-term Pain and Activity During Recovery from Major Thoracotomy Using Thoracic Epidural Analgesia.
    Date November 2002
    Journal Anesthesiology
    Excerpt

    BACKGROUND: Pain following thoracotomy can persist for years with an undetermined impact on quality of life. Factors hypothesized to modulate this painful experience include analgesic regimen, gender, and type of incision. METHODS: A total of 157 generally healthy patients of both genders scheduled for segmentectomy, lobectomy, or bilobectomy through a posterolateral or muscle-sparing incision were randomly assigned to receive thoracic epidural analgesia initiated prior to incision or at the time of rib approximation. Pain and activity scores were obtained 4, 8, 12, 24, 36, and 48 weeks after surgery. RESULTS: Overall, there were no differences in pain scores between the control and intervention groups during hospitalization (P >or= 0.165) or after discharge (P>or= 0.098). The number of patients reporting pain 1 yr following surgery (18 of 85; 21.2%) was not significantly different (P = 0.122) from the number reporting preoperative pain (15 of 120; 12.5%). During hospitalization, women reported greater pain than men (worst pain, P= 0.007; average pain, P= 0.016). Women experienced fewer supraventricular tachydysrhythmias (P = 0.013) and were thus discharged earlier (P = 0.002). After discharge women continued to report greater discomfort than men (P <or= 0.016), but did not differ from men in their level of physical activity (P = 0.241). CONCLUSIONS: Initiation of thoracic epidural analgesia prior to incision or the use of a muscle-sparing incision did not significantly impact pain or physical activity. Although women reported significantly greater pain during hospitalization and after discharge, they experienced fewer complications, were more likely to be discharged from the hospital sooner, and were just as active after discharge as men.

    Title Cardiopulmonary Bypass for Bilateral Sequential Lung Transplantation in Patients with Chronic Obstructive Pulmonary Disease Without Adverse Effect on Lung Function or Clinical Outcome.
    Date October 2002
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    OBJECTIVE: The use of cardiopulmonary bypass in lung transplantation remains controversial. Previous studies have concluded that cardiopulmonary bypass is deleterious, but these studies were confounded by the inclusion of patients with different diagnoses undergoing single- and double-lung transplantation with elective or emergency use of bypass. The goal of this study was to determine whether cardiopulmonary bypass has deleterious effects on lung function or clinical outcome by analyzing the cases of patients with a single disease entity and elective use of bypass for bilateral sequential lung transplantation. METHODS: A retrospective review of 50 patients with chronic obstructive pulmonary disease who underwent bilateral sequential lung transplantation was performed. Fourteen patients who underwent elective cardiopulmonary bypass for 218.3 +/- 75.4 minutes were compared to 36 control patients. RESULTS: After the operation, the bypass and nonbypass groups were not significantly different with respect to median duration of mechanical ventilation (1 day vs 1 day, P =.76), median stay in the intensive care unit (4 days vs 4 days, P =.44), median hospital stay (15.5 days vs 16 days, P =.74), mean increase in serum creatinine level (1.4 +/- 1.9 mg/dL vs 0.9 +/- 1.0 mg/dL, P =.33), and mean ratio of Pao(2) to fraction of inspired oxygen at 1 hour (376.6 +/- 123 vs 357.0 +/- 218, P =.75), at 24 hours (309.9 +/- 92 vs 350.6 +/- 122, P =.26), and at 48 hours (335.0 +/- 144 vs 316.2 +/- 120, P =.64). Late outcome markers compared between the bypass and nonbypass groups were the following: 1-year percentage predicted forced expiratory volume in 1 second (76.1% +/- 17.0% vs 85.3% +/- 21.7%, P =.24), 30-day mortality (7.1% vs 8.3%, P >.999), 1-year survival (85.7% vs 80.1%, P =.66), 3-year survival (64.3% vs 58.3%, P =.70), and the prevalence of bronchiolitis obliterans syndrome (0% vs 36.1%, P =.01). CONCLUSION: Cardiopulmonary bypass appears to have no deleterious effect on early lung function or clinical outcome. We hope that this pilot study removes some of the unwarranted fear of the use of bypass in lung transplantation for chronic obstructive pulmonary disease.

    Title Transcervical Thymectomy for Myasthenia Gravis Achieves Results Comparable to Thymectomy by Sternotomy.
    Date September 2002
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: It remains controversial whether transcervical thymectomy offers results equivalent to thymectomy by way of a median sternotomy in the treatment of myasthenia gravis. Furthermore, preoperative prognostic factors have not been clearly defined. METHODS: This study is a retrospective chart review and interview of 78 patients completing transcervical thymectomy for myasthenia gravis between 1992 and 1999. RESULTS: There were 24 men and 54 women. Mean age was 40 years (range, 13 to 78 years). Twelve patients were in Osserman class 1, 25 in class 2, 30 in class 3, and 11 in class 4 (mean, 2.5). There was no perioperative mortality and 6 (7.7%) morbidities. Mean length of stay was 1.5 days and mean follow-up, 54.6 months. The crude cumulative complete remission (asymptomatic off medications for 6 months) rate was 39.7% (n = 31). Only 8 patients (10.3%) failed to improve after transcervical thymectomy. Kaplan-Meier estimates of complete remission were 31% and 43% at 2 and 5 years, respectively. Eight patients with thymoma had a 5-year estimated complete remission rate of 75% in contrast to 43% in 38 patients with thymic hyperplasia and 36% in 32 patients with neither thymoma nor hyperplasia (p = 0.01). Twelve patients with ocular myasthenia had a 5-year estimated complete remission rate of 57%, whereas patients with mild-to-moderate (n = 55) or severe (n = 11) generalized symptoms had 5-year complete remission rates of 43% and 30%, respectively (p = 0.21). CONCLUSIONS: Overall, extended transcervical thymectomy offers results that are comparable to those published for the transsternal procedure. Patients with milder disease (including isolated ocular disease) and taking no preoperative immunosuppressive agents appear to experience higher remission rates. In contrast to previous studies, we also find that small thymomas predict better responses to thymectomy.

    Title Thoracic Surgery Workforce: Snapshot at the End of the Twentieth Century and Implications for the New Millennium.
    Date August 2002
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: An appropriately sized physician workforce is an essential component for healthcare planning. Contemporary economic forces and the impact of managed care have stimulated renewed interest in understanding and monitoring workforce issues. METHODS: Between August and December of 1999, the Workforce Committee of the American Association for Thoracic Surgery and The Society of Thoracic Surgeons conducted a survey detailing demographic, geographic, and socioeconomic practice characteristics of the membership. RESULTS: The 2,515 returned surveys represented a 62.6% return rate (+/- 1.6% margin of error), providing a highly statistically valid sample. Active thoracic surgeons are a mean of 50 years old, 98% men, with a high level of career satisfaction. Length of training and educational debt has been escalating. Adult cardiac surgical case volumes have increased (mean, 225 cases) and 52% of adult cardiac surgeons perform general thoracic procedures. Surgeons work 67 hours/week and 47 weeks/year. Most are organized in single specialty groups (50%) in urban areas (59%) as for-profit corporations (77%). Half of the respondents will be retired a mean of 13 years from now corresponding to a median calendar year of 2011. CONCLUSIONS: This survey highlights significant workforce retirement during the next 10 to 15 years. Currently, the workforce in thoracic surgery appears "right sized." These valuable data provide a profile of the specialty. The information enhances our ability to strategically plan.

    Title Cutting Edge: Regulatory T Cells from Lung Cancer Patients Directly Inhibit Autologous T Cell Proliferation.
    Date May 2002
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Active suppression by T regulatory cells plays an important role in the down-regulation of T cell responses to foreign and self-Ags. Thus far, the potential role of CD4(+)CD25(+) T cells in human tumors has not been reported. In this work we show that lung tumors contain large numbers of these cells and that they have constitutive high-level expression of CD152 (CTLA-4). Furthermore, the CD4(+)CD25(+) T cells mediate potent inhibition of autologous T cell proliferation. Finally, regulatory T cells from patient tumors failed to inhibit the proliferation of allogeneic T cells. Together these results suggest that the CD4(+)CD25(+) T cells found in lung tumors selectively inhibit the host immune response and therefore could contribute to the progression of lung cancer.

    Title Suction Vs Water Seal After Pulmonary Resection: a Randomized Prospective Study.
    Date April 2002
    Journal Chest
    Excerpt

    STUDY OBJECTIVE: To evaluate whether suction or water seal is superior in the management of chest tubes after pulmonary resection. DESIGN: A prospective, randomized, controlled trial. After an initial, brief period of suction, patients were randomized to water seal or - 20 cm H(2)O suction. SETTING: University hospital. PATIENTS: Sixty-eight patients who underwent wedge resection, segmentectomy, or lobectomy were included in the study. Those patients who underwent reoperative surgery or lung volume reduction surgery were excluded. RESULTS: There were 34 patients in each group. The two groups were evenly matched for age, sex, operation performed, severity of lung disease, and nutritional status. Fifteen patients in each group (44%) had an air leak at the completion of surgery. The duration of the air leak was shorter in the water seal group than in the suction group (mean +/- SEM, 1.50 +/- 0.32 days vs 3.27 +/- 0.80 days, respectively; p = 0.05). The mean times to removal of chest tubes were 3.33 +/- 0.35 days in the water seal group and 5.47 +/- 0.98 days in the suction group (p = 0.06). The length of stapled parenchyma was measured for each patient and averaged 24.9 cm for the water seal group and 18.5 cm for the suction group (p = 0.18). When corrected for the length of staple lines, the duration of air leaks and days with chest tube were dramatically lower in the water seal group (p = 0.02 and p = 0.02, respectively). CONCLUSION: Placing chest tubes on water seal after a brief period of suction after pulmonary resection shortens the duration of the air leak and likely decreases the time that the chest tubes remain in place. Adoption of this practice may result in lower morbidity and lower hospital costs.

    Title Current Presentation and Optimal Surgical Management of Sternoclavicular Joint Infections.
    Date March 2002
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Infection of the stemoclavicular joint is unusual, and treatment of this entity has not been standardized. We sought to characterize the current presentation and optimal management of this disease. METHODS: We retrospectively reviewed the records of the last 7 patients undergoing operation for suppurative infections of the stemoclavicular joint at this institution. Patients were interviewed regarding upper extremity function after formal joint resection. RESULTS: Predisposing factors were common and included diabetes mellitus (n = 2), clavicular fracture (n = 1), human immunodeficiency virus infection (n = 1), immunosuppression (n = 1), and pustular skin disease (n = 1). All patients presented with local symptoms including clavicular mass and tenderness. Diagnosis and evaluation were facilitated by cross-sectional imaging. Organisms isolated included Staphylococcus aureus, group G streptococcus, and Proteus and Propionibacterium species. Antibiotic therapy and simple drainage and debridement were generally ineffective, leading to recurrence of infection in 5 of 6 patients treated initially in this manner. Six patients were treated with resection of the stemoclavicular joint and involved portions of first or second ribs with soft tissue coverage by advancement flap from the ipsilateral pectoralis major muscle. Response to this therapy was excellent, with cure in all patients, no wound complications, and excellent upper extremity function at long-term follow-up. CONCLUSIONS: Aggressive surgical management including resection of the sternoclavicular joint and involved ribs with pectoralis flap closure would appear to be the preferred treatment for all but the most minor infections of the sternoclavicular joint. This approach has minimal impact on upper extremity function.

    Title Sarcomeres Are Added in Series to Emphysematous Rat Diaphragm After Lung Volume Reduction Surgery.
    Date February 2002
    Journal Chest
    Excerpt

    STUDY OBJECTIVES: The diaphragm adapts to its shortened state in experimental emphysema primarily by losing sarcomeres in series, thus reducing its optimal operating length. One would expect improved diaphragmatic function after lung volume reduction surgery (LVRS) only if the muscle can readapt to its elevated, lengthened postoperative position by either adding back sarcomeres or lengthening sarcomeres. We used a model of elastase-induced emphysema in rats to test the hypothesis that sarcomere addition occurs following LVRS. DESIGN: A cohort of emphysematous rats was created by the intratracheal instillation of elastase. Five months after the instillation, one group of rats underwent measurement of in situ costal diaphragm length via laparotomy, the determination of optimal muscle fiber operating length (Lo) on stimulated diaphragm strips in vitro, and the measurement of sarcomere length by electron microscopy on strips fixed at Lo. Another group of rats underwent LVRS or sham sternotomy 5 months after the instillation, and 5 months following the operation these animals underwent the same series of diaphragmatic studies. RESULTS: Lo was significantly greater in rats that underwent LVRS than those that underwent sternotomy (mean [+/- SE] Lo after LVRS, 2.50 +/- 0.08 cm; mean Lo after sternotomy, 2.27 +/- 0.06 cm; p = 0.013). There was no significant difference in sarcomere lengths between the two groups (2.95 +/- 0.04 vs 3.04 +/- 0.04 microm, respectively; p = 0.10). Using Lo as the length basis, the mean sarcomere number was calculated to be 8,712 +/- 192 in animals that had undergone LVRS and 7,144 +/- 249 in animals that had undergone sternotomy (p < 0.001). CONCLUSION: Sarcomere length is not significantly altered but sarcomeres are added in series following LVRS in this experimental model of emphysema/LVRS. It is likely that this sarcomere addition is a prerequisite to the improvement in inspiratory muscle function that has been observed following LVRS in humans.

    Title Symptomatic Dysrhythmia Caused by a Posterior Mediastinal Angiomyolipoma.
    Date January 2002
    Journal Ajr. American Journal of Roentgenology
    Title Apical Perfusion Fraction As a Predictor of Short-term Functional Outcome Following Bilateral Lung Volume Reduction Surgery.
    Date December 2001
    Journal Chest
    Excerpt

    STUDY OBJECTIVES: To examine whether relative hypoperfusion to the apical one third of the lungs as determined by lung scintigraphy predicts a favorable functional outcome following bilateral lung volume reduction surgery (LVRS). METHODS: We performed a retrospective analysis of 128 patients who underwent bilateral LVRS. An apical perfusion fraction (AP%), defined as the percentage of total lung perfusion to the apical one third of both lungs, was derived for each patient by quantitative scintigraphy technique. Pulmonary function testing and 6-min walk test (6MWT) data were obtained preoperatively and 3 to 6 months postoperatively. RESULTS: The mean (+/- SD) improvement in FEV(1) was 309 +/- 240 mL, 209 +/- 293 mL, and 116 +/- 224 mL for patients with an AP% of <or= 10%, 11 to 20%, and > 20%, respectively (p = 0.01, analysis of variance [ANOVA]). The likelihood of experiencing an increase in FEV(1) >or= 200 mL was 68% for those with an AP% <or= 10% but only 31% for those with an AP% > 20%. Preoperative and postoperative 6MWT data were available for 109 of 128 patients. Improvement was 250 +/- 252 feet, 205 +/- 299 feet, and 77 +/- 200 feet for patients with AP% <or= 10%, 11 to 20%, and > 20%, respectively (p = 0.04, ANOVA). While 50% of those with an AP% <or= 10% improved their 6MWT by >or= 180 feet, only 21% of those with an AP% > 20% did so. CONCLUSION: This retrospective analysis suggests that quantification of apical perfusion by nuclear scintigraphy assists in predicting the likelihood of short-term functional improvement after LVRS.

    Title Is There a "standard of Care" Operation for Esophageal Cancer?
    Date December 2001
    Journal Annals of Surgery
    Title Risk Factors Affecting Survival After Brain Metastases from Non-small Cell Lung Carcinoma: a Follow-up Study of 70 Patients.
    Date October 2001
    Journal Journal of Neurosurgery
    Excerpt

    OBJECT: The authors present their experience with the treatment of brain metastases from non-small cell lung carcinoma (NSCLC). METHODS: A retrospective review was conducted in which records from 74 patients treated at the authors' institution between 1994 and 1999 were assessed. Survival and functional outcome were reviewed relative to individual patient variables. The median survival time was 12.9 months, with 1-, 2-, and 5-year survival milestones reached by 52.2%, 30.7%. and 18.1% of patients, respectively. Patients were stratified into groups composed of those with synchronous brain metastases (tumors diagnosed within 3 months of NSCLC) and metachronous brain metastases (tumors diagnosed 3 months after NSCLC). The median survival time and 5-year survival rate were 18 months and 28.9% for metachronous, compared with 9.9 months and 0% for synchronous brain metastases. In univariate analyses, the stage of brain metastases, an initial Karnofsky Performance Scale (KPS) score of 90 or less, and conservative therapy for NSCLC were associated with worse outcomes (p < 0.05). In analyses in which tumors were stratified by synchronous compared with metachronous brain metastases, a preoperative KPS score of 90 or less and radiation therapy (RT) alone for brain metastases were associated with worse outcomes in patients with metachronous brain metastases but not with synchronous tumors (p < 0.05). When stratified by preoperative KPS score, the synchronous brain metastases stage or treatment of brain metastases with RT alone were associated with worse outcome in patients with KPS scores of 100, but had no discernible effect on patients with KPS scores of 90 or less (p < 0.05). CONCLUSIONS: The tumor stage and preoperative KPS score were significantly associated with survival. Craniotomy plus RT significantly improved the prognosis in patients with metachronous brain metastases or those with a preoperative KPS score of 100.

    Title The Silent Epidemic: Tobacco and the Evolution of Lung Cancer and Its Treatment.
    Date October 2001
    Journal Cancer Investigation
    Excerpt

    Considered a rare disease during the 19th century, lung cancer became the most virulent and lethal cause of cancer mortality by the end of the 20th century. In this paper, lung cancer and its treatment are addressed within the social, cultural, economic, and political context of the last century. Because lung cancer is related to the consumption of cigarettes, the battles over tobacco control are highlighted. Four time periods are addressed: the early years (1900-1930), beginning of the epidemic (1930-1960), defining the problem (1960-1980), and expanding options (1980-1990s). Although improvements have been made in science and technology, attempts at finding curative treatments have met with little success. Smoking cessation and efforts to control tobacco (especially among children and adolescents) remain the most important factors if the incidence of lung cancer is to be curtailed in the future. Providing care to individuals with the illness is a current challenge. Research examining the efficacy of treatments and their effect on survival, health-related quality of life, and cost outcomes is essential and can be best achieved through the efforts of multidisciplinary teams.

    Title Risk of Death from Intercurrent Disease is Not Excessively Increased by Modern Postoperative Radiotherapy for High-risk Resected Non-small-cell Lung Carcinoma.
    Date October 2001
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: Some studies report a high risk of death from intercurrent disease (DID) after postoperative radiotherapy (XRT) for non-small-cell lung cancer (NSCLC). This study determines the risk of DID after modern-technique postoperative XRT. PATIENTS AND METHODS: A total of 202 patients were treated with surgery and postoperative XRT for NSCLC. Most patients (97%) had pathologic stage II or III disease. Many patients (41%) had positive/close/uncertain resection margins. The median XRT dose was 55 Gy with fraction size of 1.8 to 2 Gy. The risk of DID was calculated actuarially and included patients who died of unknown/uncertain causes. Median follow-up was 24 months for all patients and 62 months for survivors. RESULTS: A total of 25 patients (12.5%) died from intercurrent disease, 16 from confirmed noncancer causes and nine from unknown causes. The 4-year actuarial rate of DID was 13.5%. This is minimally increased compared with the expected rate for a matched population (approximately 10% at 4 years). On multivariate analysis, age and radiotherapy dose were borderline significant factors associated with a higher risk of DID (P =.06). The crude risk of DID for patients receiving less than 54 Gy was 2% (4-year actuarial risk 0%) versus 17% for XRT dose > or = 54 Gy. The 4-year actuarial overall survival was 34%; local control was 84%; and freedom from distant metastases was 37%. CONCLUSION: Modern postoperative XRT for NSCLC does not excessively increase the risk of intercurrent deaths. Further study of postoperative XRT, particularly when using more sophisticated treatment planning and reasonable total doses, for carefully selected high-risk resected NSCLC is warranted.

    Title Eradication of Intraperitoneal and Distant Tumor by Adenovirus-mediated Interferon-beta Gene Therapy is Attributable to Induction of Systemic Immunity.
    Date September 2001
    Journal Cancer Research
    Excerpt

    Malignant mesothelioma remains an incurable disease for which immune-modulatory therapies, such as exogenous cytokines, have shown some promise. One such cytokine, IFN-beta, has potent antiproliferative and immunostimulatory activity in vitro, but its in vivo use has been limited by toxicity. We thus conducted studies evaluating intracavitary delivery of a replication-deficient adenoviral (Ad) vector encoding for the murine IFN-beta gene (Ad.muIFN-beta) in mouse models of malignant mesothelioma. In contrast to multiple injections of recombinant protein, a single i.p. injection of Ad.muIFN-beta into animals with established tumors elicited remarkable antitumor activity leading to long-term survival in >90% of animals bearing either AB12 or AC29 i.p. mesotheliomas. A control adenovirus vector had minimal antitumor effect in vivo. Significant therapeutic effects were also seen in animals treated with large tumor burdens. Importantly, treatment of i.p. tumor also led to reduction of growth in tumors established at a distant site (flank). A number of experiments suggested that these effects were attributable to an acquired CD8(+) T-cell-mediated response including: (a) the induction of long-lasting antitumor immunity; (b) loss of efficacy of Ad.muIFN-beta in tumor-bearing, immune-deficient (SCID, SCID/beige) mice; (c) detection of high levels of specific antitumor cytolytic activity from unstimulated splenocytes harvested from Ad.muIFN-beta-treated animals that was abolished by CD8(+) T-cell depletion; and (d) abrogation of antitumor effects of Ad.muIFN-beta in tumor-bearing CD8(+) T-cell-depleted animals. These data show that intracavitary IFN-beta gene therapy using an adenoviral vector provides strong CD8(+) T-cell-mediated antitumor effects in murine models of mesothelioma and suggest that this may be a promising strategy for the treatment of localized tumors such as mesothelioma or ovarian cancer in humans.

    Title Successful Experience with Simultaneous Lung Volume Reduction and Cardiac Procedures.
    Date August 2001
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Title Expanded Indications for Transcervical Thymectomy in the Management of Anterior Mediastinal Masses.
    Date August 2001
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Transcervical thymectomy (TCT) is an accepted though controversial approach for thymectomy in myasthenia gravis (MG). The suggestion of thymoma on computed tomography (CT) has been considered a contraindication to TCT. We sought to determine whether the indications for TCT could be safely expanded to include selected patients with thymomas as well as other types of anterior mediastinal masses. METHODS: Between January 1992 and September 1999, we performed 121 TCTs: 98 in patients with MG and 23 in patients without MG. The patients' records were retrospectively reviewed. RESULTS: Among the 98 MG patients, 28 had CT scans suspicious for thymoma. Of these, 14 had a thymoma pathologically. These were classified as stage I (5), stage II (8), and stage III (1). Five patients required extension of the incision for completion of the procedure. There have been no thymoma recurrences to date with a mean follow-up of 48 months (range 3 to 96 months). In the 23 patients without MG, 12 had new anterior mediastinal masses, 4 had a history of treated lymphoma, 1 had a history of treated germ cell tumor, and 6 had suspected mediastinal parathyroid adenoma. Diagnostic tissue was obtained in all patients undergoing the procedure for diagnosis, and in 4 of 6 patients, a parathyroid adenoma was successfully resected. CONCLUSIONS: Transcervical exploration and thymectomy offers a less invasive approach to the diagnosis and/or definitive treatment of selected anterior mediastinal masses. We suggest that it is appropriate to expand its use to several clinical scenarios beyond the typical indication of thymectomy in MG patients without thymoma.

    Title Inclusion of the Herpes Simplex Thymidine Kinase Gene in a Replicating Adenovirus Does Not Augment Antitumor Efficacy.
    Date July 2001
    Journal Gene Therapy
    Excerpt

    Replication-incompetent adenoviruses (Ad) carrying the herpes simplex thymidine kinase (HSVtk) gene have been used in a number of human cancer gene therapy trials, however transduction has generally been limited to a small minority of tumor cells. To solve this problem, replication-competent adenoviral vectors carrying transgenes such as HSVtk have been developed. However, contradictory evidence exists regarding the efficacy of these new vectors. Accordingly, we constructed and tested a replication-competent E3-deleted adenoviral vector containing the HSVtk suicide gene driven by the endogenous E3 promoter (Ad.wt.tk). This virus showed high level production of the HSVtk transgene and was more efficacious than a non-replicating virus in vitro, after injection into flank tumors, and against established intraperitoneal tumors. However, addition of ganciclovir (GCV) therapy to cells or tumor-bearing animals treated with the replicating vector containing the HSVtk suicide gene did not result in increased cell killing. Our results indicate that addition of HSVtk to a replicating Ad virus will not likely be useful in augmenting antitumor effects.

    Title A Pilot Study of Systemic Corticosteroid Administration in Conjunction with Intrapleural Adenoviral Vector Administration in Patients with Malignant Pleural Mesothelioma.
    Date July 2001
    Journal Cancer Gene Therapy
    Excerpt

    One of the primary limitations of adenoviral (Ad) -mediated gene therapy is the generation of anti-Ad inflammatory responses that can induce clinical toxicity and impair gene transfer efficacy. The effects of immunosuppression on these inflammatory responses, transgene expression, and toxicity have not yet been systematically examined in humans undergoing Ad-based gene therapy trials. We therefore conducted a pilot study investigating the use of systemic corticosteroids to mitigate antivector immune responses. In a previous phase I clinical trial, we demonstrated that Ad-mediated intrapleural delivery of the herpes simplex virus thymidine kinase gene (HSVtk) to patients with mesothelioma resulted in significant, but relatively superficial, HSVtk gene transfer and marked anti-Ad humoral and cellular immune responses. When a similar group of patients was treated with Ad.HSVtk and a brief course of corticosteroids, decreased clinical inflammatory responses were seen, but there was no demonstrable inhibition of anti -Ad antibody production or Ad-induced peripheral blood mononuclear cell activation. Corticosteroid administration also had no apparent effect on the presence of intratumoral gene transfer. Although limited by the small numbers of patients studied, our data suggest that systemic administration of steroids in the context of Ad-based gene delivery may limit acute clinical toxicity, but may not inhibit cellular and humoral responses to Ad vectors.

    Title Regulatory Cd4(+)cd25(+) T Cells in Tumors from Patients with Early-stage Non-small Cell Lung Cancer and Late-stage Ovarian Cancer.
    Date July 2001
    Journal Cancer Research
    Excerpt

    Immunosuppression may contribute to the progression of cancer. In this study we assessed the structural and functional status of T cells from tumor specimens obtained from patients with early stage non-small cell lung cancer and late-stage ovarian cancer. Although some groups have described structural alterations in the TCR in patients with other malignancies, we did not observe decreased expression of the CD3zeta subunit in the tumor-associated T cells. However, increased percentages of CD4(+)CD25(+) T cells were observed in the non-small cell lung cancer tumor-infiltrating lymphocytes and ovarian cancer tumor-associated lymphocytes. Furthermore, these CD4(+)CD25(+) T cells were found to secrete transforming growth factor-beta, consistent with the phenotype of regulatory T cells. Despite a generalized expression of lymphocyte activation markers in the tumor-associated T-cell populations, the CD8(+) T cells expressed low levels of CD25. To determine whether expression of CD25 could be restored on the CD8 cells, tumor-associated T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. After stimulation, nearly all of the CD8 T cells expressed CD25. Furthermore, despite the low levels of interleukin 2, IFN-gamma, and tumor necrosis factor-alpha secretion by the tumor-associated and peripheral blood T cells at baseline, stimulation with anti-CD3 and anti-CD28 monoclonal antibodies significantly increased the fraction of cells producing these cytokines. Thus, tumor-associated T cells from patients with early and late-stage epithelial tumors contain increased proportions of CD4(+)CD25(+) T cells that secrete the immunosuppressive cytokine transforming growth factor-beta. Furthermore, our results are consistent with previous reports showing impaired expression of CD25 on CD8(+) T cells in cancer patients. Finally, increased lymphocyte costimulation provided by triggering the CD28 receptor is able to increase CD25 expression and cytokine secretion in tumor-associated T cells. These observations provide evidence for the contribution of regulatory T cells to immune dysfunction in cancer patients.

    Title Trial of a Novel Synthetic Sealant in Preventing Air Leaks After Lung Resection.
    Date June 2001
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Postoperative air leaks are a major cause of morbidity after lung resections. This study was designed to evaluate the efficacy and safety of a new synthetic, bioresorbable surgical sealant in preventing air leaks after pulmonary resection. METHODS: In a multicenter trial, 172 patients undergoing thoracotomy were randomized intraoperatively in a 2:1 ratio to receive surgical sealant applied to sites at risk for air leak after standard methods of lung closure (treatment group) or to have standard lung closure only (control group). The primary outcome variable was the percentage of patients free of air leakage throughout hospitalization. Secondary outcome variables were the control of air leaks intraoperatively and the time to postoperative air leak cessation. Time to chest tube removal, time to hospital discharge, and safety outcomes were also evaluated. RESULTS: Air leaks were identified before randomization in 89 of 117 patients in the treatment group and in 39 of 55 patients in the control group. Application of the sealant resulted in control of air leaks in 92% of treated patients (p < or = 0.001). A significantly higher percentage of treated patients than control patients remained free of air leaks during hospitalization (39% versus 11%, p < or =0.001). The mean times to last observable air leak were 30.9 hours in the treatment group and 52.3 hours in the control group (p = 0.006). In the treatment group, trends were observed for reduced time to chest tube removal and earlier discharge. No significant difference was identified in postoperative morbidity and mortality between the two groups. CONCLUSIONS: Air leaks after lung resection occur in most patients. The application of this novel surgical sealant appears to be effective and safe in preventing postoperative air leaks.

    Title Bronchial Anastomotic Stricutre Caused by Ossification of an Intercostal Muscle Flap.
    Date June 2001
    Journal The Annals of Thoracic Surgery
    Excerpt

    We report a case of heterotopic ossification of a pedicled intercostal muscle flap that had been wrapped circumferentially around a bronchial sleeve anastomosis. This ossification caused severe bronchial stenosis and recurrent pneumonias. Stent insertion failed, and the patient ultimately required completion pneumonectomy. We recommended that caution be used when wrapping intercostal muscle around any important lumen.

    Title American Renaissance.
    Date April 2001
    Journal Michigan Health & Hospitals
    Excerpt

    A twenty-first century American renaissance is in the making. Powerful social, political, technological, economic and spiritual forces are converging to create new possibilities for our nation and our health care system. We are becoming a designer nation. An increasing percentage of our population are cultural creative with a mandate to create a healthier society that works for everyone.

    Title Lung Volume Reduction Surgery Restores the Normal Diaphragmatic Length-tension Relationship in Emphysematous Rats.
    Date March 2001
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    OBJECTIVE: Improved respiratory muscle function is a major effect of a lung volume reduction surgery. We studied length adaptation in rat diaphragmatic muscle in an attempt to elucidate the mechanism by which diaphragmatic function improves after this controversial operation. METHODS: We developed a model of elastase-induced emphysema and bilateral volume reduction through median sternotomy in rats. Five months after emphysema induction, maximum exchangeable lung volume was determined in intubated and anesthetized control animals and animals with emphysema. Costal diaphragmatic length was measured in vivo, and the length at which maximal twitch force is generated was determined on muscle strips in vitro. Also 5 months after elastase administration, another cohort underwent volume reduction or sham sternotomy. Five months after the operation, these animals were similarly studied. RESULTS: Lung volume was increased in emphysematous rats versus control rats (50.9 +/- 1.7 vs 45.4 +/- 1.3 mL, P =.001). Lung volume was decreased in emphysematous animals that had undergone volume reduction versus sham sternotomy (44.7 +/- 0.60 vs 49.4 +/- 1.0 mL, P =.001). In situ diaphragm length (1.99 +/- 0.04 vs 2.24 +/- 0.07 cm, P =.001) and the length at which maximal twitch force is generated (2.25 +/- 0.06 vs 2.48 +/- 0.09 cm, P =.038) were shorter in emphysematous than control animals. After volume reduction, in situ diaphragm length (2.13 +/- 0.06 vs 1.83 +/- 0.02 cm, P <.001) and the length at which maximal twitch force is generated (2.50 +/- 0.08 vs 2.27 +/- 0.06 cm, P =.013) were longer than in animals undergoing sham sternotomy. CONCLUSIONS: In this experimental model of emphysema and lung volume reduction surgery, emphysema shortens the length at which maximal twitch force is generated and shifts the diaphragmatic length-tension curve to lower lengths; volume reduction returns the length at which maximal twitch force is generated toward normal and shifts the diaphragmatic length-tension curve back to longer lengths. This restoration toward normal physiology may enable the improvement in diaphragmatic function seen after lung volume reduction surgery. The mechanism by which these length adaptations occur merits further investigation.

    Title Bilateral Versus Single Lung Transplantation for Chronic Obstructive Pulmonary Disease: Intermediate-term Results.
    Date January 2001
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: There is controversy regarding the transplant procedure of choice in chronic obstructive pulmonary disease. We reviewed our intermediate-term outcomes with single lung transplantation (SLT) versus bilateral lung transplantation (BLT). METHODS: We retrospectively reviewed 130 patients with chronic obstructive pulmonary disease: 84 underwent SLT, 46 BLT. The mean age was 51.1 +/- 1.2 years for those who underwent BLT and 56.2 +/- 0.7 years for those who underwent SLT (p < 0.0001). Male patients represented 65% of the BLT group and 46% of the SLT group (p = 0.04). Spirometry and 6-minute walk tests were obtained preoperatively and at 3- to 6-month intervals. Posttransplant survival and survival from time of onset of bronchiolitis obliterans syndrome were calculated by Kaplan-Meier method. The mean follow-up was 32.4 months. RESULTS: The 90-day mortality rate was 13.0% For BLT and 15.5% for SLT (p = 0.71). Actuarial survival rates at 1, 3, and 5 years were 82.6%, 74.6%, and 61.9% for BLT and 72.2%, 63.4%, and 57.4% for SLT; the favorable survival trend with BLT did not achieve statistical significance. There were no differences in preoperative spirometry or 6-minute walk tests. The improvements in forced expiratory volume in one second, forced vital capacity (FVC), and 6 MWT were significantly greater following BLT. The incidence of bronchiolitis obliterans syndrome was 22.4% in SLT and 22.2% in BLT; survival following onset of bronchiolitis obliterans syndrome was similar. CONCLUSIONS: For patients with chronic obstructive pulmonary disease, BLT is associated with superior lung function, exercise tolerance, and a trend toward enhanced survival. Younger candidates may be best suited for BLT. Given the limited donor lungs, SLT remains the preferred alternative for all other patients.

    Title Efficacy of Repeated Adenoviral Suicide Gene Therapy in a Localized Murine Tumor Model.
    Date January 2001
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Gene therapy using adenovirus to deliver herpes simplex virus thymidine kinase (Ad.HSVtk) followed by the administration of the prodrug ganciclovir has been an effective anticancer therapy in models of localized tumor (including malignant mesothelioma) and is currently being evaluated in clinical trials. To optimize this approach, we studied the effects of repeated injections of Ad.HSVtk in an animal model of localized tumor in both naive and immunized mice. METHODS: Immunocompetent animals with established abdominal tumor were treated with either one or three (given weekly) intraperitoneal injections of Ad.HSVtk (10(9) plaque-forming units) followed by daily ganciclovir and monitored for survival. Survival studies were also performed in mice previously immunized with adenovirus. RESULTS: Animals treated with multiple courses of Ad.HSVtk showed significantly improved survival versus singly injected animals and control animals with some long-term survivors in the multiple injected group. Preexisting neutralizing immunity did not diminish this survival advantage. CONCLUSIONS: Multiple treatments using an adenoviral vector to deliver HSVtk significantly improves survival in a murine intraperitoneal tumor model. The presence of preexisting neutralizing antibodies does not blunt this effect. Repeat Ad.HSVtk is a feasible approach and may be a useful strategy in human cancer gene therapy.

    Title Effect of Preexisting Anti-herpes Immunity on the Efficacy of Herpes Simplex Viral Therapy in a Murine Intraperitoneal Tumor Model.
    Date November 2000
    Journal Molecular Therapy : the Journal of the American Society of Gene Therapy
    Excerpt

    HSV-1716, a replicating nonneurovirulent herpes simplex virus type 1, has shown efficacy in treating multiple types of human tumors in immunodeficient mice. Since the majority of the human population has been previously exposed to herpes simplex virus, the efficacy of HSV-based oncolytic therapy was investigated in an immunocompetent animal tumor model. EJ-6-2-Bam-6a, a tumor cell line derived from h-ras-transformed murine fibroblast, exhibit a diffuse growth pattern in the peritoneal cavity of BALB/c mice and replicate HSV-1716 to titers observed in human tumors. An established intraperitoneal (ip) tumor model of EJ-6-2-Bam-6a in naive and HSV-immunized mice was used to evaluate the efficacy of single or multiple ip administrations of HSV-1716 (4 x 10(6) pfu/treatment) or of carrier cells, which are irradiated, ex vivo virally infected EJ-6-2-Bam-6a cells that can amplify the viral load in situ. All treated groups significantly prolonged survival versus media control with an approximately 40% long-term survival rate (cure) in the multiply treated, HSV-naive animals. Prior immunization of the mice with HSV did not significantly decrease the median survival of the single or multiply treated HSV-1716 or the carrier cell-treated groups. These studies support the development of replication-selective herpes virus mutants for use in localized intraperitoneal malignancies.

    Title Staging of Non-small Cell Lung Carcinoma. American College of Radiology. Acr Appropriateness Criteria.
    Date November 2000
    Journal Radiology
    Title Postoperative Radiotherapy in Non-small Cell Lung Cancer. American College of Radiology. Acr Appropriateness Criteria.
    Date November 2000
    Journal Radiology
    Title Non-small Cell Lung Cancer, Nonsurgical, Aggressive Therapy. American College of Radiology. Acr Appropriateness Criteria.
    Date November 2000
    Journal Radiology
    Title Neoadjuvant Therapy for Marginally Resectable (clinical N2), Non-small Cell Lung Cancer. American College of Radiology. Acr Appropriateness Criteria.
    Date November 2000
    Journal Radiology
    Title Non-aggressive, Non-surgical Treatment of Inoperable Non-small Cell Lung Cancer (nsclc). American College of Radiology. Acr Appropriateness Criteria.
    Date November 2000
    Journal Radiology
    Title Follow-up of Non-small Cell Lung Cancer. American College of Radiology. Acr Appropriateness Criteria.
    Date November 2000
    Journal Radiology
    Title Reality and Meta-analyses.
    Date October 2000
    Journal Chest
    Title Risk Analysis for Thoracoscopic Lung Volume Reduction: a Multi-institutional Experience.
    Date August 2000
    Journal European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery
    Excerpt

    OBJECTIVE: Most reports of thoracoscopic lung volume reduction (TLVR) are relatively small and early experiences from a single institution, factors which limit both the statistical validity and the applicability to the population at large. In order to address these shortcomings we undertook an analysis of the TLVR experience at five separate institutions to assess operative morbidity and identify predictors of mortality. METHODS: Questionnaires were sent to four groups of surgical investigators at five institutions actively performing TLVR. Data was requested regarding preoperative, operative and postoperative parameters. Twenty-five potential predictors of mortality were analyzed and seven proved to be at least marginally significant (P<0.10). These parameters were entered into a stepwise logistic regression analysis to identify independent predictors. RESULTS: The 682 patients (415 males, 267 females, mean age 64.0 years) underwent unilateral (410) or bilateral (272) TLVRs. Overall, operative mortality was 6% with half of the deaths resulting from respiratory causes. The remaining patients were discharged to home (88%), a rehabilitation facility (4%) or a ventilator facility (2%). There were 25 perioperative factors chosen representing clinically important indices such as spirometry, oxygenation, functional status, clinical and demographic variables. Univariate analysis identified seven variables as predictors of mortality (P<0.10) and these were entered into a stepwise logistic regression analysis. Only age, 6-min walk, gender (male 8%, female 3% mortality) and the procedure performed (unilateral 4.6%, bilateral 8%) were independent predictors while preoperative steroid therapy, preoperative oxygen administration, and time since smoking cessation dropped out of the model. The specific institution, learning curve (early vs. late experience), type of lung disease, spirometric indices and predicted maximum VO(2) were not significant predictors. CONCLUSION: This experience suggests that unilateral and bilateral lung volume reduction procedure can be performed with acceptable morbidity and mortality. Although age, gender, exercise capacity and the procedure performed are all independent predictors of mortality, the risk of operative death did not appear excessive in this fragile patient subset.

    Title Waving Goodbye to Healthcare. Execs Are Being Driven Away; It May Be Time to Take a Break Before the Industry Breaks You.
    Date August 2000
    Journal Modern Healthcare
    Title Lobectomy with Tangential Pulmonary Artery Resection Without Regard to Pulmonary Function.
    Date August 2000
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Non-small cell carcinoma of the lung invading the pulmonary artery (PA) has traditionally been treated by pneumonectomy. Although PA resection and reconstruction (PAR) has begun to gain acceptance, previous series of PAR by the simplest technique of tangential excision and primary repair have been unfavorable. We have maintained a policy of performing PAR preferentially whenever anatomically feasible, and usually this has been possible by tangential excision and primary repair. This study sought to determine if this approach is sound. METHODS: Retrospective clinical and pathologic review. RESULTS: Thirty-three PARs were performed from 1992 to 1999. The patients, followed 6 to 65 months (mean 25), were aged 36 to 80 years (mean 61), and their tumors were pathologic stage IB (n = 7), IIB (n = 13), IIIA (n = 9), and IIIB (n = 4). The mean preoperative forced expiratory volume in 1 second was 70% predicted. The procedures included 14 bronchial sleeve lobectomies with PAR and 19 simple lobectomies with PAR. The PARs were performed without heparinization and included 19 tangential excisions with primary closure, 11 larger tangential excisions with pericardial patch closure, and 3 sleeve resections. There were no operative deaths and 2 (6.1%) early major complications, all unrelated to the PAR. Thirteen patients (39%) had early minor complications. Four-year Kaplan-Meier survival was 48.3% for stages I/II and 45% for stage III. Ipsilateral, central, intrathoracic recurrence occurred in 3 patients (9.1%). CONCLUSIONS: These data are not dramatically different from those reported for standard resections. Although the numbers are small, the results suggest that lobectomy with PAR by tangential excision is an acceptable alternative to pneumonectomy whenever anatomically possible.

    Title Multi-attenuated Herpes Simplex Virus-1 Mutant G207 Exerts Cytotoxicity Against Epithelial Ovarian Cancer but Not Normal Mesothelium and is Suitable for Intraperitoneal Oncolytic Therapy.
    Date August 2000
    Journal Cancer Gene Therapy
    Excerpt

    Recombinant strains of herpes simplex virus-1 (HSV-1) harboring mutations in the infected cell product (ICP)34.5 region lose their neurovirulence and replicate more efficiently in dividing tumor cells than stationary cells, becoming replication-selective oncolytic agents. Additional mutation of the ICP6 gene, which encodes ribonucleotide reductase, further impairs the ability of HSV-1 mutants to replicate in normal cells, enhancing tumor selectivity. The present study investigated the effect of HSV-G207, a recombinant HSV-1 lacking ICP34.5 and ICP6, against epithelial ovarian cancer (EOC) in vitro and in vivo in a mouse xenograft model. To assess the selectivity of multimutated HSV-G207 against malignant cells, HSV-G207 and wild-type HSV-F were comparatively tested against normal human peritoneal mesothelial cells and EOC cells in vitro. HSV-G207 infected both EOC cells and mesothelial cells; however, unlike EOC cells, mesothelial cells provided a poor substrate for replication of HSV-G207. In contrast to wild-type HSV-F, HSV-G207 exerted a potent oncolytic effect on EOC cells but spared normal mesothelial cells in vitro. Primary EOC cells were more sensitive to the virus than established EOC cell lines. A single intraperitoneal injection of HSV-G207 resulted in a significant reduction in tumor volume and tumor spread in vivo. HSV-G207 was shown to penetrate deeply within tumor nodules and caused no apparent intraperitoneal toxicity. Oncolytic therapy with multimutated replication-restricted HSV may offer a novel approach in the treatment of EOC.

    Title Comparison of Clinical Results for Unilateral and Bilateral Thoracoscopic Lung Volume Reduction.
    Date July 2000
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: It is widely believed that bilateral thoracoscopic lung volume reduction (BTLVR) yields superior results when compared with unilateral thoracoscopic lung volume reduction (UTLVR) with regard to spirometry, functional capacity, oxygenation and quality of life results. METHODS: To address these issues, we compared the results of patients undergoing UTLVR (N = 338 patients) and BTLVR (N = 344 patients) from 1993 to 1998 at five institutions. Follow-up data were available on 671 patients (98.4%) between 6 and 12 months after surgery, and a patient self-assessment was obtained at a mean of 24 months. RESULTS: It was found that BTLVR provides superior improvement in measured postoperative percent change in FEV1 (L) (UTLVR 23.3% +/- 55.3 vs BTLVR 33% +/- 41, p = 0.04), FVC(L) (10.5% +/- 31.6 vs 20.3% +/- 34.3, p = 0.002) and RV(L) (-13% +/- -22 vs -22% +/- 17.9, p = 0.015). BTLVR also provides a slight improvement over UTLVR in patient's perception regarding improved quality of life (UTLVR 79% vs BTLVR 88%, p = 0.03) and dyspnea relief (71% vs 61%, p = 0.03). There was no difference in mean changes in PO2 (mm Hg) (UTLV 4.5 +/- 12.3 vs BTLVR 4.9 +/- 13.3, p = NS), 6-minute walk (UTLVR 26% +/- 66.1 vs BTLVR 31% +/- 59.6, p = NS) or decreased oxygen utilization (UTLVR 78% vs BTLVR 74%, p = NS). CONCLUSIONS: These data suggest that both UTLVR and BTLVR yield significant improvement, but the results of BTLVR seem to be superior with regard to spirometry, lung volumes, and quality of life.

    Title Cationic Lipid:bacterial Dna Complexes Elicit Adaptive Cellular Immunity in Murine Intraperitoneal Tumor Models.
    Date June 2000
    Journal Cancer Research
    Excerpt

    Previous studies with a mycobacterial heat shock protein (hsp-65) have demonstrated some efficacy using cationic liposome-mediated gene transfer in murine i.p. sarcoma models. To further analyze the efficacy of hsp-65 immunotherapy in clinically relevant models of localized cancer, immunocompetent mice bearing i.p. murine mesothelioma were treated with four i.p. doses of a cationic lipid complexed with plasmid DNA (pDNA) containing hsp65, LacZ, or a null plasmid. We observed >90% long-term survival (median survival, 150 days versus approximately 25 days, treated versus saline control, respectively) in a syngeneic, i.p. murine mesothelioma model (AC29). Long-term survivors were observed in all groups treated with lipid complexed with any pDNA. Lipid alone or DNA alone provided no demonstrable survival advantage. In a more aggressive i.p. model of mesothelioma (AB12), we observed >40% long-term survival in groups treated with lipid:pDNA complexes, again irrespective of the transgene. To ask whether these antitumor effects had led to an adaptive immune response against the tumor cell, we rechallenged long-term survivors in both murine models s.c. with the parental tumor cell line. Specific, long-lasting systemic immunity against the tumor was readily demonstrated in both models (AB12 and AC29). Consistent with these results, splenocytes from long-term survivors specifically lysed the parental tumor cell lines. Depleting the CD8+ T-cells from the splenocyte pool eliminated this lytic activity. Lipid:pDNA treatment of athymic, SCID, and SCID/Beige mice bearing a murine i.p. mesothelioma (AC29) resulted in only a slight survival advantage, but there were no long-term survivors. Treatment of immunocompetent mice depleted of specific immune effector cells demonstrated roles for CD8+ and natural killer cells. Although the exact mechanism(s) responsible for these antitumor effects is unclear, the results are consistent with roles for both innate and adaptive immune responses. An initial tumor cell killing stimulated by cationic lipid:pDNA complexes appears to be translated into long-term, systemic immunity against the tumor cell. These results are the first to demonstrate that adaptive immunity against a tumor cell can be induced by the administration of lipid:pDNA complexes. Multiple administrations of cationic lipid complexed with pDNA lacking an expressed transgene could provide a promising generalized immune-mediated modality for treating cancer.

    Title The Academic Surgeon and Industry.
    Date May 2000
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    Academic surgeons should be aware of the tremendous potential that exists to partner with private companies on projects relating either to basic or clinical research. This is particularly timely now because many of these companies are experiencing unprecedented growth and market valuation. The development of these relationships requires knowing who to deal with as well as how to negotiate. Most academic medical centers have individuals who have expertise in developing sponsored research agreements, and young investigators should take advantage of this expertise.

    Title Lung Volume Reduction Surgery.
    Date May 2000
    Journal Current Problems in Surgery
    Title Spirituality and the Physician Executive.
    Date April 2000
    Journal Physician Executive
    Excerpt

    The "s" word can now be spoken without flinching in health care organizations. Spirituality is becoming a common topic in management conferences around the world. Many U.S. corporations are recognizing the role of spirituality in creating a new humanistic capitalism that manages beyond the bottom line. Spirituality refers to a broad set of principles that transcend all religions. It is the relationship between yourself and something larger, such as the good of your patient or the welfare of the community. Spirituality means being in right relationship to all that is and understanding the mutual interdependence of all living beings. Physician executives should be primary proponents of spirituality in their organizations by: Modeling the power of spirituality in their own lives; integrating spiritual methodologies into clinical practice; fostering an integrative approach to patient care; encouraging the organization to tithe its profits for unmet community health needs; supporting collaborative efforts to improve the health of the community; and creating healing environments.

    Title General Thoracic Surgery.
    Date February 2000
    Journal Journal of the American College of Surgeons
    Title Fatal Hyperammonemia After Orthotopic Lung Transplantation.
    Date February 2000
    Journal Annals of Internal Medicine
    Excerpt

    BACKGROUND: A case of fatal hyperammonemia complicating orthotopic lung transplantation was previously reported. OBJECTIVE: To describe the incidence, clinical features, and treatment of hyperammonemia associated with orthotopic lung transplantation. DESIGN: Retrospective cohort analysis. SETTING: Academic medical center and lung transplantation center in Philadelphia, Pennsylvania. PATIENTS: 145 sequential adult patients who underwent orthotopic lung transplantation. MEASUREMENTS: Plasma ammonium levels. RESULTS: Six of the 145 patients who had had orthotopic lung transplantation developed hyperammonemia, all within the first 26 days after transplantation. The 30-day post-transplantation mortality rate was 67% for patients with hyperammonemia compared with 17% for those without hyperammonemia (P = 0.01). Development of major gastrointestinal complications (P = 0.03), use of total parenteral nutrition (P < 0.001), and lung transplantation for primary pulmonary hypertension (P = 0.045) were associated with hyperammonemia. CONCLUSIONS: Hyperammonemia is a potentially fatal event occurring after orthotopic lung transplantation. It is associated with high nitrogen load, concurrent medical stressors, primary pulmonary hypertension, and hepatic glutamine synthetase deficiency.

    Title Long-term Survival After Thoracoscopic Lung Volume Reduction: a Multiinstitutional Review.
    Date January 2000
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: It has been suggested that bilateral thoracoscopic lung volume reduction (BTLVR) yields significantly better long-term survival than unilateral thoracoscopic lung volume reduction (UTLVR). METHODS: All perioperative data were collected at the time of the procedure. Follow-up data were obtained during office visits or by telephone. RESULTS: A total of 673 patients underwent thoracoscopic LVR: 343 had either simultaneous or staged BTLVR and 330, UTLVR. As of July 1998, follow-up was available on 667 (99%) of the 673 patients with a mean follow-up of 24.3 months. The patients in the BTLVR group were significantly younger (62.6+/-8.0 years versus 65.4+/-8.1 years; p < 0.0001), had a higher preoperative arterial oxygen tension (69.7+/-12 mm Hg versus 65.3+/-11 mm Hg; p < 0.0001), and had a superior preoperative 6-minute walk performance (279.9+/-93.6 m [933+/-312 feet] versus 244.5+/-101.4 m [815+/-338 feet] p < 0.0001). There was no difference in the operative mortality rate between the two groups (UTLVR, 5.1%, and BTLVR, 7%). Actuarial survival rates for the UTLVR group at 1 year, 2 years, and 3 years were 86%, 75%, and 69%, respectively versus 90%, 81%, and 74%, respectively, for the BTLVR group (p = not significant). CONCLUSIONS: Contrary to previous reports, survival after BTLVR was not superior to that after UTLVR even though the former group appeared to have a lower risk preoperatively because of younger age, higher arterial oxygen tension, more advantageous anatomy, and better functional status. Despite thoracoscopic LVR, the actuarial mortality rate approached 30% at 3 years, and this calls into question whether this procedure offers any survival advantage to patients with end-stage emphysema.

    Title Combined Therapy with Chemotherapeutic Agents and Herpes Simplex Virus Type 1 Icp34.5 Mutant (hsv-1716) in Human Non-small Cell Lung Cancer.
    Date January 2000
    Journal Human Gene Therapy
    Excerpt

    A replication-selective herpes simplex virus type 1 ICP34.5 mutant (HSV-1716) has shown efficacy both in vitro and in vivo against human non-small cell lung cancer (NSCLC) cell lines but complete eradication of tumor has not been accomplished with a single viral treatment in our murine xenograft models. Therefore, strategies to enhance the efficacy of this treatment were investigated. We determined the oncolytic activity of HSV-1716 in NCI-H460 cells in combination with each of four chemotherapeutic agents: mitomycin C (MMC), cis-platinum II (cis-DDP), methotrexate (MTX), or doxorubicin (ADR). Isobologram analysis was performed to evaluate the interaction between the viral and chemotherapeutic agents. The oncolytic effect of HSV-1716 in combination with MMC was synergistic in two of five NSCLC cell lines. In the other three cell lines, the combined effect appeared additive. No antagonism was observed. The in vivo effect of this combination was then examined in a murine xenograft model. NCI-H460 flank tumors were directly injected with HSV-1716 (4 x 106 PFU) followed by intravenous MMC administration (0.17 mg/kg) 24 hr later. After 3 weeks, the mean tumor weight in the combined treatment group was significantly less than either individual treatment in an additive manner. The synergistic dose of MMC neither augmented nor inhibited viral replication in vitro and HSV-1716 infection did not upregulate DT-diaphorase, which is the primary enzyme responsible for MMC activation. In summary, the combination of HSV-1716 with common chemotherapeutic agents may augment the effect of HSV-based therapy in the treatment of NSCLC.

    Title Looking Ahead Through the Eyes of the Pros.
    Date December 1999
    Journal Healthcare Alabama / Alabama Hospital Association
    Title Non-small Cell Lung Cancer: Prognostic Factors in Patients Treated with Surgery and Postoperative Radiation Therapy.
    Date December 1999
    Journal Radiology
    Excerpt

    PURPOSE: To determine survival outcomes, to identify adverse prognostic factors for relapse, and to compare American Joint Commission on Cancer (AJCC) staging systems in patients with non-small cell lung cancer (NSCLC) treated with surgery and postoperative radiation therapy. MATERIALS AND METHODS: Between 1980 and 1995, 211 patients with NSCLC underwent surgery and postoperative radiation therapy. Surgery consisted of wedge resection (12.5%), lobectomy (67.8%), or pneumonectomy (19.7%). Pathologic stages (1992 AJCC) included I (n = 22), II (n = 70), IIIA (n = 104), and IIIB (n = 12). Indications for radiation therapy included compromised margins (n = 81) and/or positive mediastinal nodes (n = 55). Prognostic factors were identified by using univariate and multivariate models. RESULTS: Overall 3-year survival for patients with stage I, II, and IIIA cancer was 58.9%, 44.1%, and 43.2%, respectively. Older age (P = .008), male sex (P = .021), large primary tumor (P = .004), and multiple positive mediastinal nodes (P = .046) were associated with worse rates of survival. Actuarial risk of local-regional relapse (36 patients) was 21.4% at 3 years. In a multivariate model, use of wedge resection (P = .001), positive margins (P = .010), and larger pathologic tumor (P = .059) were risk factors for local-regional recurrence. Actuarial rate of distant failure was 55.2% at 3 years. CONCLUSION: Local-regional control can be achieved with surgery and radiation therapy in approximately 80% of patients; however, the rate of distant metastasis remains unacceptably high. Other variables, such as multiple positive nodes, may serve to identify patients at higher risk for relapse and poorer survival. Methods for improving treatment outcomes in these patients should be pursued.

    Title Oncolytic Therapy Using a Mutant Type-1 Herpes Simplex Virus and the Role of the Immune System.
    Date December 1999
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Herpes simplex virus (HSV)-1716, a replication-restricted herpes simplex virus type 1, has shown efficacy as an oncolytic treatment for central nervous system tumors, breast cancer, ovarian cancer, and malignant mesothelioma. We evaluated the efficacy of HSV-1716 in a murine lung cancer model, Lewis lung carcinoma. METHODS: Lewis lung carcinoma cells were infected with HSV-1716 and implanted in the flanks of mice at varying ratios of infected to uninfected cells. Tumor burden was assessed by measurement of the weight of the tumor nodule. The role of the immune system was examined by performing experiments in both immunocompetent and SCID mice. Tumors were implanted in the opposite flank to evaluate the vaccine effect. RESULTS: In immunocompetent and SCID animals, ratio of 1:10 (infected-to-uninfected) cells completely prevented tumor formation and ratio of 1:100 suppressed tumor growth. Established tumors at a distant site in the groups receiving HSV-1716 infected cells showed no difference in size versus control, suggesting absence of a vaccine effect. CONCLUSIONS: We conclude that HSV-1716 may provide a oncolytic therapy for lung cancer even in the absence of immune system induction and a "carrier" cell could potentially deliver this vector.

    Title Management of Chylothorax by Percutaneous Catheterization and Embolization of the Thoracic Duct: Prospective Trial.
    Date November 1999
    Journal Journal of Vascular and Interventional Radiology : Jvir
    Excerpt

    PURPOSE: To prospectively assess the efficacy of percutaneous transabdominal thoracic duct catheterization and embolization in the management of patients with high-output chylothoracic effusions. MATERIALS AND METHODS: Eleven consecutive patients (four women and seven men; mean age, 53 years) were referred with chylothorax secondary to esophagectomy (n = 4), lobectomy (n = 1), lung transplant (n = 1), coronary artery bypass (n = 1), aortic graft (n = 2), lymphangioleiomyomatosis (n = 1), and gunshot wound (n = 1). Two patients were brought by ambulance and referred back to their hospital on the same day. Pedal lymphography was used to opacify the cisterna chyli or major retroperitoneal lymphatic trunks. When patent, these were punctured under local anesthesia with a fine needle and the thoracic duct was catheterized over a microguide wire with use of a 3-F catheter; the duct was embolized with platinum coils. Patients were followed up for decrease in thoracic drainage output and morbidity. RESULTS: There were no retroperitoneal ducts suitable for catheterization in six patients because of previous abdominal surgery, trauma, or lymphangioleiomyomatosis; the thoracic duct was successfully catheterized in five patients, a 45% technical success rate. Thoracic duct embolization was performed in four patients, with cure of effusion in two. In the other two patients, one with lymphangioleiomyomatosis and the other with nonchylous pleural fluid, continued effusion was successfully treated by means of pleurodesis. Of two patients with previous thoracic duct ligation, one was found to have the duct incompletely tied. The authors were surprised to find that previous major abdominal surgery, chronic aortic dissection, and lymphangioleiomyomatosis could obliterate major retroperitoneal lymphatic ducts and the cisterna chyli. Percutaneous study of the thoracic duct with aqueous contrast medium was more sensitive than lymphography with iodinated oil. There was no morbidity. CONCLUSIONS: Catheterization of the thoracic duct was possible in all patients who had patent major retroperitoneal lymphatic trunks. Thoracic duct embolization was curative in patients with demonstrable duct leakage. Previous abdominal surgery, aortic dissection, and lymphangioleiomyomatosis can lead to silent occlusion of retroperitoneal lymphatic trunks. Percutaneous thoracic duct catheterization and embolization is safe and can replace surgical ligation in some patients.

    Title Thoracoscopic Lung Biopsy. Five Commonly Asked Questions About Video-assisted Thoracic Surgery.
    Date November 1999
    Journal Postgraduate Medicine
    Excerpt

    VATS has proved to be an extremely useful diagnostic tool. Perhaps its most frequent application has been in lung biopsy to diagnose indeterminate solitary pulmonary nodules and interstitial infiltrates. In many institutions, VATS procedures have largely replaced previous methods of attempting to establish the nature of a solitary pulmonary nodule. In ambulatory patients with indeterminate infiltrates, VATS techniques have prompted earlier referral to establish a tissue diagnosis, with apparently decreased morbidity. VATS has clearly found a place in the modern practice of thoracic surgery and is likely to play an ever-increasing role in the management of diseases of the chest.

    Title Hyperacute Rejection of a Pulmonary Allograft. Immediate Clinical and Pathologic Findings.
    Date October 1999
    Journal American Journal of Respiratory and Critical Care Medicine
    Excerpt

    The clinical and pathologic findings seen in hyperacute rejection are well documented in renal and cardiac allografts. We describe the second case of hyperacute rejection in a pulmonary allograft and detail the immediate clinicopathologic findings. The patient underwent a single lung transplant for severe COPD with postoperative course complicated by acute rejection and graft failure. Eleven days later, the patient underwent a second transplant with intra-operative course complicated by rapid pulmonary edema and copious production of frothy, pink fluid from the bronchial orifice of the allograft followed by death within four hours of anastomoses. Intraoperative biopsy and autopsy demonstrated platelet/fibrin thrombi, marked interstitial neutrophilia, alveolar edema, and antibody deposition on the endothelial surface and vasculature walls. Prior to the first transplant, the patient's serum had 0% panel reactive antibody and was crossmatch compatible with the first allograft. The patient's serum prior to the second transplant contained cross-reacting antibodies to the donor's B and T lymphocytes. The immediate clinical findings in this case are similar to the findings in a previously reported case. This report is the first documentation of the immediate pathologic features of hyperacute rejection in a lung allograft which are similar to those seen with other organ allografts.

    Title Use of Carrier Cells to Deliver a Replication-selective Herpes Simplex Virus-1 Mutant for the Intraperitoneal Therapy of Epithelial Ovarian Cancer.
    Date September 1999
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    Epithelial ovarian cancer (EOC) remains localized within the peritoneal cavity in a large number of patients, lending itself to i.p. approaches of therapy. In the present study, we investigated the effect of replication-selective herpes simplex virus-1 (HSV-1) used as an oncolytic agent against EOC and the use of human teratocarcinoma PA-1 as carrier cells for i.p. therapy. HSV-1716, a replication-competent attenuated strain lacking ICP34.5, caused a direct dose-dependent oncolytic effect on EOC cells in vitro. A single i.p. administration of 5 x 10(6) plaque-forming units resulted in a significant reduction of tumor volume and tumor spread and an increase in survival in a mouse xenograft model. PA-1 cells supported HSV replication in vitro and bound preferentially to human ovarian carcinoma surfaces compared with mesothelial surfaces in vitro and in vivo. In comparison with the administration of HSV-1716 alone, irradiated PA-1 cells, infected at two multiplicities of infection with HSV-1716 and injected i.p. at 5 x 10(6) cells/animal, led to a significant tumor reduction in the two models tested and the significant prolongation of mean survival in one model. Histological evaluation revealed extensive necrosis in tumor areas infected by HSV-1716. Immunohistochemistry against HSV-1 revealed areas of viral infection within tumor nodules, which persisted for several weeks after treatment. Administration of HSV-infected PA-1 carrier cells resulted in larger areas of tumor infected by the virus. Our results indicate that replication-competent attenuated HSV-1 exerts a potent oncolytic effect on EOC, which may be further enhanced by the utilization of a delivery system with carrier cells, based on amplification of the viral load and possibly on preferential binding of carrier cells to tumor surfaces.

    Title Cadherin and Catenin Expression in Normal Human Bronchial Epithelium and Non-small Cell Lung Cancer.
    Date September 1999
    Journal Lung Cancer (amsterdam, Netherlands)
    Excerpt

    Cadherins are transmembrane cell adhesion molecules (CAMS) that mediate cell-cell interactions and are important for maintenance of epithelial cell integrity. This function is dependent on an indirect interaction between the cytoplasmic domain of the cadherin molecule with three cytoplasmic proteins known as alpha-, beta-, and gamma-catenin (-cat). Growing evidence suggests that alterations in cadherin or catenin expression or function may be important to the development of an invasive or metastatic phenotype. Immunohistochemical techniques were used to study the expression of the two major epithelial cadherins, E-cadherin (E-cad) and P-cadherin (P-cad) as well as alpha- and gamma-cat in normal bronchial epithelium and in a series of carefully TMN-staged pulmonary adenocarcinomas (n = 21) and squamous cell carcinomas (n = 7). The cadherin profile of normal pseudostratified bronchial epithelium was heterogeneous. Basilar cells strongly expressed P-cad, alpha- and gamma-cat, while columnar cells moderately expressed E-cad, alpha- and gamma-cat. In contrast to other epithelial tumors, E-cad on non-small cell lung carcinomas was actually upregulated, however, a decrease in P-cad expression was noted in 68%. At least one cadherin or catenin was downregulated, compared to normal bronchial epithelium, in 82% of tumors examined. With the exception of an association between loss of P-cad expression and poorly differentiated state, changes in cadherin and catenin expression levels were not significantly correlated to tumor stage, cell type, or nodal status. These findings illustrate that alteration of expression of cadherins and catenins are often found in non-small cell lung carcinoma when compared to the progenitor bronchial epithelium, and may play a role in the development of the malignant phenotype.

    Title Prognostic Value of Fdg Pet Imaging in Malignant Pleural Mesothelioma.
    Date September 1999
    Journal Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
    Excerpt

    Despite several attempts at treating malignant pleural mesothelioma with various modalities, mortality remains high, with median survival between 12 and 18 mo. This disease may have a highly variable clinical course, with occasional long-term survivors. The purpose of this study was to assess whether tumor metabolic activity, as assessed by fluorodeoxyglucose (FDG) PET imaging, correlates inversely with survival. METHODS: Twenty-eight patients with suspected mesothelioma underwent FDG PET scanning between September 1995 and May 1997. A diagnosis of mesothelioma was confirmed in 22. Fully corrected scans with attenuation correction of the entire chest were available in 17 patients with sufficient follow-up for survival analysis. Standardized uptake values (SUVs) were determined from the most active tumor site in each patient. RESULTS: Seven patients died during follow-up, at a median period of 5.3 mo after FDG PET scanning. Follow-up information was available on the remaining 10 patients for a median period of 15.6 mo after the PET study. The mean SUV of the deceased patients was 6.6+/-2.9, compared with 3.2+/-1.6 among the combined survivors. The deceased patients had tumor SUVs that were highly correlated with duration of survival after the PET study (r = 0.87, P < 0.05). The cumulative survival estimate by the Kaplan-Meier product limit method was 0.17 at 12 mo for the patients with tumor SUVs greater than the median value and 0.86 for those with lower SUVs. The survival distribution of the high SUV group showed significantly shorter survivals compared with the low SUV group (P < 0.01). CONCLUSION: Patients with highly active mesotheliomas on FDG PET imaging have a poor prognosis. High FDG uptake in these tumors indicates shorter patient survival.

    Title Advances in the Treatment of Malignant Pleural Mesothelioma.
    Date September 1999
    Journal Chest
    Excerpt

    Malignant pleural mesothelioma is a neoplasm that is commonly fatal and for which there are no widely accepted curative approaches. Mesothelioma is unresponsive to most chemotherapy and radiotherapy regimens, and it typically recurs even after the most aggressive attempts at surgical resection. Multimodality approaches have been of some benefit in prolonging survival of very highly selected subgroups of patients, but they have had a relatively small impact on the majority of the patients diagnosed with this disease. As the incidence of pleural mesothelioma peaks in the United States and Europe over the next 10 to 20 years, new therapeutic measures will be necessary. This review will discuss the roles of chemotherapy, radiotherapy, surgery, and combined modality approaches in the treatment of pleural mesothelioma, as well as scientific advances made in the past decade that have led to the development of experimental techniques, such as photodynamic therapy, immunotherapy, and gene therapy, that are currently undergoing human clinical trials. These promising new avenues may modify the therapeutic nihilism that is rampant among clinicians dealing with mesothelioma.

    Title Is Meta-analysis Really Meta-physics?
    Date September 1999
    Journal Chest
    Title The Evaluation of Adenoviral P53-mediated Bystander Effect in Gene Therapy of Cancer.
    Date August 1999
    Journal Cancer Gene Therapy
    Excerpt

    Because many tumors have mutated p53, one potential strategy proposed for cancer gene therapy is the introduction of the wild-type p53 gene into tumor cells. One puzzling aspect of this approach is that currently available gene transfer protocols result in a small percentage of tumor cells being transduced in vivo, thus implicating a "bystander effect" to achieve therapeutic efficacy. Because bystander effects in the context of p53-mediated gene therapy have not been well characterized, we evaluated the role of in vitro and in vivo bystander effects of adenovirally delivered p53 (AdWTp53). Using human tumor cell lines that did not express p53 protein but were infectible with adenovirus and showed sensitivity to p53-mediated apoptosis, we were unable to demonstrate an AdWTp53-mediated in vitro bystander effect, despite seeing strong bystander effects when cells were infected with an adenovirus containing the suicide gene herpes simplex virus thymidine kinase and treated with ganciclovir. In contrast, in vivo flank mixing studies using one of these cell lines showed a weak but significant p53-mediated bystander effect (a 40% inhibition of tumor growth). This bystander effect translated into a small survival advantage in an established intraperitoneal tumor model when tumor burden was low at the time of viral instillation. The survival advantage was lost, however, when tumor burden was increased. This study indicates that treatment of human tumors using AdWTp53 may be possible; however, because of the weak bystander effect in vivo, effective treatment will likely require a large percentage of tumor cells to be transduced.

    Title Management of Exsanguinating Hemoptysis During Cardiopulmonary Bypass.
    Date June 1999
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Large-volume hemoptysis during cardiopulmonary bypass is an infrequent, but life-threatening event. Rapid airway clearance and control are the primary prerequisites for successful management. METHODS: The cases of 3 patients with different sources of exsanguinating hemoptysis during cardiopulmonary bypass managed initially with rigid bronchoscopy were reviewed. RESULTS: In all patients, airway control was rapidly established and weaning from cardiopulmonary bypass CPB was accomplished. Two patients survived the operative procedure. The other patient died in the operating room of unremitting bilateral pulmonary hemorrhage. CONCLUSIONS: Major hemoptysis during cardiopulmonary bypass is best dealt with initially by rapid airway control and cessation of bypass in an expeditious manner. An algorithm for suggested management is provided. The rigid bronchoscope is the optimal tool for initial management and it should always be available. Definitive treatment is determined by the cause and the persistence of hemorrhage once these maneuvers have been performed.

    Title The Physician Executive in a Changing World.
    Date May 1999
    Journal Physician Executive
    Excerpt

    Physicians are losing their historic franchise as sole and primary providers of medical care. In addition to eroding moral and scientific authority, physicians are also losing income and status. It is no wonder that physicians are retrenching--confused and angry about the increasing marginalization of their profession and about society's changing expectations. Physicians are caught in a transition zone between the world that was and the one that will soon be. This is destabilizing and causes great anxiety. Rather than being buffeted by changing social and cultural definitions of health care, physicians must become proactively involved in the future of their profession. Physicians can only do this by offering a better mental model of health, medicine, and the community. This cannot be a defensive retreat from engagement. Rather, it must be an imaginative vision, vigorously set forth--a vision that will enlist the support of all constituencies involved in the effort to improve the health and well-being of all members of our society. The physician executive needs to work with physicians to orchestrate this effort to create a new vision of health in the 21st century.

    Title Evaluation of an E1e4-deleted Adenovirus Expressing the Herpes Simplex Thymidine Kinase Suicide Gene in Cancer Gene Therapy.
    Date May 1999
    Journal Human Gene Therapy
    Excerpt

    Studies with first-generation adenoviral vectors have uncovered limitations that include finite transgene persistence, potential hepatotoxicity, and contamination with replication-competent adenovirus (RCA). To address these limitations within the context of cancer suicide gene therapy, a new adenoviral vector was developed containing the herpes simplex virus type 1 thymidine kinase (HSV tk) gene inserted in the E1 region of a recombinant vector containing deletions in the E1 and E4 regions of the Ad5 genome. The HSV tk minigene was placed under transcriptional control of a Rous sarcoma virus (RSV) promoter. This new E1E4-deleted vector was compared with the first-generation E1E3-deleted Ad.RSVtk vector. Generation of replication-competent adenovirus during production was eliminated. Using semiquantitative immunoblotting, the two vectors produced equivalent amounts of the expected 44-kDa tk-encoded protein in three different cell lines tested. The ability of the E1E4-deleted vector to sensitize tumor cells to ganciclovir (GCV) using in vitro assays and mixing studies was comparable to that of the E1E3-deleted vector. In vivo bystander effects were investigated using mixing studies in a syngeneic flank tumor model and demonstrated no difference between vectors in either immunocompetent or immunodeficient mice. To test the efficiency of these vectors in treating tumors in clinically relevant models, virus was injected intraperitoneally into tumor-bearing SCID mice and intrapleurally in a syngeneic rat mesothelioma model. After treatment of animals with ganciclovir, both vectors were roughly equivalent in their ability to increase mean survival (from approximately 40 to approximately 70 days) and markedly reduce tumor burden. Finally, formal toxicology studies were performed and showed similar amounts of local inflammation without systemic toxicity. In summary, this series of in vitro and in vivo experiments indicates that the performance of the recombinant E1E4-deleted adenoviral vector was virtually identical to that of the E1E3-deleted vector. Since the E1E4 vector has a much lower rate of recombination during production and has been shown to be less hepatotoxic in animal models, this new vector should prove superior to the first-generation Ad.HSVtk vectors in clinical cancer gene therapy trials.

    Title Comparison of Open and Thoracoscopic Bilateral Volume Reduction Surgery: Complications Analysis.
    Date February 1999
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: The effectiveness of lung volume reduction for the treatment of patients with emphysema is well established, but data about the surgical approach, the postoperative management, and complications are limited. We report a comparison of patients undergoing bilateral lung volume reduction (BLVRS) via median sternotomy and thoracoscopic techniques with emphasis on hospital course and complications. METHODS: All patients undergoing BLVRS at Hospital of University of Pennsylvania were analyzed for mortality and morbidity, using a combination of prospective data analysis and retrospective chart review. RESULTS: Patients undergoing BLVRS via median sternotomy were older than those undergoing video-assisted thoracoscopic surgery (VATS) procedures (63.9+/-6.89 vs 59.3+/-9.4 years, p = 0.005). Operating time was longer for the VATS procedure (147 versus 129 minutes, p = 0.006) while estimated blood less was greater for median sternotomy (209 versus 82 L, p = 0.0000017). Significant differences were found in intensive care unit stay, days intubated, life-threatening complications, respiratory complications, requirement for tracheostomy, and death that favored VATS BLVRS. When only later cohorts of patients were compared, more life-threatening complications and deaths were found in patients undergoing BLVRS by median sternotomy. There were no differences between early and late median sternotomy BLVRS patients. Twenty-six percent of the lethal complications in median sternotomy BLVRS patients were bowel perforations, equally divided between duodenal ulcers and colons. CONCLUSIONS: Managing patients after BLVRS remains complex. Bilateral video-assisted volume reduction offers equivalent functional outcome with potentially decreased morbidity and mortality. Gastrointestinal perforations can complicate the management of these patients.

    Title Impact of Preexisting and Induced Humoral and Cellular Immune Responses in an Adenovirus-based Gene Therapy Phase I Clinical Trial for Localized Mesothelioma.
    Date December 1998
    Journal Human Gene Therapy
    Excerpt

    Little is known about the immune responses induced by recombinant adenoviral (Ad) vectors in humans. The humoral and cellular immune responses were therefore analyzed in 21 patients with localized malignancy (mesothelioma), who received intrapleurally high doses of a replication-defective Ad5 vector carrying a suicide gene. Eight of 21 patients had pretreatment titers of neutralizing antibodies (NAb) to Ad at > or =1:100. Peripheral blood mononuclear cells (PBMCs) proliferated in response to adenoviral 5 structural proteins before treatment in 17 of 21 patients. Preexisting humoral and cellular immunity did not preclude gene transfer. Vector instillation induced high titers of nonneutralizing and neutralizing anti-Ad antibody (4- to 341-fold increase in 18 of 20 patients) in a dose-dependent manner. Three patients generated antibodies to the transgene, herpes simplex virus thymidine kinase. Ad5-specific proliferation of PBMCs increased significantly (>3-fold) after vector administration in 12 of 21 patients in a dose-dependent manner. Thus, replication-defective Ad5 administered intrapleurally induced significant humoral and cellular immune responses that induced no obvious adverse clinical sequelae.

    Title Course Guidelines for Minimally Invasive Cardiac Surgery. Sts/aats Ad Hoc Committee on New Technology Assessment. American Association for Thoracic Surgery.
    Date November 1998
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Title Gene Therapy for Malignant Pleural Mesothelioma.
    Date October 1998
    Journal Hematology/oncology Clinics of North America
    Excerpt

    Malignant mesothelioma (MM) is a fatal malignancy refractory to all forms of standard anticancer therapy. This article reports the results of a phase I clinical trial assessing the safety of intrapleural delivery and efficacy of intratumoral gene transfer of recombinant adenovirus (rAd) containing herpes simplex virus thymidine kinase (HSVtk) gene into the pleural space of patients with MM, followed by systematic treatment with the antiviral drug ganciclovir (GCV) for 14 days. AD.RSVtk/GCV gene therapy proved to be well tolerated, with evidence of significant gene transfer particularly at high vector doses and with elimination of preliminary biopsy. Ongoing gene therapy trials for mesothelioma at two other centers, focusing on immunostimulation and using suicide gene therapy as a tumor vaccine, are also reviewed in this article.

    Title Metabolic Imaging of Malignant Pleural Mesothelioma with Fluorodeoxyglucose Positron Emission Tomography.
    Date September 1998
    Journal Chest
    Excerpt

    BACKGROUND: The diagnosis of malignant mesothelioma is a challenging medical problem. CT often cannot differentiate between benign diffuse pleural thickening and malignant mesothelioma, while thoracentesis and CT-guided biopsies are insensitive. We have assessed the value of positron emission tomography (PET) with 2-fluoro-2-deoxy-D-glucose (FDG) in the evaluation of malignant mesothelioma. METHODS: Twenty-eight consecutive patients referred for the evaluation of suspected malignant mesothelioma were evaluated by FDG-PET imaging. Measured attenuation correction was performed in 26 of 28 cases for quantitation with the standardized uptake value (SUV) method. The results of PET imaging were compared with those of video-assisted thoracoscopy or surgical biopsies. RESULTS: Surgical biopsy specimens confirmed the presence of malignant disease in 24 patients and demonstrated benign processes in the remaining four. The uptake of FDG was significantly higher in malignant than in benign lesions (SUV=4.9+/-2.9 and SUV=1.4+/-0.6, respectively; p<0.0001). With a SUV cutoff of 2.0 to differentiate between malignant and benign disease, a sensitivity of 91% and a specificity of 100% could be achieved, although the activity in some epithelial mesotheliomas tended to be close to this threshold. FDG-PET images provided excellent delineation of the active tumor sites. Hypermetabolic lymph node involvement was noted on FDG-PET images in 12 patients, 9 of which appeared normal on CT scans. Histologic examination in six patients confirmed malignant nodal disease in five cases and indicated granulomatous lymphadenitis in one. CONCLUSION: In this highly selected population, FDG-PET imaging was a sensitive method to identify malignant mesothelioma and determine the extent of the disease process.

    Title Mediastinoscopic Subtotal Removal of Mediastinal Cysts.
    Date September 1998
    Journal Chest
    Excerpt

    STUDY OBJECTIVE: Evaluate the use of mediastinoscopy in the surgical diagnosis and treatment of mediastinal cystic masses in adults. DESIGN: Case reports and literature review. SETTING: Academic department of surgery. PATIENTS: Three consecutive adults with mediastinal masses identified on plain radiographs and CT. INTERVENTIONS: Operative mediastinoscopy. MEASUREMENTS AND RESULTS: All patients were successfully treated with removal of cyst wall, establishment of diagnosis, and same-day hospital discharge. CONCLUSIONS: Simple mediastinoscopic removal of mediastinal cysts offers the same potential for diagnosis and treatment as more conventional methods, with a potential for less morbid and more cost-effective care.

    Title Cancer Chemotherapy Using Suicide Genes.
    Date August 1998
    Journal Surgical Oncology Clinics of North America
    Excerpt

    Suicide gene therapy is a unique form of drug delivery system that allows for negative selection of malignant cells using a prodrug approach. Malignant cells are transduced with a gene encoding an enzyme that can metabolize an otherwise nontoxic prodrug into a toxic metabolite. The prototype of this system is the herpes simplex virus thymidine kinase gene (HSV-tk). Suicide genes may be introduced into tumor cells either by viral vectors or nonviral methods. Current work is underway to fine tune both the delivery systems and optimize the efficacy of the production of the toxic metabolites. Suicide gene therapy is an exciting strategy currently in clinical trial in the treatment of a number of tumors.

    Title Severe Acute Extrinsic Airway Compression by Mediastinal Tumor Successfully Managed with Extracorporeal Membrane Oxygenation.
    Date August 1998
    Journal Asaio Journal (american Society for Artificial Internal Organs : 1992)
    Excerpt

    The successful use of femoral venoarterial extracorporeal membrane oxygenation to support an adult patient with extrinsic airway compression secondary to a large mediastinal tumor is presented. Extracorporeal membrane oxygenation was continued until a combination of chemotherapy and radiation therapy allowed sufficient tumor shrinkage to permit decannulation. This method should be considered and available before manipulation of the airway in similar patients.

    Title Primary Graft Failure Following Lung Transplantation.
    Date August 1998
    Journal Chest
    Excerpt

    STUDY OBJECTIVES: To determine the incidence of primary graft failure (PGF) following lung transplantation, assess possible risk factors, and characterize its effect on outcomes. METHODS: Retrospective review of 100 consecutive patients undergoing lung transplantation at the University of Pennsylvania Medical Center. Fifteen patients meeting diagnostic criteria for PGF (PGF+ group) were compared with 85 patients without this complication (PGF- group). RESULTS: The incidence of PGF was 15%. There was no significant difference in age, sex, underlying pulmonary disease, preoperative pulmonary artery systolic pressure, type of transplant, allograft ischemic times, use of cardiopulmonary bypass, or use of postoperative prostaglandin E1 infusion between the PGF+ and PGF- groups. Induction therapy with antilymphocyte globulin was used less frequently in the PGF+ group (p<0.005). Duration of mechanical ventilatory support was 36+/-43 days vs 4+/-6 days for the PGF+ and PGF- groups, respectively (p<0.0001). Hospital stay was significantly longer in the PGF+ group, averaging 75+/-105 days, compared with 27+/-38 days in the PGF group (p<0.005). One-year actuarial survival for the PGF+ group was only 40% compared with 69% for the PGF- group (p<0.005). Five of the six PGF+ survivors were ambulatory by 1 year; three were completely independent while two continued to require assistance with activities of daily living. Six-minute walk test distance among the ambulatory patients averaged 883+/-463 feet (range, 200 to 1,223 feet) compared with 1513+/-424 feet for the PGF- group (p<0.005). Among the subset of survivors who underwent single lung transplantation for COPD, the mean percent predicted FEV1 at 1 year was 43% for the PGF+ group and 55% for the PGF- groups, but this difference was not statistically significant. CONCLUSIONS: PGF is a devastating postoperative complication, occurring in 15% of patients in the current series, and it is associated with a high mortality rate, lengthy hospitalization, and protracted and often compromised recovery among survivors.

    Title Adenovirus-mediated Herpes Simplex Virus Thymidine Kinase/ganciclovir Gene Therapy in Patients with Localized Malignancy: Results of a Phase I Clinical Trial in Malignant Mesothelioma.
    Date August 1998
    Journal Human Gene Therapy
    Excerpt

    Malignant pleural mesothelioma is a fatal neoplasm that is unresponsive to standard modalities of cancer therapy. We conducted a phase I dose-escalation clinical trial of adenoviral (Ad)-mediated intrapleural herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) gene therapy in patients with mesothelioma as a model for treatment of a localized malignancy. The goals of this phase I trial were to assess the safety, toxicity, and maximally tolerated dose of intrapleural Ad.HSVtk, to examine patient inflammatory response to the viral vector, and to evaluate the efficiency of intratumoral gene transfer. Twenty-one previously untreated patients were enrolled in this single-arm, dose-escalation study with viral doses ranging from 1 x 10(9) plaque-forming units (pfu) to 1 x 10(12) pfu. A replication-incompetent recombinant adenoviral vector containing the HSVtk gene under control of the Rous sarcoma virus (RSV) promoter-enhancer was introduced into the pleural cavity of patients with malignant mesothelioma followed by 2 weeks of systemic therapy with GCV at a dose of 5 mg/kg twice a day. The initial 15 patients underwent thoracoscopic pleural biopsy prior to, and 3 days after, vector delivery. The last six patients underwent only the post-vector instillation biopsy. Dose-limiting toxicity was not reached. Side effects were minimal and included fever, anemia, transient liver enzyme elevations, and bullous skin eruptions, as well as a temporary systemic inflammatory response in those receiving the highest dose. Strong intrapleural and intratumoral immune responses were generated. Using RNA PCR, in situ hybridization, immunohistochemistry, and immunoblotting, HSVtk gene transfer was documented in 11 of 20 evaluable patients in a dose-related fashion. This study demonstrates that intrapleural administration of an adenoviral vector containing the HSVtk gene is well tolerated and results in detectable gene transfer when delivered at high doses. Further development of therapeutic trials for treatment of localized malignancy using this vector is thus warranted.

    Title Comparison of Short-term Functional Outcomes Following Unilateral and Bilateral Lung Volume Reduction Surgery.
    Date May 1998
    Journal Chest
    Excerpt

    STUDY OBJECTIVES: To compare short-term functional outcomes following unilateral and bilateral lung volume reduction surgery (LVRS) performed in patients with advanced emphysema. METHODS: LVRS was performed unilaterally in 32 patients and bilaterally in 119 patients. Pulmonary function testing and 6-min walk test (6MWT) were performed preoperatively and repeated at 3 to 6 months postoperatively. RESULTS: Bilateral LVRS was associated with increased in-hospital mortality (10% vs 0%, p<0.05) and a higher incidence of postoperative respiratory failure (12.6% vs 0%; p<0.05) compared with unilateral LVRS. There was no significant difference in duration of air leaks between unilateral and bilateral groups, but the mean hospital stay was significantly longer following bilateral LVRS (21.1+/-32.0 days vs 14.2+/-14.0 days; p<0.05). Preoperatively, there was no significant difference between the unilateral and bilateral groups with respect to FEV1, FVC, residual volume, or 6MWT distance. However, for all of these parameters, the magnitude of improvement was significantly greater following bilateral LVRS. Notably, the magnitude of improvement in each parameter following unilateral LVRS exceeded half that following bilateral LVRS, suggesting that functional outcomes after the unilateral procedure were disproportionate to the amount of tissue resected. Serial functional assessment of seven patients undergoing staged unilateral procedures (two unilateral procedures separated in time by at least 3 months) demonstrated somewhat unpredictable responses; failure to achieve a favorable response to the initial procedure did not necessarily portend a similar outcome with the contralateral side, and vise versa. CONCLUSIONS: Bilateral LVRS produces a greater magnitude of short-term functional improvement than does the unilateral procedure and should be considered the procedure of choice for most patients. Unilateral LVRS should be reserved for patients in whom factors contraindicating entrance into one hemithorax exist.

    Title Tithing: Why Now?
    Date April 1998
    Journal Trustee : the Journal for Hospital Governing Boards
    Title Effect of Volume Reduction on Lung Transplant Timing and Selection for Chronic Obstructive Pulmonary Disease.
    Date February 1998
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    BACKGROUND: End-stage chronic obstructive pulmonary disease has traditionally been treated with lung transplantation. For 2 years, our lung transplantation program has placed patients with appropriate criteria for lung transplantation and volume reduction into a prospective management algorithm. These patients are offered the lung volume reduction option as a "bridge" to "extend" the eventual time to transplantation. We examine the results of this pilot program. METHODS: From October 11, 1993, to April 17, 1997, 31 patients were evaluated for lung transplantation who also had physiologic criteria for volume reduction (forced expiratory volume in 1 second < or = 25%; residual volume > 200%; significant ventilation/perfusion heterogeneity). All patients completed 6 weeks of pulmonary rehabilitation and then had baseline pulmonary function and 6-minute walk tests. These patients were then offered volume reduction as a "bridge" and were simultaneously listed for transplantation. Postoperatively, these 31 patients were then divided into two groups: Those with satisfactory results at 4 to 6 months after volume reduction and those with unsatisfactory results. Volume reduction was performed through a video thoracic approach in 87% of the patients and bilateral median sternotomy in the remaining 13%. The condition of the patients was monitored after the operation with repeated pulmonary function tests and 6-minute walk tests at 3-month intervals. RESULTS: Twenty-four of 31 patients (77.4%) had primary success (at 4 to 6 months) results after lung volume reduction and 7 patients (22.6%) had primary failure, including 1 patient who died in the perioperative period (3.2%). Four patients (16.7%) from the primary success cohort had significant deterioration in their pulmonary function during intermediate-term follow-up and were then reconsidered for lung transplantation. Two of them have subsequently undergone transplantation with good postoperative pulmonary function results. Interestingly, three patients had alpha 1-antitrypsin deficiency; two had a poor outcome of lung volume reduction and primary failure. CONCLUSIONS: Lung volume reduction in these patients is safe. Seventy-seven percent of otherwise suitable candidates for lung transplantation achieved initial good results from volume reduction and were deactivated from the list (placed on status 7). Most patients entering our prospective management algorithm have either significantly delayed or completely avoided lung transplantation after volume reduction. Lung volume reduction has substantially affected the practice, timing, and selection of patients for lung transplantation. Our waiting list now has a reduced percentage of patients with a diagnosis of chronic obstructive pulmonary disease compared with 3 years ago. Our experience suggests that lung volume reduction may be limited as a "bridge" in alpha 1-antitrypsin deficiency.

    Title New Therapies in the Treatment of Malignant Pleural Mesothelioma.
    Date December 1997
    Journal Seminars in Thoracic and Cardiovascular Surgery
    Excerpt

    It can be safely stated that currently there exists no standard therapy for malignant mesothelioma. The "standard" methods of chemotherapy, radiation therapy, and surgery have all been used with little improvement in overall survival. Trimodality therapy that involves a combination of all three standard treatment modalities has been shown to improve survival in selected patients. New and innovative treatment strategies clearly are needed for a disease which, because of the disappointment with standard therapy, is most commonly approached with only palliative intent. The location of this malignancy and its tendency to remain localized make it an ideal target for intracavitary approaches using photodynamic therapy, targeted cytokines, and gene therapy. Strategies using modulation of the immune system in an attempt to elicit a specific response to the tumor have been combined with chemotherapy to optimize response. Lessons learned from treating this localized malignancy with novel therapies may have much broader implications for other tumors in which systemic disease predominates.

    Title Retinoids Augment the Bystander Effect in Vitro and in Vivo in Herpes Simplex Virus Thymidine Kinase/ganciclovir-mediated Gene Therapy.
    Date November 1997
    Journal Gene Therapy
    Excerpt

    Metabolic cooperation via gap junctional intercellular communication (GJIC) is an important mechanism of the bystander effect in gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) 'prodrug' system. Since retinoids have been reported to increase GJIC by induction of connexin expression, we hypothesized that these compounds could be used to augment the HSVtk/GCV bystander effect. Addition of all-trans retinoic acid increased GJIC in tumor cell lines, augmented expression of connexin 43, and was associated with more efficient GCV-induced in vitro bystander killing in cells transduced with HSVtk via either retrovirus or adenovirus vectors. This augmentation of bystander effect could also be seen in vivo. HSVtk-transduced tumors in mice treated with the combination of GCV and retinoids were significantly smaller than those treated with GCV or retinoids alone. These results provide evidence that retinoids can augment the efficiency of cell killing with the HSVtk/GCV system by enhancing bystander effects and may thus be a promising new approach to improve responses in gene therapy utilizing the HSVtk/GCV system to treat tumors or vascular restenosis.

    Title Loss of Alpha-v Integrin Expression and Recurrence in Node-negative Lung Carcinoma.
    Date November 1997
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Despite "curative" resection, metastases develop in many patients with node-negative (N0) non-small cell lung carcinoma. Alternative biologic markers for this tumor would be useful. Integrins are cell adhesion molecules that are thought to be important in tumor progression, and expression of these molecules previously has been shown to be altered in non-small cell lung carcinoma. We evaluated alterations in integrin expression and clinical outcome. METHODS: Immunohistochemical staining of tumor specimens was performed, and clinical data were reviewed retrospectively. RESULTS: Data were complete for 42 patients. Half of all patients (21/42) and 9 of 26 patients with negative nodes experienced tumor recurrence during follow-up. Neither histologic type nor tumor differentiation status correlated with recurrence. However, loss of the alpha v integrin subunit was associated significantly with recurrence in the N0 group. Seventy-five percent of patients with negative nodes who exhibited recurrence lost alpha v expression, compared with only 10% of patients with negative nodes who did not exhibit recurrence (p = 0.012). Alterations of other integrin subunits did not correlate significantly with prognostic follow-up variables. CONCLUSIONS: Loss of alpha v expression may serve as a marker for patients with node-negative non-small cell lung carcinoma who are at high risk for recurrence, potentially directing additional therapies.

    Title Bilateral Sequential Lung Transplantation for Pulmonary Alveolar Microlithiasis.
    Date November 1997
    Journal Chest
    Excerpt

    Pulmonary alveolar microlithiasis (PAM) is characterized by deposition of calcium phosphate within the alveolar airspaces. There is currently no effective medical therapy and affected individuals may progress to end-stage lung disease requiring transplantation. Two patients with PAM underwent bilateral sequential lung transplantation. This study reviews the clinical manifestations of PAM and discusses the particular difficulties that may be encountered in the use of lung transplantation as treatment for this uncommon disease. Also addressed is the question of recurrence in the allograft.

    Title Thoracoscopic Management of Descending Necrotizing Mediastinitis.
    Date October 1997
    Journal Chest
    Excerpt

    Descending necrotizing mediastinitis (DNM) is a lethal process originating from odontogenic, pharyngeal, or cervical infectious sources that descends along fascial planes into the mediastinum. Despite earlier use of antibiotics and surgical drainage, the mortality (>50%) has changed little since the first large series reported in the preantibiotic era. The surgical management remains controversial, with support ranging from cervical drainage alone to cervical drainage and routine thoracotomy. We report a case of thoracoscopic drainage and debridement of a mediastinal abscess resulting from descending necrotizing mediastinitis. The decreased morbidity of this approach compared with posterolateral thoracotomy and the improved drainage of the mediastinum compared with cervical drainage support this method as an attractive management of patients with DNM.

    Title The Effect of Promoter Strength in Adenoviral Vectors Containing Herpes Simplex Virus Thymidine Kinase on Cancer Gene Therapy in Vitro and in Vivo.
    Date September 1997
    Journal Cancer Gene Therapy
    Excerpt

    The use of adenoviral vectors to deliver the herpes simplex virus thymidine kinase (HSVtk) gene followed by treatment with the prodrug ganciclovir (GCV) has promise for a variety of applications where excess cell proliferation is detrimental such as treatment of tumors and vascular restenosis. Optimizing this system is thus an important goal. The purpose of this study was to determine if the induction of higher levels of HSVtk expression would augment the sensitivity to GCV. This was accomplished by generating adenoviral vectors that expressed HSVtk from promoters of different efficiencies (the CMV versus RSV promoters). Despite higher levels of HSVtk expression per cell with the CMV promoter, there was no significant enhancement of antitumor effects between RSV- and CMV-driven adenovirus vectors in in vitro and in vivo studies indicating that simply increasing HSVtk enzyme levels per cell above a minimal threshold level will not be effective in augmenting the HSVtk/GCV system. These results suggest that other strategies, e.g., the use of higher doses of GCV, augmentation of the "bystander effect," the generation of mutant HSVtk genes with higher substrate affinities, the discovery of improved vectors with increased transduction efficiencies, or the development of new prodrugs with higher affinities for HSVtk will therefore be needed to enhance therapeutic responses.

    Title Gene Transfer and Thoracic Surgery: More to Come.
    Date July 1997
    Journal The Annals of Thoracic Surgery
    Title Adjuvant Therapy of Lung Cancer: Introduction.
    Date June 1997
    Journal Seminars in Thoracic and Cardiovascular Surgery
    Title Epidemiology of Lung Cancer.
    Date June 1997
    Journal Seminars in Thoracic and Cardiovascular Surgery
    Excerpt

    Lung cancer is the leading cause of cancer deaths for men and women in the United States, accounting for more cancer deaths since 1930 than all other cancer deaths combined. Whereas primary lung cancer was a relatively rare malignancy in the early 1900s, in 1994 there were approximately 170,000 new cases of lung cancer in the United States, of which roughly 100,000 were in men and 70,000 were in women. Despite numerous medical and surgical advances in the past several decades, there has not been a dramatic increase in the percentage of patients being cured of this lethal disease. Smoking is the primary factor responsible for the lung cancer epidemic, but there are numerous other environmental and genetic factors that have been implicated in the pathogenesis of the disease. Recently, it has become evident that passive smoking may also play a significant role in the development of lung cancer. Although screening has not been proven effective in the past, it may be time to reevaluate this technique because early detection of lung cancer affords the best chance for cure.

    Title The Role of Surgery in the Multimodality Management of Non-small Cell Lung Cancer.
    Date June 1997
    Journal Seminars in Thoracic and Cardiovascular Surgery
    Excerpt

    The majority of patients with lung cancer have disseminated disease at the time of presentation. For the minority of patients with disease localized to the chest, the concept of staging becomes particularly important because it has a major impact on the treatment plan. Guided by findings on the computed tomographic scan, mediastinoscopy remains the definitive invasive staging procedure to document unequivocally the involvement of the mediastinal lymph nodes. Equally as important is the documentation of absence of disease in contralateral lymph nodes. Patients with locally advanced non-small cell lung cancer, especially those with involvement of mediastinal lymph nodes (N2), are candidates for a multimodality approach to treatment involving either chemotherapy alone or in combination with radiation therapy. Surgical excision may be important in the management of these patients after an induction regimen. If surgical excision is performed, complete excision is the single most important factor. Postoperative adjuvant therapy may reduce the incidence of local recurrence but has not been shown to improve survival.

    Title The Role of Chemotherapy in the Treatment of Non-small Cell Carcinoma of the Lung.
    Date June 1997
    Journal Seminars in Thoracic and Cardiovascular Surgery
    Excerpt

    Within the past 10 years, the role of chemotherapy in the treatment of patients with non-small cell lung cancer has expanded greatly. Previously chemotherapy was used only for patients with disseminated disease and, despite advances in combination therapy with new agents, response rates remained low, response duration was short, and cures were rare. Performance status is an important prognostic indicator both from the standpoint of response and duration of survival. Patients with locally advanced disease who are otherwise candidates for operation have a significantly higher response rate to chemotherapy and tolerate the treatment reasonably well. Combination chemotherapy given preoperatively seems to be associated with improved survival, especially in those patients able to undergo complete resection. Radiation therapy and chemotherapy given preoperatively may be even more efficacious than either modality alone. The question as to whether surgical resection improves on what can be accomplished with radiation therapy and chemotherapy in patients with mediastinal lymph node involvement remains an open one and is currently being evaluated.

    Title Bilateral Versus Single Lung Transplantation for Chronic Obstructive Pulmonary Disease.
    Date April 1997
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    OBJECTIVE: Traditionally, despite ventilation/perfusion mismatch, single lung transplantation has been the mainstay for end-stage chronic obstructive pulmonary disease. We tested the hypothesis that bilateral sequential lung transplantation has better short- and intermediate-term results than single lung transplantation for chronic obstructive pulmonary disease. METHODS: One hundred twenty-six consecutive lung transplants have been performed from November 1991 to March 1996. Seventy-six have been for chronic obstructive pulmonary disease. The diagnosis of this disease includes emphysema (80.3%), alpha 1-antitrypsin deficiency (9.2%), lymphangioleiomyomatosis (7.9%), and obliterative bronchiolitis (2.6%). Twenty-nine transplants have been bilateral and 47 have been single. Mean age was 55.3 for patients having single lung transplantation and 48.8 for those having bilateral lung transplantation (p = 0.001). The distribution of the diagnoses was similar between the two groups. At 6 months, there were 29 survivors of single lung transplantation and 20 survivors of bilateral lung transplantation, with complete data for evaluation. Pulmonary function tests and 6-minute walk tests were evaluated at a mean of 15.4 and 12.8 months after transplantation, respectively. RESULTS: Sixty-day mortality was 21.3% for single lung transplantation versus only 3.45% for bilateral lung transplantation (p = 0.03). Additionally, Kaplan-Meier analysis revealed 1- and 2-year survivals of 71.1% and 63.3% for single lung transplantation versus 90% and 90% for bilateral lung transplantation, respectively. Multiple major morbidities were analyzed. Primary graft failure was significantly reduced in the bilateral group (p = 0.049). Both 6-minute walk tests and forced expiratory volume in 1 second were improved from baseline by both single and bilateral lung transplantation (p = 0.001). CONCLUSIONS: Bilateral lung transplantation improves forced expiratory volume in 1 second and 6-minute walk tests significantly over single lung transplantation (p < 0.0001). Both perioperative mortality and Kaplan-Meier survival (to 3 years) are significantly improved when bilateral rather than single lung transplantation is used for chronic obstructive pulmonary disease in our series (p < 0.05). This is probably the result of significantly reduced primary graft failure.

    Title Gap Junctions Play a Role in the 'bystander Effect' of the Herpes Simplex Virus Thymidine Kinase/ganciclovir System in Vitro.
    Date March 1997
    Journal Gene Therapy
    Excerpt

    Tumor cells transduced with the herpes simplex virus thymidine kinase (HSVtk) gene are sensitive to the anti-viral drug ganciclovir (GCV). However, nearby untransduced tumor cells are also efficiently killed. The mechanism of this 'bystander effect' was studied by comparing pairs of tumor cell lines transfected with connexin genes that differed only in their degree of gap junctional communication. More efficient cell killing was uniformly seen in connexin transfectants compared with the less coupled cell lines. These results provide direct evidence that gap junctional communication plays an important role in mediating the bystander effect of the HSVtk/GCV system in vitro and have important prognostic and therapeutic implications for future gene therapy trials.

    Title Safety of Intrapleurally Administered Recombinant Adenovirus Carrying Herpes Simplex Thymidine Kinase Dna Followed by Ganciclovir Therapy in Nonhuman Primates.
    Date March 1997
    Journal Human Gene Therapy
    Excerpt

    Preclinical safety and toxicity studies of intrapleural administration of recombinant adenovirus carrying the herpes simplex thymidine kinase gene (H5.010RSVtk) were performed. Previously reported experimental evidence has demonstrated the efficacy of this approach in animal models of a localized thoracic cancer, malignant mesothelioma. H5.010RSVtk was delivered at high dose (10(12) pfu) into the pleural cavity of three non-human primates followed by systemic administration of ganciclovir. No clinical toxicity was noted. Although an inflammatory reaction observable by microscopy was noted in the serosal spaces of the chest cavity, these changes were reversible and were not associated with radiographic sequelae. Extrathoracic viral dissemination was minimal and detectable only by sensitive polymerase chain reaction techniques. This low level of viral dissemination was not associated with detectable clinical, biochemical, or pathologic abnormalities.

    Title Treatment of Advanced Mesothelioma with the Recombinant Adenovirus H5.010rsvtk: a Phase 1 Trial (bb-ind 6274).
    Date February 1997
    Journal Human Gene Therapy
    Title Use of a "replication-restricted" Herpes Virus to Treat Experimental Human Malignant Mesothelioma.
    Date February 1997
    Journal Cancer Research
    Excerpt

    Modified, nonneurovirulent herpes simplex viruses (HSVs) have shown promise in the treatment of brain tumors. However, HSV-1 can infect and lyse a wide range of cell types. In this report, we show that HSV-1716, a mutant lacking both copies of the gene coding ICP-34.5, can effectively treat a localized i.p. malignancy. Human malignant mesothelioma cells supported the growth of HSV-1716 and were efficiently lysed in vitro. i.p. injection of HSV-1716 into animals with established tumor nodules reduced tumor burden and significantly prolonged survival in an animal model of non-central nervous system-localized human malignancy without dissemination or persistence after i.p. injection into SCID mice bearing human tumors. These findings suggest that this virus may be efficacious and safe for use in localized human malignancies of nonneuronal origin such as malignant mesothelioma.

    Title Bilateral Lung Volume Reduction Surgery for Advanced Emphysema. A Comparison of Median Sternotomy and Thoracoscopic Approaches.
    Date January 1997
    Journal Chest
    Excerpt

    STUDY OBJECTIVES: To compare short-term outcomes following bilateral lung volume reduction surgery performed by median sternotomy (MS) and video-assisted thoracoscopic surgery (VATS). METHODS: Bilateral lung volume reduction surgery was performed by MS in 80 patients and by VATS in 40. All patients underwent preoperative assessment with pulmonary function testing, arterial blood gas determination, and 6-min walk test (6MWT). Pulmonary function testing and 6MWT were repeated at 3 to 6 months postoperatively. RESULTS: The mean age of the VATS group was lower than that of the MS group (59.3 +/- 9.4 vs 62.4 +/- 6.9 years; p = 0.001), but there were no differences in baseline functional parameters of disease severity (FEV1, FVC, residual volume [RV], arterial PCO2, or 6MWT). All patients in both groups were extubated at the completion of surgery, but 17.5% of patients in the MS group and 2.5% in the VATS group (p = 0.02) subsequently required reintubation at some point during the postoperative course. Thirty-day operative mortality was 4.2% for the MS group and 2.5% for the VATS group (p = not significant). However, total in-hospital mortality was 13.8% for the MS group, while it remained 2.5% for the VATS group (p = 0.05). Mortality was largely confined to patients 65 years of age or older. There was no significant difference in duration of air leaks or length of hospital stay between the two groups. Functional outcomes achieved with the two techniques were similar. Specifically, there was no difference between the two groups in mean postoperative FEV1, FVC, RV, or 6MWT, or in the magnitude of change in these parameters over preoperative values. CONCLUSIONS: Bilateral lung volume reduction surgery performed by either MS and VATS approaches leads to similar improvements in pulmonary function and exercise tolerance. VATS is associated with a significantly lower incidence of respiratory failure and a trend toward decreased in-hospital mortality and may be the preferred technique, particularly for high-risk patients.

    Title Fatal Hyperammonemia Following Orthotopic Lung Transplantation.
    Date January 1997
    Journal Gastroenterology
    Excerpt

    There have been anecdotes of unexplained coma and death in patients after otherwise successful orthotopic lung transplantation. A patient with primary pulmonary hypertension who underwent a technically uncomplicated single orthotopic lung transplantation is described. The patient developed intractable status epilepticus 4 days after surgery in association with the presence of a markedly elevated plasma ammonium level. Despite multiple therapeutic interventions, the hyperammonemia ultimately resulted in the patient's death. Both metabolic and enzymatic studies showed that the unique physiological disturbance in this disorder results at least in part from defective in vivo conversion of waste nitrogen to urea and increased production of waste nitrogen. Although the rate of hepatic ureagenesis was therefore insufficient to prevent accumulation of ammonium, the cause was not severe liver disease. Liver histology showed widespread, microvesicular steatosis on light-microscopic examination, but only electron-microscopic examination showed severe microvesicular steatosis with severe mitochondrial injury. As in Reye's syndrome, it was unclear whether the hepatic mitochondrial injury played a role in development or if it was the result of hyperammonemia. We recommended that any patient with an unexplained alteration of mental status after solid organ transplantation be evaluated for hyperammonemia.

    Title Gi Complications After Orthotopic Lung Transplantation.
    Date December 1996
    Journal The American Journal of Gastroenterology
    Excerpt

    OBJECTIVES: Recently, lung transplantation has been performed with increasing frequency and improved outcomes. GI complications have been observed and reported in patients undergoing cardiac and renal transplantations but only recently have been reported in patients after lung transplantation. No large cohort has been systematically analyzed for all GI complications after lung transplantation. The present study describes, categorizes, and assesses risk factors for the development of such GI complications. METHODS: Records of 45 patients who underwent 47 single or bilateral orthotopic lung transplants between November 1991 and January 1994 were reviewed. RESULTS: Twenty-three patients (51%) had 64 GI complications requiring 13 operations on eight patients. The incidence of major abdominal procedures in the entire transplant cohort was 18% (8/45). Their operative mortality rate was 63% (5/8). Eighteen different types of nonoperative complications occurred and were subclassified into major and minor complications. Complications were defined as major if they required medical or surgical intervention and altered patient management. Most GI complications (73%) occurred within 1 month after transplantation. No risk factors were identified to ascertain who will develop GI complications. CONCLUSIONS: GI complications occur in more than one-half of lung transplant recipients early after transplantation and in the absence of identifiable risk factors. Because there are no precedent risk factors to suggest who will develop GI complications, clinicians must be alert to any warning signs and symptoms. The majority of complications are nonoperative, responding to conservative therapy, but there is a higher overall mortality rate for patients requiring operative intervention, necessitating an aggressive search for major, life-threatening complications in these immunosuppressed patients.

    Title Lepidic Intrapulmonary Growth of Malignant Mesothelioma Presenting As Recurrent Hydropneumothorax.
    Date November 1996
    Journal Human Pathology
    Excerpt

    We report a case of malignant mesothelioma with unusual clinical and histological findings. The patient presented with recurrent hydropneumothorax and minimal pleural thickening on chest computed tomography (CT). Histologically, the pleura was involved by the malignant mesothelioma, albeit to a limited degree. Unexpectedly, the lung parenchyma from two different lobes showed focal nests of mesothelioma cells filling the alveolar spaces and growing on the luminal surface of the alveolar septa, closely resembling the multicentric growth pattern of bronchioloalveolar adenocarcinoma. Immunohistochemical and ultrastructural studies confirmed that the pulmonary lesions were an extension of the malignant mesothelioma. This case illustrates clinically, the importance of a high index of suspicion for malignancy in older patients with unexplained recurrent hydropneumothorax; and histologically the potential of malignant mesothelioma to invade the lung at an early stage of growth.

    Title Herpes Simplex 1716--an Icp 34.5 Mutant--is Severely Replication Restricted in Human Skin Xenografts in Vivo.
    Date November 1996
    Journal Virology
    Excerpt

    HSV-1716 is a replication-restricted, neuroattenuated ICP 34.5 gene mutant of herpes simplex virus type 1 (HSV-1). Because of the attenuated phenotype of ICP 34.5 mutants in rodent models of HSV disease, they have been promoted as potential vaccine strains and gene therapy vectors and have been used by us and others as therapeutic agents for the treatment of experimental malignant tumors. However, all data on the phenotype of HSV-1716 and other ICP 34.5 mutants are from animal model systems, while humans are the natural hosts of HSV-1. To achieve an initial characterization of the phenotype of 1716 in human tissue, we have studied its replication in mature human skin xenografts on SCID mice. We find that replication of 1716 is severely restricted in such human skin grafts relative to both parental wild-type HSV-1 strain 17+ and the HSV-1716 revertant virus 1716R, in which the 759-bp ICP 34.5 gene deletions have been repaired. Moreover, the replication of both 1716 and 17+ is significantly better in the human skin grafts than it is in mouse skin. The implications of these findings are discussed.

    Title Treatment of Pleural Mesothelioma in an Immunocompetent Rat Model Utilizing Adenoviral Transfer of the Herpes Simplex Virus Thymidine Kinase Gene.
    Date October 1996
    Journal Human Gene Therapy
    Excerpt

    Previously, we have treated malignant mesothelioma (MM) growing in the peritoneal cavity of immunodeficient mice utilizing a recombinant adenovirus vector carrying the herpes simplex virus-thymidine kinase gene (Ad.RSVtk) followed by administration of the anti-viral drug ganciclovir (GCV). To mimic more closely the clinical situation in human MM, a syngeneic model of pleural MM was developed in immunocompetent Fischer rats. Administration of Ad.RSVtk into the pleural space of animals with established multifocal tumor followed by systemic GCV therapy resulted in significant tumor regression at 20 days in HSVtk/GCV-treated animals (average tumor weight 0.6 +/- 0.2 gram; n = 12) versus control animals (average weight 5.4 +/- 0.2 grams; n = 21; p < 0.001). In additional studies, Ad.RSVtk/GCV-treated animals had a mean survival of 34 days (average tumor weight 1.0 +/- 0.3 gram at death) versus 26 days in control animals (average tumor weight 6.2 +/- 0.6 grams at death). A significant reduction in tumor burden was also seen when more advanced, bulkier disease was treated. These studies demonstrate the Ad.RSVtk/GCV system is effective in the treatment of pleural-based tumors in an immunocompetent host. However, there are limitations to this treatment approach that result in only small increments in survival.

    Title Plenary Session: Creating a New Future--pushing the Edges of the Envelope.
    Date October 1996
    Journal Journal of Healthcare Design : Proceedings from the ... Symposium on Healthcare Design. Symposium on Healthcare Design
    Title Thoracoscopic Resection of Mediastinal Tumors and the Thymus.
    Date July 1996
    Journal Chest Surgery Clinics of North America
    Excerpt

    Videothoracoscopic techniques have proven their usefulness in dealing with pathology in the anterior mediastinum and should be considered in many cases as the procedure of choice. The surgeon's judgment, as always, is key in deciding which procedure is best suited for dealing with a particular lesion in any given patient. Thoracic surgeons need to be facile with these techniques in order to be able to provide the best approach for each patient. We need to be vigilant in observing and reporting results with these still relatively new procedures to ensure that outcomes are equivalent to the standard open procedures. The cost effectiveness of these minimally invasive procedures compared with the analogous open procedure still remains to be determined. Despite a shortened hospital stay for many of these procedures the equipment is more expensive and time in the operating room may be longer. It is safe to say, however, that many of these minimally invasive procedures are here to stay even if they fail to show a reduction in costs.

    Title Health Care in the 21st Century.
    Date May 1996
    Journal Physician Executive
    Excerpt

    Our primary agenda for the 21st Century is the reinvention of America. We must reinvent democracy, capitalism, entrepreneurism, and community. Indeed, we must recreate all of our major social institutions. This includes health care. A design for a new society requires a new design for health care. In fact, health care enjoys a special privilege in this regard. It is the gateway to total societal redesign. Health is the common denominator in any society. If you loose your health you cannot work, you cannot play, you cannot study; and, if you lose it sufficiently, you cannot even pray. Health and well-being create the foundation for all other constructive human endeavors. Therefore, the design of healthy communities is the necessary first step in the redesign of total human habitats. This massive redesign effort will take a century. However, it will be launched in the next few years.

    Title Integrin Expression in Non-small Cell Carcinoma of the Lung.
    Date February 1996
    Journal Cancer Metastasis Reviews
    Excerpt

    Alteration of integrin expression in a number of different malignant diseases has been recognized, with a trend of downregulation of collagen-laminin binding integrin expression in epithelial tumor types noted. This study evaluated the expression of a panel of integrin subunits that included subunits that form receptors that bind to collagen and laminin (alpha 2, alpha 3, alpha 6 beta 4) and subunits that form receptors that bind to fibronectin and fibrinogen (alpha 5, alpha V, beta 3, beta 6) in 51 specimens of non-small cell carcinoma (NSCCA) of the lung by use of immunohistochemistry. Integrin expression was then correlated with histologic type (squamous vs. adenocarcinoma), absence or presence of hilar or mediastinal nodal metastasis at resection, and cellular differentiation (well or poorly differentiated). In general, downregulation of the collagen-laminin binding subunits was noted in tumor cells of the NSCCA specimens when compared to the progenitor normal bronchial epithelium. No differences were noted in integrin expression between squamous cell and adenocarcinoma or between node-positive or node-negative tumors. However, downregulation of the integrin subunit alpha 3 was noted to be significantly more common in poorly differentiated tumors (p = 0.02) and several of the other collagen-laminin binding subunits also appeared to be more downregulated in poorly differentiated tumors. No upregulation was seen in the alpha 5 subunit of the fibronectin receptor or the beta 3 subunit of the vitronectin receptor, however, approximately 50% of tumors showed upregulation of the beta 6 subunit, the great majority of these being well-differentiated, node-negative tumors. Downregulation of the collagen-laminin integrins may thus be associated with differentiation of NSCCA, but not metastasis, and may serve as an adjunctive prognostic marker of disease. The beta 6 subunit appears to be associated with malignant transformation, but may serve as a positive prognostic factor.

    Title Video-assisted Thoracic Surgery: the Current State of the Art.
    Date November 1995
    Journal Ajr. American Journal of Roentgenology
    Excerpt

    Surgical thoracoscopy (or pleuroscopy) has historically been underused in the diagnosis and therapy of diseases of the chest. The rapid developments in laparoscopy in recent years caused thoracic surgeons to reconsider the use of endoscopic techniques in surgery of the chest. Advances in video camera technology and the use of digital processing technology so expanded the potential of thoracoscopy that an entirely new set of procedures, called video-assisted thoracic surgery, has emerged. This article reviews situations in which video-assisted procedures have proven useful, the techniques by which these procedures are performed, and the rationale behind using the video-assisted in lieu of the open approach. Video-assisted surgery often allows one to accomplish the same goal as the comparable open procedure but with less morbidity and a shorter hospital stay. With continued development of instrumentation, increasingly complex procedures continue to be accomplished. It is important for radiologists to be aware of these new developments in minimally invasive surgery, as the techniques have major implications for the practice of chest medicine and surgery as a whole. The evolution of the management of the solitary pulmonary nodule is but one example of the way video-assisted thoracic surgery has called into question the traditional approach to diseases of the chest.

    Title Pleural-based Mesothelioma in Immune Competent Rats: a Model to Study Adenoviral Gene Transfer.
    Date October 1995
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND. Despite multimodality approaches, pleural-based malignant mesothelioma remains a disease with a very poor prognosis. Novel therapeutic strategies such as gene therapy clearly are needed to improve the survival of patients with this neoplasm. To aid in the evaluation of new treatment strategies, animal models that closely mimic human disease are required. This article describes the establishment of a pleural-based model of malignant mesothelioma in immune-competent Fischer rats. METHODS. Via a modified left anterior lateral thorocotomy, a syngeneic malignant mesothelioma cell line, called II-45, was placed into the pleural cavity of Fischer rats. RESULTS. Placement of II-45 cells into the pleural cavity of Fischer rats results in a model of pleural mesothelioma that closely resembles the disease seen in patients and is highly reproducible, with animals dying within 1 month. We also demonstrate the feasibility of adenoviral-mediated gene transfer to normal mesothelial cells lining the pleural cavity, as well as to malignant cells deep within the substance of pleural-based malignant mesothelioma. CONCLUSIONS. The model described here offers the opportunity to study a variety of new treatment modalities, especially somatic gene transfer, against pleural-based malignant mesothelioma in an immune competent setting.

    Title The Role of Immunosuppression in the Efficacy of Cancer Gene Therapy Using Adenovirus Transfer of the Herpes Simplex Thymidine Kinase Gene.
    Date October 1995
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: To determine whether the immune system limits or improves the therapeutic efficacy of an adenovirus vector expressing the herpes simplex thymidine kinase (HSVtk) gene in a subcutaneous tumor model. BACKGROUND DATA: Enhanced immune reactions against tumors may be therapeutically useful. However, recent studies with adenoviral vectors show that immune responses limit the efficacy and persistence of gene expression. The effect of the immune response on cancer gene therapy with HSVtk gene delivery by an adenovirus vector followed by treatment with ganciclovir is unclear. METHODS: After adenoviral transduction of a Fischer rat syngeneic mesothelioma cell line with the HSVtk gene in vitro, subcutaneous flank tumors were established. The ability of the HSVtk/ganciclovir system to inhibit tumor growth was compared among normal Fischer rats, immunodeficient nude rats, and Fischer rats immunosuppressed with cyclosporin. RESULTS: HSVtk/ganciclovir therapy was more effective in nude rats and immunosuppressed Fischer rats than in immunocompetent Fischer rats. CONCLUSION: These results indicate that the immune response against adenovirally transduced cells limits the efficacy of the HSVtk/ganciclovir system and that immunosuppression appears to be a useful adjunct. These findings have important implications for clinical trials using currently available adenovirus vectors as well as for future vector design.

    Title Treatment of Experimental Human Mesothelioma Using Adenovirus Transfer of the Herpes Simplex Thymidine Kinase Gene.
    Date August 1995
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: The authors demonstrate the ability of an adenovirus vector expressing the herpes simplex thymidine kinase (HSVtk) gene to treat human malignant mesothelioma growing within the peritoneal cavity of severe combined immunodeficient (SCID) mice. BACKGROUND DATA: Introduction of the HSVtk gene into tumor cells renders them sensitive to the antiviral drug ganciclovir (GCV). This approach has been used previously to treat experimental brain tumors. Although malignant mesothelioma is refractory to current therapies, its localized nature and the accessibility of the pleural space make it a potential target for a similar type of in vivo gene therapy using adenovirus. METHODS: An adenovirus containing the HSVtk gene (Ad.RSVtk) was used to transduce mesothelioma cells in vitro. These cells were then injected into the flanks of SCID mice. Ad.RSVtk was also injected directly into the peritoneal cavity of SCID mice with established human mesothelioma tumors. Mice were subsequently treated for 7 days with GCV at a dose of 5 mg/kg. RESULTS: Mesothelioma cells transduced in vitro with Ad.RSVtk formed nodules when injected in the subcutaneous tissue. These tumors could be eliminated by the administration of GCV, even when as few as 10% of cells were transduced to express HSVtk (bystander effect). Administration of Ad.RSVtk into the peritoneal space of animals with established multifocal human mesothelioma followed by GCV therapy resulted in the eradication of macroscopic tumor in 90% of animals and microscopic tumor in 80% of animals when evaluated after 30 days. The median survival of animals treated with Ad.RSVtk/GCV was significantly longer than that of control animals treated with similar protocols. CONCLUSION: These results indicate that an adenoviral vector containing the HSVtk gene is effective in treating established malignant mesothelioma in an in vivo setting and raise the possibility of using adenovirus transfer of HSVtk for clinical trials in mesothelioma and other localized tumors.

    Title Gene Therapy Using Adenovirus Carrying the Herpes Simplex-thymidine Kinase Gene to Treat in Vivo Models of Human Malignant Mesothelioma and Lung Cancer.
    Date August 1995
    Journal American Journal of Respiratory Cell and Molecular Biology
    Excerpt

    Previous studies have shown adenoviral transfer of the herpes simplex virus thymidine kinase (HSVtk) gene followed by the anti-viral drug ganciclovir (GCV) can be used to successfully treat established human mesothelioma tumors growing within the peritoneal cavities of severe combined immune deficient (SCID) mice. These findings raised a number of questions important to the applicability, efficiency, and safety of this treatment strategy. In this report, we have further characterized the use of recombinant adenovirus carrying the HSVtk gene to treat mesothelioma and other localized malignancies. Our results indicate that the Ad.RSVtk/GCV system is effective in causing tumor regression in animals inoculated with another mesothelioma cell line and a lung cancer cell line and that animals with bulky disease can be successfully treated. Effects are seen at a wide range of virus doses and significant anti-tumor activity is present at doses of ganciclovir that are clinically achievable. Finally, this treatment approach appears safe, with limited dissemination of virus using a sensitive RT-PCR detection system. These studies further characterize the use of adenoviral transfer of the HSVtk gene to treat experimental mesothelioma and suggest that clinical trials using this approach may be feasible.

    Title Successful Nonoperative Management of Secondarily Infected Pulmonary Pseudocyst: Case Report.
    Date August 1995
    Journal The Journal of Trauma
    Excerpt

    Pulmonary contusion is a frequent sequelae of blunt chest trauma. If significant shear forces are encountered during energy transfer to the chest wall, pulmonary laceration may result. Most traumatic pulmonary lacerations resolve spontaneously. However, secondary infection of a posttraumatic laceration often leads to serious complications that may be lethal. We report a case of a secondarily infected pulmonary laceration resulting from blunt trauma that was successfully treated by computerized tomogram-guided drainage and review the literature on this unusual complication.

    Title Adenovirus-mediated Gene Transfer to Human Bronchial Submucosal Glands Using Xenografts.
    Date May 1995
    Journal The American Journal of Physiology
    Excerpt

    The cystic fibrosis (CF) transmembrane conductance regulator has been localized to both submucosal glands and surface epithelium, suggesting that both glandular and surface epithelium may be important targets for gene therapy. To determine the distribution and efficiency of recombinant adenovirus-mediated gene transfer to human airway submucosal glands, an in vivo model was developed by heterotopically transplanting human bronchial segments from both normal and CF lung tissue into severe combined immunodeficient mice. A serotype 5 E1-deleted recombinant adenovirus containing a lacZ reporter gene driven by the cytomegalovirus promoter (H5.010CMVlacZ) was used to infect the xenografts. Transgene expression was correlated with three factors: 1) viral titer, 2) penetration of microspheres, and 3) dwell time of the viral instillate. At viral titers ranging from 10(8) to 10(11) plaque forming units/ml, expression of the lacZ gene was observed in a subpopulation of epithelial cells within approximately 40% of submucosal glands, with more efficient gene transfer to the ducts than the secretory tubules. Within individual glands, gene transfer varied from < 1% to approximately 20% of submucosal cells, including duct, mucous, and serous cells. Adenovirus-sized fluorescent microspheres were found to penetrate only some of the submucosal glands, suggesting that the gene transfer efficiency to submucosal tubules is due to limited viral particle penetration rather than tropism. Gene transfer to surface epithelial cells was inefficient. However, the percentage of transduced surface epithelial cells increased from < 1% to 5-10% as the dwell time of viral solution was increased from 5 min to 1 h, indicating that the time allowed for virus binding and entry is important for gene transfer efficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Differential Sensitivity of Thoracic Malignant Tumors to Adenovirus-mediated Drug Sensitization Gene Therapy.
    Date May 1995
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    Malignant mesothelioma may prove to be an attractive candidate for somatic gene therapy with replication-deficient recombinant adenovirus transfer of a toxic, or drug sensitization gene. Transfer of the herpes simplex thymidine kinase type I gene (HSVtk), followed by exposure to the acyclic nucleoside drug ganciclovir, has been shown to be an effective tumor cell killing system. To study generalized applicability, we tested a number of thoracic malignant cell lines for their sensitivity to gancyclovir after infection with an adenoviral vector containing the HSVtk gene (Ad.RSVtk). Using the concentration of gancyclovir required to kill 50% of the cells (IC50) as a measure of sensitivity, we detected variable sensitivity among cell lines, with mesothelioma most sensitive (IC50 = 0.075 to 2.8 mumol/L gancyclovir), and non-small-cell carcinoma lines having an intermediate sensitivity (IC50 = 1.5 to 100 mumol/L). In contrast, an ovarian carcinoma line was extremely resistant (IC50 > 2000 mumol/L). To study the possible mechanisms for these differences, we studied cell lines with regard to their ability to be infected with an adenoviral vector containing a marker gene (Ad.CMVlacZ) and expression of the vitronectin receptor alpha v (an integrin cell adhesion molecule shown to be required for adenovirus internalization after initial binding). We found that the degree of lacZ transduction correlated with HSVtk sensitivity, whereas vitronectin receptor expression did not, suggesting that differences in initial viral binding ability, rather than internalization, may explain the sensitivity differences seen in vitro.

    Title Fungal Pulmonary Abscess in an Adult Secondary to Hyperimmunoglobulin E (job's) Syndrome.
    Date April 1995
    Journal The Annals of Thoracic Surgery
    Excerpt

    Job's syndrome is characterized by recurring bacterial infections of the skin and sinopulmonary tract. Laboratory evaluation reveals consistent elevation of circulating immunoglobulin E levels. The syndrome has been reported as a rare cause of bacterial pulmonary abscess and pneumatocele formation in childhood; here we present a case of cavitating fungal abscess in an adult with Job's syndrome.

    Title Thoracoscopic Removal of Mediastinal Parathyroid Adenoma.
    Date February 1995
    Journal The Annals of Thoracic Surgery
    Excerpt

    Mediastinal parathyroid tissue hyperfunctions in as much as 25% of the patients with primary hyperparathyroidism, and this may be responsible for causing conventional operative procedures to fail in as much as one-third of the cases. When lesions prove to not be accessible through a cervical incision, or when a mediastinal adenoma is diagnosed before cervical procedures, median sternotomy and angiographic ablation have been considered the only options for removal. However, thoracoscopy has theoretic advantages over both. Two patients underwent successful thoracoscopic removal of a hyperfunctioning ectopic mediastinal parathyroid adenoma and their cases are presented here.

    Title Video-assisted Thoracic Surgery. Current State of the Art.
    Date January 1995
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE. The author reviews the current state of the art of video-assisted thoracic surgery in the context of modern thoracic surgical practice. SUMMARY BACKGROUND DATA. Thoracoscopy has been a part of thoracic surgical practice for many years, but was used mainly for diagnosis of pleural disease. The development of laparoscopic cholecystectomy awakened a new interest in this technique and led to the development of many new therapeutic and diagnostic applications of video-assisted thoracic surgery. METHODS. Current literature and the author's personal experience with more than 500 cases are reviewed. RESULTS. Video-assisted techniques have proven useful for the performance of a broad spectrum of thoracic surgical procedures. Patients may experience less pain and have a shorter hospital stay after a video-assisted procedure. Definitive proof of less morbidity when compared with the analagous open procedure remains to be determined. Patient acceptance has been high, and most thoracic surgeons use these techniques in their practice. CONCLUSIONS. Video-assisted thoracic surgical procedures have made a significant impact on the practice of thoracic surgery. Advantages and disadvantages of specific procedures remain to be definitively determined. Surgeons have learned these techniques and have kept morbidity to acceptance levels during the learning phase. Where these techniques ultimately fit into the overall practice remains to be determined as more experience is gained.

    Title Plenary Session: A Conversation with Dr. Leland R. Kaiser. Panel Discussion.
    Date December 1994
    Journal Journal of Healthcare Design : Proceedings from the ... Symposium on Healthcare Design. Symposium on Healthcare Design
    Title Keynote Address: Transforming Healthcare--designing for Quality.
    Date December 1994
    Journal Journal of Healthcare Design : Proceedings from the ... Symposium on Healthcare Design. Symposium on Healthcare Design
    Title Expression of Endothelial Cell Adhesion Molecules in Human Bronchial Xenografts.
    Date October 1994
    Journal American Journal of Respiratory and Critical Care Medicine
    Excerpt

    The role of endothelial cell adhesion molecules (CAMs) in the selective recruitment of leukocyte subsets to the airway remains unclear. The goal of the present study was to examine the expression of human endothelial CAM in a cytokine-induced airway inflammatory response. To accomplish this, an in vivo model of human bronchus was developed by heterotopically transplanting intact sections of human airway into severe combined immunodeficient (SCID) mice. Three weeks after transplantation, the xenografts closely resembled normal bronchus with little evidence of rejection. Less than 15% of the submucosal vessels expressed E-selectin and vascular cell adhesion molecule-1 (VCAM-1), whereas intercellular adhesion molecule-1 (ICAM-1) was present constitutively on approximately 35% of bronchial microvessels. Intrabronchial instillation of tumor necrosis factor-alpha (TNF-alpha) significantly increased expression of microvascular E-selectin to 40%, ICAM-1 to 65%, and VCAM-1 to 41%, and was accompanied by an influx of murine leukocytes into the bronchial submucosa. These results demonstrate that the human bronchial microvasculature expresses cytokine-inducible adhesion molecules. Mast cells and other resident or migratory cells that secrete TNF-alpha may thus activate the bronchial microvasculature and thereby recruit leukocytes to the airway.

    Title Thymoma. The Use of Minimally Invasive Resection Techniques.
    Date September 1994
    Journal Chest Surgery Clinics of North America
    Excerpt

    Surgery remains the cornerstone of therapy for thymoma whether the lesion is encapsulated or invasive. Video-assisted thoracic surgical techniques may be applicable in a number of patients with encapsulated thymoma for definitive therapy, especially when combined with a transcervical approach to achieve total thymectomy. Initial experience with a minimally invasive approach for resection of thymomas is described. The development of new instrumentation facilitates the performance of these procedures.

    Title Prevention and Potentiation: Two New Dimensions of American Health Care.
    Date July 1994
    Journal California Hospitals
    Title Successful Adenovirus-mediated Gene Transfer in an in Vivo Model of Human Malignant Mesothelioma.
    Date July 1994
    Journal The Annals of Thoracic Surgery
    Excerpt

    Malignant mesothelioma remains a frustrating clinical problem with uniformly poor responses to current therapeutic regimens. However, the localized nature of the disease, the potential accessibility of the tumor, and the relative lack of distant metastases make it a particularly attractive candidate for somatic gene therapy. The purpose of this study was to evaluate the ability of an adenoviral vector system to transfer genetic material to human mesothelioma cells in vitro and in vivo. Using a replication-deficient recombinant adenovirus carrying the Escherichia coli lacZ marker gene, we found that human mesothelioma cell lines were susceptible to adenovirus infection. Furthermore, surprisingly effective gene transfer was accomplished within tumor implants of human mesothelioma growing within the peritoneal cavity of immunodeficient mice after intraperitoneal administration of virus. These studies demonstrate that adenoviral vectors hold promise as vehicles to deliver gene therapy in human malignant mesothelioma.

    Title Use of Recombinant Adenovirus to Transfer the Herpes Simplex Virus Thymidine Kinase (hsvtk) Gene to Thoracic Neoplasms: an Effective in Vitro Drug Sensitization System.
    Date June 1994
    Journal Cancer Research
    Excerpt

    Transfer of the herpes simplex virus thymidine kinase (HSVtk) gene into tumor cells using retroviral vectors followed by administration of ganciclovir provides a potential strategy for the treatment of malignancy. Because of the limitations of using retroviral vectors for clinical application, the feasibility of using a recombinant adenovirus containing HSVtk was examined. Cell lines derived from human malignant mesotheliomas and non-small cell lung cancers infected with a recombinant adenovirus containing HSVtk showed strong expression of HSVtk protein as determined by immunohistochemical staining. Infection with a recombinant adenovirus containing HSVtk rendered cells sensitive to doses of ganciclovir that were 2-3 logs lower than uninfected cells or those infected with a control virus. A strong "bystander effect" was noted in mesothelioma lines; there was no diminution in the efficacy of ganciclovir treatment until the ratio of infected:uninfected cells fell below 1:10. This study thus demonstrates in vitro efficacy of an adenovirus-transduced HSVtk drug sensitization gene therapy system in thoracic malignancies. Recombinant adenovirus transfer of the HSVtk gene followed by ganciclovir may have promise as an in situ treatment for tumors.

    Title Esophageal Disease in the Elderly Patient.
    Date March 1994
    Journal The Surgical Clinics of North America
    Excerpt

    Disorders of the esophagus in elderly patients are usually associated with the classic symptoms of dysphagia, regurgitation, chest pain, and heartburn. Pulmonary complaints as a result of undiagnosed esophageal disease are common in this age group. Diagnosis is often delayed because symptoms are attributed to underlying cardiac and pulmonary disease. Elderly patients are more susceptible to the complications of aspiration and malnutrition that often accompany inadequately treated esophageal disease; therefore, prompt and aggressive treatment is indicated. Criteria for surgical intervention in esophageal disease do not change with age. Properly selected elderly patients tolerate esophageal surgery well. Age alone should not constitute a contraindication to surgery of the esophagus.

    Title The Donor Lung: Infectious and Pathologic Factors Affecting Outcome in Lung Transplantation.
    Date November 1993
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    The prevalence of posttransplantation pulmonary infection and the importance of this complication with respect to morbidity in patients undergoing lung transplantation is significant. Over a 1-year period, case histories of all patients undergoing lung transplantation at Barnes Hospital, Washington University, were reviewed to examine the importance of organisms isolated in the donor lung in the development of subsequent invasive infection in transplant recipients. Twenty-eight of 29 bronchial washings (97%) taken from donors before retrieval grew at least one organism. The most common organisms identified were Staphylococcus and Enterobacter. In 12 of these cases (43%), similar organisms were isolated from the tracheobronchial tree of the recipients, and 6 of these recipients (21%) subsequently had invasive pulmonary infections as a result of the organism originally isolated in the donor. We recommend that antibiotic coverage in transplant recipients should be initiated on the basis of Gram stain results and modified on the basis of cultures obtained from the donor lungs. Pathologic analysis of donor lung tissue taken before transplantation was available in 12 cases. Four donors had histologic evidence of established pneumonia in the donor lung, and infections then developed in the recipients. One other patient who received a lung that had widespread bone marrow emboli and subsequent infarction later had a complete anastomotic dehiscence. An additional patient had profound early donor lung dysfunction without any evidence of rejection or infection. Pathologic findings from the donor in this case demonstrated preexistent acute vasculitis with emboli. We suggest that as preservation techniques improve, the opportunities for closer scrutiny of donor lung tissue before implantation will become increasing desirable and feasible.

    Title Complications of Thoracoscopy.
    Date October 1993
    Journal The Annals of Thoracic Surgery
    Excerpt

    Although thoracoscopy has been a part of thoracic surgical practice for many years, the advent of video-assisted techniques has greatly expanded the indications and the uses of this procedure. Where previously thoracoscopy was performed mainly for diagnostic purposes, it now has assumed a major role in the therapy of chest pathology. In an attempt to inject a modicum of perspective into the tremendous enthusiasm that has accompanied the meteoric rise of video-assisted thoracoscopy, we have reviewed the experience at the Hospital of the University of Pennsylvania accumulated over the 1-year period from December 1991 to December 1992, specifically looking at complications resulting from the thoracoscopic procedure. During this period we performed 266 thoracoscopic procedures with no deaths. The overall incidence of complications was 10%, with the most prevalent complication being prolonged air leak (3.7%). There were five superficial wound infections (1.9%) and 5 patients who bled significantly enough to require either transfusion or reoperation, or both. In 11 patients (4.1%), the proposed thoracoscopic procedure could not be completed as planned, and a thoracotomy was required. The incidence of complications is certainly acceptable and similar to that seen after thoracotomy, although overall hospital stay is shorter and patients seem to have less pain and return to normal activity sooner. One would expect the incidence of complications to further decrease as surgeons acquire more experience with this significant modification and improvement of an old technique.

    Title Active Collagen Synthesis by Pulmonary Arteries in Human Primary Pulmonary Hypertension.
    Date July 1993
    Journal The American Journal of Pathology
    Excerpt

    Immunohistochemistry was performed on lung tissue obtained from patients with severe unexplained pulmonary hypertension using an antibody to the amino-terminal end of the procollagen type I propeptide. This antibody identifies newly synthesized alpha I(I) procollagen before cleavage of the amino-terminal propeptide following secretion and, therefore, can identify sites of active collagen deposition. Procollagen was detected in the media, media and neointima, or neointima alone of a large number of small muscular arteries from hypertensive lungs. Normal adult lungs were negative. Neointimal cells in remodeled small muscular arteries stained positively for alpha-smooth muscle actin and desmin consistent with a smooth muscle lineage. These data suggest smooth muscle-like cells in small muscular arteries are actively synthesizing collagen in patients with severe unexplained pulmonary hypertension.

    Title Managing in Uncertain Times.
    Date June 1993
    Journal Journal of Healthcare Materiel Management
    Excerpt

    Radical change, often referred to as a paradigm shift, will occur in the wake of the United States healthcare reform effort currently underway. It will be value-based, community-oriented and patient- and family-centered. These changes will pose great challenges for materiel management. The future will call for integrated healthcare delivery networks that will see hospitals lose their preeminence as providers and, subsequently, needed revenues. Strategies such as implementation of total quality management, and vendor and community partnering will become more pronounced. Materiel managers will see their role change to one of information gathering and disseminating. All healthcare managers will need new skills to help shape the future of healthcare delivery, including the ability to challenge assumptions, understand that there are alternative realities, anticipate business trends, and create and implement a vision of the future of their organization.

    Title Weaving Together New Alliances. Community Health Networks: Meeting the Challenge of the 21st Century.
    Date April 1993
    Journal California Hospitals
    Title Neointimal Macrophages Colocalize with Extracellular Matrix Gene Expression in Human Atherosclerotic Pulmonary Arteries.
    Date March 1993
    Journal The Journal of Clinical Investigation
    Excerpt

    Vascular remodeling in adult atherosclerotic pulmonary arteries is characterized by discrete areas of neointimal extracellular matrix gene expression, suggesting regulation by local factors. Though the factors responsible for inducing matrix gene expression in atherosclerotic lesions are largely unknown, several observations suggest macrophages may be a focal source of those factors. Immunohistochemistry confirmed the presence of macrophages in the neointima of atherosclerotic elastic pulmonary arteries from patients with unexplained pulmonary hypertension. Areas of neointima containing dense clusters of macrophages were separated by sparsely populated areas. Foamy macrophages resided more deeply within the neointima than nonfoamy macrophages, which were found more often subjacent to the endothelium or within the lumenal one-third of the neointima. Combined immunohistochemistry-in situ hybridization indicated neointimal fibronectin and type I procollagen gene expression was intimately associated only with nonfoamy neointimal macrophages. These observations suggest that: (a) nonfoamy neointimal macrophages participate in the local regulation of extracellular matrix gene expression in atherosclerotic pulmonary arteries; (b) foamy macrophages, which are not associated with matrix gene expression, have undergone modulation of their secretory phenotype.

    Title Technology: Redesigning the Medical System.
    Date January 1993
    Journal Medical Group Management Journal / Mgma
    Excerpt

    During the next century, medical technology will become the driving force in American health care, according to Leland Kaiser, Ph.D., FACMGA. Society will no longer view health care as simply a cost to be reduced to the lowest possible level. Health expenditures will be seen as a societal investment in human resource productivity.

    Title Pulmonary "twinning" Procedure: Use of Lungs from One Donor for Single-lung Transplantation in Two Recipients.
    Date December 1992
    Journal The Annals of Thoracic Surgery
    Excerpt

    Since the introduction of lung transplantation as an option for patients with end-stage respiratory disease in the early 1980s, there have been substantial advances made in the technical aspects of transplantation as well as the early clinical results. With an ever-increasing number of patients being designated suitable candidates for transplantation, the volume of transplants in the foreseeable future will be limited more on the basis of donor lung supply than any other single factor. Pulmonary "twinning" provides an important step in ensuring that all suitable and available donor lungs are utilized whenever feasible. This report reviews the results of 20 single-lung transplantations carried out in five separate transplantation centers using organs retrieved from ten donors. The overall mortality rate in this group of patients was 5%, which compares very favorably with historical controls. No serious problem was noted with respect to increased perioperative morbidity or increased ischemic times in this group of patients. We suggest that this process should be considered and, wherever possible, adopted by all major lung transplant centers.

    Title The Role of Transbronchial Lung Biopsy in the Treatment of Lung Transplant Recipients. An Analysis of 200 Consecutive Procedures.
    Date November 1992
    Journal Chest
    Excerpt

    STUDY OBJECTIVE: The purposes of this study were as follows: (1) to establish the positivity rate and complication rate of transbronchial lung biopsies in the treatment of lung transplant recipients; (2) to determine the sensitivity of transbronchial lung biopsy specimens for the diagnosis of clinically suspected acute rejection and cytomegalovirus pneumonia; and (3) to examine the results of surveillance transbronchial lung biopsies in clinically and physiologically stable recipients. DESIGN: Retrospective review and analysis of 203 consecutive procedures. SETTING: Washington University Lung Transplantation Program, Washington University School of Medicine and Barnes Hospital, St. Louis, Mo. PATIENTS: Fifty-five lung transplant recipients. INTERVENTIONS: Biopsies were done with 2-mm fenestrated forceps using fluoroscopic guidance. Two hundred three bronchoscopies with transbronchial lung biopsy were performed for clinical indications (n = 88), routine surveillance (n = 90), or follow-up of a previous biopsy (n = 25). Biopsy specimens showing acute allograft rejection were classified according to the scheme recommended by the Lung Rejection Study Group. MEASUREMENTS AND RESULTS: The positivity rate and complication rate were determined for the procedures. In procedures performed for clinical indications, the sensitivity for the diagnosis of acute rejection and cytomegalovirus pneumonia was calculated by a decision-to-treat analysis. A specific histologic diagnosis was detected in 69 percent of the clinical procedures, 57 percent of the surveillance procedures, and 64 percent of the follow-up procedures. For clinical indications, the sensitivity of transbronchial lung biopsy was 72 percent for the diagnosis of acute rejection and 91 percent for the diagnosis of cytomegalovirus pneumonia. Surveillance biopsy specimens often showed clinically inapparent rejection or cytomegalovirus pneumonia. The overall complication rate was 8.9 percent; none of the complications were life threatening. CONCLUSIONS: Transbronchial lung biopsy is a useful and safe procedure in the treatment of lung transplant recipients. When performed for clinical indications, the procedure proved to be sensitive for the diagnosis of acute rejection and cytomegalovirus pneumonia. When performed for surveillance in clinically and physiologically stable recipients, the incidence of rejection and cytomegalovirus pneumonia was unexpectedly high; the potential clinical implications of these findings will require further study.

    Title Pulmonary Vein Obstruction Following Single Lung Transplantation.
    Date September 1992
    Journal Chest
    Excerpt

    Angiographic documentation after single lung transplant showed pulmonary venous obstruction due to compression by the omental pedicle. Retransplantation is described, and this complication is examined.

    Title Pediatric Lung Transplantation for Pulmonary Hypertension and Congenital Heart Disease.
    Date August 1992
    Journal The Annals of Thoracic Surgery
    Excerpt

    Five children underwent lung transplantation for end-stage pulmonary hypertension and respiratory insufficiency associated with congenital heart disease. One (17 mo) had pulmonary hypertension with a patent ductus arteriosus and required two periods of preoperative extracorporeal membrane oxygenation before successful bilateral sequential lung transplantation. One (21 mo) required bilateral lung transplantation for pulmonary hypertension and bronchopulmonary dysplasia associated with iatrogenic injury to the left pulmonary artery. This child also had patent ductus arteriosus ligation and preoperative catheter closure of an atrial septal defect. Extracorporeal membrane oxygenation was required for early postoperative pulmonary support. One child underwent right single-lung transplantation and closure of an atrial septal defect for pulmonary hypertension. Two patients had single-lung transplantation for Eisenmenger's syndrome: 1 with muscular inlet ventricular septal defect closure, atrial septal defect closure, and right single-lung transplantation; 1 with ventricular septal defect closure, patent ductus arteriosus ligation, right ventricular outflow tract patch repair, and single-lung transplantation. All patients survived operation, with one late death (lymphoproliferative disease). The 4 survivors are all ambulatory without oxygen and have evidence of normal pulmonary artery pressure 9 to 12 months after transplantation.

    Title Morbidity, Mortality, and Early Results of Single Versus Bilateral Lung Transplantation for Emphysema.
    Date July 1992
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    Both single lung transplantation and bilateral lung transplantation have been successful in patients with chronic obstructive pulmonary disease. Limited availability of donor lungs dictates wider use of single lung transplantation as long as this procedure provides a comparable functional result at less risk. Early morbidity, mortality rates, and functional results were compared in 32 consecutive patients undergoing either single or bilateral lung transplantation for end-stage chronic obstructive pulmonary disease. When pretransplantation and posttransplantation values of forced expiratory volume in 1 second, single breath diffusing capacity, total lung capacity, arterial oxygen tension, and 6-minute walking distance were compared, statistically significant improvement (p less than 0.01) was seen in both groups. However, significantly higher values (p less than 0.01) were attained for forced expiratory volume in 1 second, single breath diffusing capacity, and arterial oxygen tension in the bilateral transplantation group than in the single lung transplantation group. Patients receiving bilateral lung transplants were at greater risk for postoperative complications, especially cardiac arrhythmias and bronchial anastomotic defects. Actuarial survival for the single lung transplantation group was 93% at 1 year, versus 87% at 6 months and 71% at 1 year for the bilateral lung transplantation group. The optimal transplantation procedure for patients with chronic obstructive pulmonary disease has not been determined. Longer follow-up periods are needed to define better the roles of bilateral and single lung transplantation in this group of patients.

    Title Management of Dysfunction in the Transplanted Lung: Experience with 7 Clinical Cases. Washington University Lung Transplant Group.
    Date April 1992
    Journal The Annals of Thoracic Surgery
    Excerpt

    In a series of 34 lung transplant patients, donor lung dysfunction occurred on 7 occasions. One patient underwent retransplantation and the remaining 6 were treated conservatively. Survival was 100% in the donor lung dysfunction group. Percent predicted forced expiratory volume in 1 second, carbon monoxide diffusion, room air oxygen tension, and distance walked in 6 minutes were all lower (p less than 0.05) at 1 month after transplantation in those patients with donor lung dysfunction as compared with those without. These differences were not significant at 3 months after transplantation. We conclude that donor lung dysfunction can usually be managed conservatively with satisfactory results. Longer follow-up of this group of patients will be necessary to determine the long-term consequences of early graft injury.

    Title Single Lung Transplantation for Pulmonary Hypertension. Technical Aspects and Immediate Hemodynamic Results.
    Date April 1992
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    Donor availability has limited the clinical applicability of heart-lung transplantation in patients with end-stage pulmonary hypertension. Satisfaction with single lung transplantation in other patient groups prompted its extension to patients with pulmonary hypertension. Nine patients with end-stage pulmonary hypertension underwent single lung transplantation. Important technical considerations included routine use of cardiopulmonary bypass, simultaneous closure of significant associated cardiac defects (n = 4), and use of remaining thoracic donor organs in multiple recipients (total thoracic transplants from eight donors = 21). Analysis of immediate postoperative hemodynamics suggests that early relief of pulmonary hypertension and improvement in right ventricular function can be expected. There was one postoperative death. Eight patients have been discharged and are alive and well at a mean follow-up period of 1 year. All eight survivors have returned to New York Heart Association functional class I from their preoperative levels of III or IV. These results support the use of single lung transplantation as a transplant option in patients with end-stage pulmonary hypertension. The question of long-term durability remains unanswered.

    Title Extracellular Matrix Protein Gene Expression in Atherosclerotic Hypertensive Pulmonary Arteries.
    Date March 1992
    Journal The American Journal of Pathology
    Excerpt

    Lobar pulmonary arteries from patients with unexplained pulmonary hypertension were obtained at the time of single-lung transplantation to determine the response of large elastic vessels to increased intraluminal pressure. Specifically, human pulmonary arteries were examined to determine if remodeling remained active at the time of surgery and whether remodeling was similar to previously reported remodeling observed in several animal models. Grossly, the hypertensive vessels appeared atherosclerotic. Histochemical stains revealed a thick, diffuse neointima in hypertensive vessels compared with normal vessels. Immunohistochemistry demonstrated elastin protein in the neointima and in situ hybridization studies demonstrated tropoelastin mRNA largely in the neointima. Similarly, immunohistochemistry and in situ hybridization detected cellular fibronectin, thrombospondin and type I collagen protein and mRNA within the thickened intima from hypertensive vessels. These studies provide evidence that hypertensive vessels in patients with severe chronic pulmonary hypertension are actively remodeling but that the pattern of remodeling is different from previously described animal models.

    Title Lung Transplantation. Analysis of Thirty-six Consecutive Procedures Performed over a Twelve-month Period. The Washington University Lung Transplant Group.
    Date March 1992
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    A consecutive series of 36 lung transplant procedures in 35 patients, performed over a 12-month period, has been reviewed. There were 14 men and 21 women undergoing 23 single, 12 bilateral, and one en bloc double lung transplant. There were one hospital death and three late deaths in the series, giving a hospital survival rate of 97.2% and a 1-year actuarial survival figure of 91.7%. Airway complications occurred in six patients (17.2%), one of whom died. Cytomegalovirus infection was demonstrated in 18 patients (51%), but no deaths have resulted. The most common cardiac complication was an atrial tachyarrhythmia (nine patients, 25.7%) and three patients had a cardiac arrest, but all were successfully resuscitated. Twelve patients required a further 25 surgical procedures after transplantation; however, renal and hematologic complications were uncommon. The prevalence and management of the other associated complications is discussed.

    Title Lung Transplantation of Ventilator-dependent Patients. The Washington University Lung Transplantation Group.
    Date February 1992
    Journal Chest
    Excerpt

    During the last few years, lung transplantation has been extended to patients with a variety of end-stage lung diseases, but recipient selection guidelines have remained relatively strict. Ventilator-dependent patients have traditionally been considered poor candidates for transplantation. However, patients who have been thoroughly evaluated and accepted for transplantation and subsequently develop respiratory failure caused by progression and/or exacerbation of their underlying disease and recipients who experience respiratory failure caused by graft failure may be suitable candidates while ventilator-dependent if no other major complications or contraindications arise before a donor organ becomes available.

    Title Single-lung Transplantation for Pulmonary Hypertension. Three-month Hemodynamic Follow-up.
    Date January 1992
    Journal Circulation
    Excerpt

    BACKGROUND. Shorter waiting times, relative technical simplicity, and satisfactory application to a broad spectrum of patients has made single-lung transplantation an attractive option in the treatment of patients with end-stage pulmonary hypertension. METHODS AND RESULTS. Seven patients with pulmonary hypertension underwent single-lung transplantation. Simultaneous closure of associated atrial septal defects was accomplished in two patients. Despite severely compromised pretransplant right ventricular function in all patients, there was no early or late mortality. Right ventricular functional recovery as characterized by hemodynamic assessment before and at a mean of 13 weeks posttransplant was nearly uniform and characterized by a drop in 1) pulmonary arterial systolic pressure from 92 +/- 7 mm Hg to 29 +/- 6 mm Hg (p = 0.001), 2) central venous pressure from 10 +/- 6 mm Hg to 1 +/- 2 mm Hg (p = 0.02), and 3) pulmonary vascular resistance index from 1,924 +/- 663 to 232 +/- 73 dyne.sec.cm-9 (p = 0.001). Radionuclide ventriculography before and at a mean of 17 weeks posttransplant documented a significant (p = 0.006) increase in right ventricular ejection fraction from 22 +/- 15% to 51 +/- 11%. Quantitative pulmonary perfusion scintigraphy at a mean of 17 weeks posttransplant demonstrated a significant (p = 0.001) increase in perfusion to the transplanted lung from 56 +/- 6% to 89 +/- 7%. There was a concomitant, slight but significant (p = 0.004) decrease in ventilation to the transplanted side from 56 +/- 6% to 49 +/- 8%. After transplantation, all patients returned to New York Heart Association functional class I or II from their preoperative levels of class III or IV. CONCLUSIONS. These early follow-up data cautiously support the option of single-lung transplantation in patients with pulmonary hypertension, although long-term durability of these hemodynamic changes deserves documentation before widespread application.

    Title Intraoperative Use of Transesophageal Echocardiography with Pulsed-wave Doppler Evaluation of Ventricular Filling Dynamics During Pericardiotomy.
    Date November 1991
    Journal Anesthesiology
    Title Bilateral Sequential Lung Transplantation: the Procedure of Choice for Double-lung Replacement.
    Date October 1991
    Journal The Annals of Thoracic Surgery
    Excerpt

    We recently described a technique for bilateral sequential lung transplantation that replaces the en bloc double-lung operation, a procedure that was accompanied by frequent problems with airway healing. Twenty-seven patients have undergone 28 bilateral sequential lung transplantations over the past 14 months. Eighteen patients had transplantation because of end-stage emphysema; 6, cystic fibrosis; and 1 each, obliterative bronchiolitis, usual interstitial pneumonitis with pulmonary fibrosis, and bronchiectasis. Cardiopulmonary bypass was used electively in the first 5 patients until it was recognized that the procedure could be done safely without it, and in only 3 additional recipients has it been employed. Mean ischemic time for the first lung was 276 +/- 43 minutes and for the second lung, 410 +/- 64 minutes. There have been five deaths, three in the postoperative period (11% operative mortality) and two late. The other patients are alive and well and do not require oxygen 2 to 15 months after transplantation. Mean forced expiratory volume in 1 second rose from 16% +/- 8% of predicted to 84% +/- 17% at 12 weeks. Six-minute walk values increased from a mean of 251 +/- 91 m to 666 +/- 42 m at 24 weeks. The excellent exposure afforded to both hemithoraces by the thoracosternotomy incision and the rare need of cardiopulmonary bypass have allowed us to offer the option of transplantation to patients who formerly would have been turned down because of previous pulmonary resection or pleurectomy. On four occasions, ventilator-dependent patients underwent successful transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title The Washington University-barnes Hospital Experience with Lung Transplantation. Washington University Lung Transplantation Group.
    Date October 1991
    Journal Jama : the Journal of the American Medical Association
    Excerpt

    OBJECTIVE.--To review our experience with lung transplantation, emphasizing recipient selection, choice of procedure, functional results, and outcome. DESIGN.--Retrospective review of patients who received lung transplants at Barnes Hospital, St Louis, Mo, between July 1, 1988, and January 31, 1991. SETTING.--Washington University School of Medicine, St Louis, Mo, and Barnes Hospital, a medical school and its affiliated referral hospital, respectively. PATIENTS.--Sixty-nine lung transplant procedures were performed in 66 recipients. Patients with clinically and physiologically severe lung disease were selected according to predetermined guidelines. Underlying diseases in the recipients included chronic obstructive pulmonary disease, alpha 1-antitrypsin deficiency emphysema, cystic fibrosis, pulmonary fibrosis, primary pulmonary hypertension, Eisenmenger's syndrome associated with an atrial septal defect, bronchiectasis, eosinophilic granuloma, and lymphangiomyomatosis. INTERVENTION.--Double-lung, bilateral sequential, and single-lung transplantations were performed. Eight patients underwent en bloc double-lung transplantations or a modification of this procedure with separate bronchial anastomoses. Thereafter, the bilateral sequential approach to replacement of both lungs was performed in 26 patients. Thirty-two patients underwent single-lung transplantations. MAIN OUTCOME MEASURES.--Pulmonary function tests, arterial blood gas levels, pulmonary artery pressure, pulmonary vascular resistance, and actuarial survival. RESULTS.--Actuarial survival at 1 year for the 66 lung transplant recipients was 79%. Actuarial survival at 1 year was 82% for the bilateral lung transplant recipients and was 90% for the single-lung transplant recipients. In patients with either restrictive or obstructive lung disease, pulmonary function tests and arterial blood gas levels improved markedly after lung transplantation. In patients with primary pulmonary hypertension or Eisenmenger's syndrome, the pulmonary artery pressure decreased and the cardiac index increased into the normal range after single-lung transplantation. CONCLUSIONS.--In carefully selected patients with end-stage lung disease, single-lung and bilateral lung transplantations can significantly improve functional capacity, with promising early actuarial survival statistics after 1 year.

    Title The Evolution of Single Lung Transplantation for Emphysema. The Washington University Lung Transplant Group.
    Date October 1991
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    Classic transplantation dogma mandated bilateral lung replacement for lung transplant candidates with end-stage emphysema to avoid air trapping in the native lung and subsequent crowding of the newly transplanted lung. During a recent 12-month period 11 patients with emphysema received a single lung transplant. There was no hospital mortality and only one patient had any notable degree of air trapping in the native lung. Substantial improvement in pulmonary function was seen as early as 2 weeks after transplantation, with significant functional improvement seen by 6 weeks, despite some residual ventilation-perfusion mismatch. We have demonstrated the utility and safety of single lung transplantation for patients with end-stage emphysema, and it is our operation of choice in recipients more than 50 years of age.

    Title The Future of Group Practice and Mgma (medical Group Management Association). Interview by Dennis Barnhardt.
    Date November 1990
    Journal Medical Group Management Journal / Mgma
    Title Improved Technique for Bilateral Lung Transplantation: Rationale and Initial Clinical Experience.
    Date June 1990
    Journal The Annals of Thoracic Surgery
    Excerpt

    We previously described a technique for en bloc double-lung transplantation that was initially applied to select patients with cystic fibrosis and emphysema. This procedure is quite complex and associated with several limitations, including a substantial incidence of airway ischemia, postoperative myocardial depression, and cardiac denervation. To address these problems we have developed a simpler procedure for replacing both lungs. The operation is done through a transverse thoracosternotomy and involves sequential replacement of the two lungs. Positive features include separate bronchial anastomoses to reduce ischemic airway complications, elimination of the need for total cardiopulmonary bypass and a period of ischemic cardiac arrest, improved exposure to reduce intraoperative and postoperative hemorrhage, and maintenance of cardiac innervation. Additionally, the technique can be more easily mastered and widely applied. Details of the procedure and its initial clinical application in 3 patients having emphysema, cystic fibrosis, and bronchiolitis obliterans following previous double-lung transplantation, respectively, are described. All 3 patients recovered without complication. Postoperative function was excellent in spite of lung ischemic times ranging up to 91/2 hours.

    Title Lung Transplantation.
    Date December 1989
    Journal Current Problems in Surgery
    Excerpt

    The supply of donor organs remains extremely limited, and improved methods of maintaining the lungs of potential donors to allow for transplantation must be developed. Currently the upper limit of donor lung ischemic even with our "best" preservation techniques is approximately 4 to 6 hours. Improved methods for preservation will increase the supply of suitable lungs and will considerably simplify the logistics of transplantation just as has occurred with liver transplantation. Efficient use of donor organs remains of paramount importance. We recently performed two single-lung transplants utilizing lungs from one donor. Likewise, there is no reason why a lung could not be sent to another center for transplantation if the harvesting group uses only one lung. Sufficient progress has been achieved to date to warrant continued application of lung transplantation for end-stage pulmonary disease. With increasing experience, one can anticipate refinement of techniques and broader application of these procedures. Single lung transplantation, initially restricted to patients with end-stage pulmonary fibrosis, has now been successfully applied to patients with emphysema, pulmonary hypertension, and other conditions. Although transplantation currently can offer real benefit only to a limited number of persons, it serves to create hope for many others. An additional benefit may prove to be the interest and attention that transplantation focuses on patients with end-stage lung disease and on the pathophysiology of chronic respiratory failure. Knowledge gained may ultimately result in the prevention of many of the disorders for which lung transplantation currently offers the only hope.

    Title Single Lung Transplantation for Severe Chronic Obstructive Pulmonary Disease. Washington University Lung Transplant Group.
    Date November 1989
    Journal Chest
    Excerpt

    Single lung transplantation (SLT) has been considered physiologically inappropriate for patients with chronic obstructive pulmonary disease (COPD). It has been postulated that the high static compliance and elevated pulmonary vascular resistance of the native lung functioning in parallel with the more normal allografted lung could cause unacceptable ventilation-perfusion mismatching and/or overinflation of the native lung with encroachment on the expansion of the transplanted lung. While some degree of ventilation-perfusion imbalance may be physiologically obligatory after SLT for COPD, a significant disruption in gas exchange may not occur unless a complication, such as rejection or infection, arises in the transplanted lung. A 60-year-old man with COPD who underwent successful SLT is presented and discussed. In spite of scintigraphic evidence of ventilation-perfusion mismatching between the native lung and the allograft during the first six postoperative weeks, the recipient had normal resting gas exchange on room air after the second postoperative week. Fourteen weeks after transplantation, his maximum oxygen uptake was 37.3 percent of the predicted maximal value, and no evidence of ventilatory limitation was detected. His functional status and lifestyle have been markedly improved by SLT. The role of SLT for COPD should be reconsidered. It may be a reasonable transplantation alternative for selected patients with COPD who are not candidates for double lung transplantation (DLT).

    Title Indeterminate Mediastinal Invasion in Bronchogenic Carcinoma: Ct Evaluation.
    Date October 1989
    Journal Radiology
    Excerpt

    The computed tomographic (CT) scans of 80 patients with bronchogenic carcinoma classified as indeterminate for direct mediastinal invasion were retrospectively reviewed after the patients had undergone thoracotomy. Forty-eight (60%) of the masses were resectable, without invasion of the mediastinum, 18 (22%) focally invaded the mediastinum but were technically resectable, and 14 (18%) invaded the mediastinum and were not technically resectable. Although in most circumstances in this relatively small subset of patients CT was not helpful in differentiating masses with and without mediastinal invasion, CT was able to separate a large group of masses that were likely to be technically resectable. Thirty-six (97%) of 37 masses with one or more of these CT findings were considered technically resectable: contact of 3 cm or less with mediastinum, less than 90 degrees of contact with aorta, and mediastinal fat between mass and mediastinal structures. Of these 36 masses, 28 were resectable without mediastinal invasion, and eight were resectable with focal limited mediastinal invasion.

    Title Surgical Considerations in the Management of the Immunocompromised Patient.
    Date February 1989
    Journal Critical Care Clinics
    Excerpt

    We have attempted to give a broad overview of issues of importance to the surgeon that may arise in the management of the immunocompromised patient. These include airway obstruction, diffuse and focal pulmonary lesions, vascular access problems, gastrointestinal bleeding, perforation, obstruction, and soft tissue infections. Principles of perioperative management in this patient group are discussed in detail. Often they will require broad metabolic and hemodynamic support. The spectrum of pathology ranges from common problems found in the general patient population that present with only subtle clinical findings, making diagnosis difficult, to conditions unique to the patient with a deficient immune system. The importance of early consultation with the surgeon for the indications that have been described cannot be overemphasized. One should attempt to identify certain surgeons who have a particular interest in dealing with these complex problems. It is of the utmost importance for the surgeon to have the guidance of the primary physician with regard to aggressiveness of therapy. This decision must take into account the basic underlying disorder as well as the wishes of the patient and family. Many of these patients can be salvaged despite the seemingly endless problems that may arise along the way.

    Title The Effects of Preoperative Chemotherapy on the Resectability of Non-small Cell Lung Carcinoma with Mediastinal Lymph Node Metastases (n2 M0).
    Date May 1988
    Journal The Annals of Thoracic Surgery
    Excerpt

    We have defined "clinical N2" disease in non-small cell lung cancer to mean the presence of enlarged metastatic mediastinal nodes evident on plain chest roentgenograms or widening of the carina at bronchoscopy. Forty-one patients with non-small cell carcinoma of the lung and clinical N2 M0 disease presumed operable received 2 to 3 cycles of high-dose cisplatin with vindesine (or vinblastine sulfate) with or without mitomycin-C. Following chemotherapy, 30 patients (73%) had a major radiographic response. Of these patients, 28 had thoracotomy, and 21 (75%) of them had complete resection of the disease, 8 of whom had total sterilization of the tumor proven histologically. An additional 4 patients had limited microscopic foci of residual tumor either in lung or lymph nodes. Survival at 3 years from diagnosis was 34% for all patients, 40% for those who completed the combined treatment (chemotherapy and surgery), and 54% for those who had complete resection with a median follow-up of 44 months and a median survival not yet attained.

    Title Results of Surgical Treatment of Stage Iii Lung Cancer Invading the Mediastinum.
    Date October 1987
    Journal The Surgical Clinics of North America
    Excerpt

    From 1974 to 1984, 225 patients underwent thoracotomy at Memorial Sloan-Kettering Cancer Center for primary non-small cell lung cancer invading only the mediastinum (T3). The perioperative mortality was 2.7 per cent, and the nonfatal complication rate 13 per cent. Forty-nine patients underwent complete resection of all intrathoracic disease, with a median survival of 17 months, 3-year survival of 21 per cent, and 5-year survival of 9 per cent. Thirty-three patients underwent pulmonary resection with simultaneous iodine-125 interstitial implantation or iridium-192 delayed afterloading to areas of unresectable primary or nodal disease, with a median survival of 12 months, 3-year survival of 22 per cent, and 5-year survival of 22 per cent. One hundred and one patients underwent interstitial implantation without resection, with a median survival of 11 months, 3-year survival of 9 per cent, and no 5-year survivors. Forty-two patients had incomplete resection without intraoperative radiation therapy and fared no better than a cohort group of 44 unoperated patients with clinical evidence of mediastinal invasion--both groups had a median survival of 8 months and no 3-year survivors. An aggressive surgical approach with pulmonary resection and/or brachytherapy appears to offer some survival advantage to this group of patients. In particular, 5-year survival rates ranging from 7 to 15 per cent were observed in subsets of intraoperatively treated patients with invasion of pulmonary vein, phrenic nerve, esophagus, or pericardium and in those with clinically occult T3 disease.

    Title Methods of Skeletal Reconstruction Following Resection of Lung Carcinoma Invading the Chest Wall.
    Date October 1987
    Journal The Surgical Clinics of North America
    Excerpt

    The 5 per cent of patients with carcinoma of the lung directly invading the chest wall present a challenge for treatment. Complete resection of all tumor, including the chest wall, should be done. Immediate reconstruction to prevent a flail chest ensures a smooth postoperative course. Excellent palliation and a 46 per cent 5-year survival rate can be achieved if there is no spread to mediastinal lymph nodes.

    Title Pleural Mesothelioma.
    Date February 1987
    Journal The Annals of Thoracic Surgery
    Excerpt

    Pleural mesotheliomas are uncommon tumors. Correct diagnosis of the benign variant is rarely made preoperatively, and resection is the treatment of choice and is curative. Malignant pleural mesotheliomas are locally aggressive and difficult to treat. They may be seen clinically as localized pleural tumors or as diffuse pleural disease with effusion and encasement of the lung and obliteration of the pleural space. The localized forms of malignant mesotheliomas are fibrosarcomatous. Their diagnosis and treatment do not differ from those for soft-part sarcomas seen elsewhere. Wide en-bloc excision is the treatment of choice and can be curative. The diffuse forms of malignant mesotheliomas are mainly epithelial. Treatment is generally unsatisfactory, and long-term survival is rare. Two surgical approaches are currently available: an extrapleural pneumonectomy and a pleurectomy with irradiation. The authors favor the latter approach because of its wider applicability, lower morbidity rate, and better survival advantage. Steps in selecting the best surgical mode of treatment are presented.

    Title Two-dimensional Echocardiography for Diagnosing Acute Ascending Aortic Dissection.
    Date September 1985
    Journal Canadian Journal of Surgery. Journal Canadien De Chirurgie
    Excerpt

    The diagnosis of type A aortic dissection (involving the ascending aorta) can be made with two-dimensional echocardiography, but surgeons usually demand angiographic confirmation. Between January 1983 and February 1984, 10 patients presented at St. Michael's Hospital in Toronto with type A aortic dissection. Six patients underwent two-dimensional echocardiography early in their evaluation. A positive diagnosis was made in four, based upon visualization of an intimal flap or a false lumen. In the other two patients, the findings of an enlarged ascending aorta and pericardial effusion were suggestive but not diagnostic. Three patients survived operation and are alive and well (follow-up ranging from 3 to 5 months). One patient died while awaiting surgery, one died during aortography and one died during operation. All echocardiographic and angiographic findings were confirmed at surgery or at autopsy. It is concluded that two-dimensional echocardiography can diagnose ascending aortic dissection quickly, accurately, easily and without risk to the patient. In selected cases the presence of a false lumen or of an intimal flap makes it possible to proceed with operation without delay or the potential hazards of aortography.

    Title Coronary Artery Bypass in Patients with Total Laryngectomy.
    Date June 1985
    Journal The Annals of Thoracic Surgery
    Excerpt

    Patients who have undergone laryngectomy pose a challenge when they require coronary artery bypass grafting. The location of the tracheal stoma just above the jugular notch may interfere with the sternotomy, increase the risk of infection, and add some difficulty to the operative procedure. We describe the surgical technique used in 2 such patients.

    Title Upper Extremity Vein Graft.
    Date December 1984
    Journal The Annals of Thoracic Surgery
    Title Clinical Thermochemotherapy. A Controlled Trial in Advanced Cancer Patients.
    Date March 1984
    Journal Cancer
    Excerpt

    In vitro and in vivo animal studies and some clinical trials have shown apparent benefit from thermochemotherapy; however, this treatment modality has not been adequately tested in humans. This investigation evaluated response to and toxicity of secondary thermochemotherapy, using each patient as his own control. Patients with advanced cancer who had documented disease progression while receiving chemotherapy alone were subsequently treated with the same drug, by the same dose and route, combined with localized hyperthermia. Thirty-four patients whose diseases included metastatic colon carcinoma, melanoma, sarcoma and hepatoma in viscera (29) or surface tissues (5) were treated with combination thermochemotherapy for 1 hour daily for 5 days/month. Effective heating from 41 to 45 degrees C minimum tumor temperature was possible in 17/19 (89%) tumors in which temperatures could be measured safely. The authors observed 5 (15%) tumor regressions for 1 to 5 months (median, 2 months), and 19 (56%) tumor stabilizations (growth arrest of previously progressive disease) for 1 to 9 months (median, 4 months). Subjective improvement in activity and/or pain control occurred in 6 (18%) patients and 20 (59%) had no progression of symptoms during treatment. Moreover, there was no detectable morbidity from localized hyperthermia, and no evidence of increased chemotherapy toxicity. While the mechanism(s) of response is poorly understood, the documented disease regressions and stabilizations of previously progressive disease in 24 (71%) patients during secondary combination thermochemotherapy indicates that the addition of hyperthermia may have useful anticancer activity. Expanded trials are warranted.

    Title Predictability of Response to Clinical Thermochemotherapy by the Clonogenic Assay.
    Date November 1983
    Journal Cancer
    Excerpt

    In order to assess the value of the clonogenic assay for predicting clinical response to dimethyl-triazeno-imidazole-carboxamide (DTIC) plus hyperthermia (42 degrees C), the responses of patients with measurable disease, who received combined therapy, were compared with assay results. The clonogenic assay was used independently to determine in vitro sensitivities of 53 melanomas to DTIC, with and without hyperthermia. Separate cell suspensions were incubated for 1 hour with DTIC at 37 degrees C and at 42 degrees C. In vitro sensitivity was determined by inhibition of colony formation in a double-layer agar system. Three of the 53 (6%) melanomas were sensitive to DTIC at 37 degrees C, 13 of the 53 (25%) were sensitive to 42 degrees C hyperthermia alone, and 22 of the 53 (42%) were sensitive to DTIC at 42 degrees C. Nine patients were treated with DTIC, plus hyperthermia, to the areas of their melanoma metastases (one pulmonary, four hepatic, and four subcutaneous). In five patients, the clonogenic assay results predicted positive tumor sensitivity to combined therapy, and 4 of the 5 had objective tumor regression. Tumors were resistant in vitro for four patients, and all had disease progression during treatment. Statistical analysis suggested that some responses were due to synergism of the combination of heat and drug, whereas others were due to an additive effect. The apparent direct correlation between in vitro tumor cell sensitivity to DTIC at 42 degrees C and actual clinical response to chemotherapy, plus hyperthermia, in this limited trial, has been encouraging. The clonogenic assay and in vitro evaluation of drug-heat interaction may prove helpful for selecting those patients in whom hyperthermia should be used as an adjunct to chemotherapy, and may help determine the most effective drug/heat scheduling. Further trials with other malignancies and other chemotherapeutic agents are warranted.

    Title Biopsy of Thoracic Neoplasms for Assay of Chemosensitivity. New Indication for Thoracotomy.
    Date October 1983
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    Eighty-six thoracic neoplasms, both primary and metastatic, were removed at thoracotomy from 86 patients and were tested for chemosensitivity in the clonogenic assay. Substantial tumor growth was achieved in 79% (67/86). Fifty-two percent (16/31) of the primary lung tumors and 45% (15/33) of the metastatic tumors were sensitive to at least one tested drug. Clinical correlations between in vitro chemosensitivity and in vivo response were possible in 20 patients. The assay was 83% accurate for predicting in vivo sensitivity and 86% accurate for predicting in vivo resistance. The value of the assay as it pertains to lung cancer has been demonstrated. On the basis of the results, thoracotomy is indicated in selected patients as a diagnostic procedure to obtain tissue for chemosensitivity testing.

    Title Blood Flow in Human Tumors During Hyperthermia Therapy: Demonstration of Vasoregulation and an Applicable Physiological Model.
    Date July 1983
    Journal Journal of Surgical Oncology
    Excerpt

    A quantitative assessment of the effect of localized magnetic-loop hyperthermia on blood flow was performed in 12 human tumors using the 133Xe clearance method. Because blood flow in these tumors changed in response to needle injection, a physiologically based, one-compartment model was developed that included both a hyperemic and a steady-state component. In six tumors, changes in blood flow induced by heat were also observed. The ability of tumor vessels to respond dynamically to stress and the degree of response may be predictive of tumor heating capacity and subsequent therapeutic response.

    Title Clinical Radiofrequency Hyperthermia: a Review.
    Date February 1983
    Journal National Cancer Institute Monograph
    Excerpt

    Localized radiofrequency (RF) hyperthermia is being investigated for potential use in cancer therapy, both as a single agent and in combination with radiation therapy and chemotherapy. Standard capacitive and inductive heating techniques and new technology, including magnetrode magnetic-loop induction, are being compared for safety and efficacy. Clinical trials suggest that effective localized RF hyperthermia may be administered safely to both superficial and deep visceral tumors with proper equipment. Temperatures of 42 degrees C or greater appear to be tumoricidal, though higher temperatures and longer and multiple treatments seem most beneficial. Effective heating of tumors has been independent of histology but could be related to size and blood flow. Combined with radiation therapy and chemotherapy, hyperthermia appears to have a synergistic or additive effect. These trials indicate that localized RF hyperthermia may soon provide a significant contribution to our armamentarium against cancer.

    Title Thermochemotherapy for Melanoma Metastases in Liver.
    Date May 1982
    Journal Cancer
    Excerpt

    Metastatic melanoma in the liver has carried an extremely poor prognosis regardless of therapy. Because transient responses (1/6 disease regressions and 2/6 disease stabilizations for four months) in selected patients treated with intraarterial (IA) DTIC infusion were encouraging and because localized hyperthermia may be both tumoricidal and synergistic with chemotherapy, these modalities were combined for treatment of patients with advanced liver metastases. Of 10 patients treated with IA-DTIC plus heat, three (30%) had disease-regression and five (50%) had disease stabilization for 3-14 months (median 6.5 months) and survived 3.5-18 months (median 8.5 months). During treatment, 4/5 patients had pain relief and 7/10 retained or acquired normal activities. Myelosuppression was minimal and no hyperthermia toxicity occurred. A retrospective review of 10 patients with similar disease levels who were treated with conventional intravenous (IV)-DTIC indicated no responses, and no responses were seen in five patients treated with IV-DTIC plus heat. However, this latter group may have been selected patients due to the inability to place a percutaneous hepatic artery infusion catheter. This pilot study suggests that combination IA-DTIC and hyperthermia has a high response rate, is safe, and can provide quality survival for many patients.

    Title Radiographic Features of Osseous Metastases of Soft-tissue Sarcomas.
    Date May 1982
    Journal Radiology
    Excerpt

    In contrast to most other neoplastic processes of bone, in our study osseous metastases from soft-tissue sarcomas (STS) were more reliably detected by radiography than by scintigraphy. The radiographic manifestations of 65 skeletal metastases in 23 patients with STS were reviewed. Although most metastases (88%) were osteolytic, eight (12%) lesions were osteoblastic. The destructive patterns were geographic in 29%, moth-eaten in 55%, and permeative in 12% of the lesions. The axial skeleton was most commonly involved. In the long bones the diaphyses were the predominant sites of involvement. The bony cortex was frequently breached, with resultant soft-tissue swelling and pathologic fractures. Noteworthy features included subarticular location, involvement of the sacroiliac joint, and an expansile appearance.

    Title Clinical Correlations with Drug Sensitivities in the Clonogenic Assay: a Retrospective Study.
    Date March 1982
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    We tested the ability of the in vitro clonogenic assay (CLAS) to predict clinical response for patients with solid tumors. Patients had objectively measurable disease and received at least one course of chemotherapy. The correlation between clinical responses and in vitro sensitivity was evaluated retrospectively. Tumor types included melanoma (19), sarcoma (five), hepatoma (one), and carcinoma of the stomach (two), colon (three), lung (one), and breast (one). Five patients received two separate courses of chemotherapy with different drugs or drug regimens. In nine of 11 (82%) instances, tumors were sensitive to a particular drug, and the patient had at least 50% regression of tumor following treatment with the tested drug. Two patients whose tumors were sensitive in vitro had no evidence of clinical response. In 25 of 26 assays, the CLAS accurately predicted tumor resistance, and only one patient had evidence of clinical response (96%). Associations of in vitro results with clinical responses were highly significant. The CLAS can accurately predict the chemosensitivity of a variety of solid tumors.

    Title Clinical Radiofrequency Hyperthermia by Magnetic-loop Induction.
    Date March 1982
    Journal The Journal of Microwave Power
    Title In Vitro Assessment of Antineoplastic Therapy. New Indication for Thoracotomy?
    Date November 1981
    Journal The Journal of Thoracic and Cardiovascular Surgery
    Excerpt

    Selection and determination of the efficacy of antineoplastic agents has been dependent upon the trial and error method of observing measurable disease. Such methods subject the patient not only to loss of precious time but to needless toxicity if the drug is ineffective. The clonogenic assay, an in vitro assessment of tumor cell sensitivity to antineoplastic agents, has the potential for individualizing therapy. In this assay, tumor cells exposed to various drugs are cloned in soft agar. In the 16 primary and 24 metastatic pulmonary tumors tested with this technique, a growth rate of 80% was achieved. Fifty-five percent of the primary tumors and 60% of the metastatic lesions responded in vitro to one or more of the test drugs. There were twelve possible correlations between in vitro and in vivo results. In four of 12 assays, in vivo sensitivity was predicted and three of four patients demonstrated a clinical response. No drug that was inactive in vitro had activity in vivo. Prior knowledge of in vitro sensitivity may dictate a more aggressive surgical approach to pulmonary metastatic disease, whereas in vitro resistance would call for more conservative treatment. Just as with estrogen receptor status in breast cancer, data derived from the clonogenic assay may ultimately be of such import that thoracotomy would be warranted solely for the purpose of obtaining tissue for the assay.

    Title Radio Frequency Hyperthermia of Advanced Human Sarcomas.
    Date August 1981
    Journal Journal of Surgical Oncology
    Excerpt

    Hyperthermia greater than or equal to 42 degrees C is tumoricidal in vitro and in many animal models, although such temperatures have only recently been achieved experimentally in some human cancers. A recently developed radio frequency device that provides safe hyperthermia to any depth without surface tissue injury now permits evaluation of the effects of hyperthermia on advanced human sarcomas. Twelve patients with large sarcomas located intraabdominally [7], in the chest wall [2], proximal extremity [2], and the neck [1], were evaluated in this study. Tumor types include liposarcoma [3], rhabdomyosarcoma [2], leiomyosarcoma [2], neurofibrosarcoma [2], and one each malignant mesothelioma, undifferentiated sarcoma, and osteosarcoma. Intratumor temperatures greater than or equal to 42 degrees C were observed in all tumors, with virtually no normal tissue injury. Selective tumor heating greater than or equal to 45 degrees C occurred in 9/12 (75%) and greater than or equal to 50 degrees C in 6/12 (50%). One to five weekly treatments greater than or equal to 50 degrees C and ten daily treatments greater than or equal to 45 degrees C resulted in significant tumor necrosis and pain relief in some patients. Hyperthermia of advanced sarcomas is possible with little host toxicity and may be of potential therapeutic benefit.

    Title B-cell Depletion Using an Anti-cd20 Antibody Augments Antitumor Immune Responses and Immunotherapy in Nonhematopoetic Murine Tumor Models.
    Date
    Journal Journal of Immunotherapy (hagerstown, Md. : 1997)
    Excerpt

    The role played by B cells in cancer biology is complex and somewhat controversial. Previous studies using genetically engineered mice suggest that B cells may be immunosuppressive and inhibit tumor rejection. However, the effects of B-cell depletion employing an antibody in mice bearing solid tumors has not been tested owing to difficulties in making an effective antimouse CD20 antibody (similar to rituximab). Injection of a newly developed antimouse CD20 antibody was effective in depleting circulating B cells from blood and lymph nodes, although depletion was less complete in the spleen. B-cell depletion slowed the growth of new solid tumors (not expressing CD20) and retarded the growth of established tumors but did not induce tumor regression. However, when the antibody was combined with an active immunotherapy approach using an adenovirus vaccine expressing the human papilloma virus-E7 gene (Ad.E7) in mice bearing TC1 tumors (murine lung cancer cells expressing human papilloma virus-E7), we noted enhanced antitumor effects and increased numbers of tetramer+/CD8+ T cells within the spleens and activated CD8+ T cells within tumors. B-cell depletion using an anti-CD20 antibody was thus effective in retarding tumor growth in multiple solid tumor models and augmenting immunotherapy in a tumor vaccine model. These studies raise the possibility that B-cell depletion may be a useful adjunct in human immunotherapy trials.

    Title Contributions of Surgical Residents to Patient Satisfaction: Impact of Residents Beyond Clinical Care.
    Date
    Journal Journal of Surgical Education
    Excerpt

    PURPOSE: Little is known about the relationship between resident performance and patient satisfaction. To this end, our institution added housestaff-specific questions to Press-Ganey surveys (Press-Ganey, South Bend, Indiana) administered to patients. This study sought to investigate the impact residents have on patients' overall rating of care compared with faculty and nursing staff. Our hypothesis was that residents play an important but historically underappreciated role in patient satisfaction. METHODS: Between April 2005 and June 2006, half of all discharged patients randomly received Press-Ganey surveys, including questions on the following categories: admissions, patient room, food, diagnostic testing, guest services, faculty/attending physician, discharge, emotional needs, housestaff, nurse practitioners, and primary nurse. responses were grouped into overall category scores and used as predictor variables for regression analysis. a separate question asked patients to rate overall care provided. Chief resident schedules and evaluation scores by faculty were provided by the Division of Surgery Education. Regression, and ANOVA models were run using JMP 6 software (JMP 6, SAS Institute, Cary, North Carolina). RESULTS: During this period, 49,081 patients were discharged, 24,540 surveys were mailed, and 5828 surveys were returned (24% response rate). In a simple regression analysis, the predictor variables for nursing, housestaff, and faculty accounted for 57%, 33%, and 28%, respectively, of the variation of overall rating of care delivered (p < 0.005). The actual overall score for each group varied slightly: faculty (89.8), nursing (86.6), and housestaff (84.2) (p < 0.005). In a multiple regression analysis, all predictors above were significant (p < 0.05). A small difference in scores existed between surgical (83.9) and nonsurgical (85.0) housestaff (p < 0.05). When data were sorted by surgical services, ratings of surgical housestaff ranged from a high of 86.8 (thoracic) to a low of 79.0 (orthopedics) (p < 0.05). Admission month had no significant effect on overall rating of care (range, 85-90), although comparing the means of resident scores by month (range, 81-86) showed that at the end (May-June) and at the beginning (July-Aug) of an academic year, a significant reduction in resident scores occurred (p < 0.05). The lowest score of the year (82.4) occurred in June, whereas the highest scores occurred in January-April (85-86). Resident evaluation scores by faculty and ratings of housestaff by patients were completely uncorrelated, although certain housestaff achieved significantly higher ratings by patients than others. CONCLUSIONS: Compared with faculty and residents, nurses have a greater impact on the variation of patient satisfaction. However, the actual scores given to residents, faculty, and nurses are all high. A slight difference exists in scores of surgical and nonsurgical residents. For all residents, the time of the academic year impacts resident scores positively in the middle and negatively in the beginning and end. For surgical residents clear differences exist between specialty services, but it is not apparent whether these differences are caused by individual residents or by the clinical service milieu. Residents contribute significantly to overall satisfaction, and additional investigation of the variation in resident scores is needed.

    Title Bilocular Pericardial Cyst in an Aberrant Location.
    Date
    Journal Interactive Cardiovascular and Thoracic Surgery
    Excerpt

    Pericardial cysts classically are found in the right or left cardiophrenic angle and rarely are located outside of this location. An 82-year-old man presented with an asymptomatic cystic mass on chest CT-scan located in the upper right mediastinum and measuring 7x6x4 cm. A follow-up chest CT-scan 12 months later showed that the cyst had increased in size to where it now measured 10x9x8 cm and was noted to be dislocating and compressing the superior vena cava. The patient underwent surgical excision because of the uncertain diagnosis and the compression of contiguous organs. Two cystic masses were able to be completely excised intact. A definitive diagnosis of double pericardial cyst was histopathologically confirmed. Radiological findings of pericardial cyst in the upper mediastinum are extremely rare. In particular there have been no reports of bilocular or double pericardial cysts. Keywords: Pericardial cyst; Mediastinum.

    Title Increased Proteolysis, Myosin Depletion, and Atrophic Akt-foxo Signaling in Human Diaphragm Disuse.
    Date
    Journal American Journal of Respiratory and Critical Care Medicine
    Excerpt

    Rationale: Patients on mechanical ventilation who exhibit diaphragm inactivity for a prolonged time (case subjects) develop decreases in diaphragm force-generating capacity accompanied by diaphragm myofiber atrophy. Objectives: Our objectives were to test the hypotheses that increased proteolysis by the ubiquitin-proteasome pathway, decreases in myosin heavy chain (MyHC) levels, and atrophic AKT-FOXO signaling play major roles in eliciting these pathological changes associated with diaphragm disuse. Methods: Biopsy specimens were obtained from the costal diaphragms of 18 case subjects before harvest (cases) and compared with intraoperative specimens from the diaphragms of 11 patients undergoing surgery for benign lesions or localized lung cancer (control subjects). Case subjects had diaphragm inactivity and underwent mechanical ventilation for 18 to 72 hours, whereas this state in controls was limited to 2 to 4 hours. Measurements and Main Results: With respect to proteolysis in cytoplasm fractions, case diaphragms exhibited greater levels of ubiquitinated-protein conjugates, increased activity of the 26S proteasome, and decreased levels of MyHCs and α-actin. With respect to atrophic signaling in nuclear fractions, case diaphragms exhibited decreases in phosphorylated AKT, phosphorylated FOXO1, increased binding to consensus DNA sequence for Atrogin-1 and MuRF-1, and increased supershift of DNA-FOXO1 complexes with specific antibodies against FOXO1, as well as increased Atrogin-1 and MuRF-1 transcripts in whole myofiber lysates. Conclusions: Our findings suggest that increased activity of the ubiquitin-proteasome pathway, marked decreases in MyHCs, and atrophic AKT-FOXO signaling play important roles in eliciting the myofiber atrophy and decreases in diaphragm force generation associated with prolonged human diaphragm disuse.

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