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Otolaryngologist (ear, nose, throat)
26 years of experience
Accepting new patients
Video profile

Credentials

Education ?

Medical School Score Rankings
University of Michigan Medical School (1986)
  •  
Top 25%

Awards & Distinctions ?

Awards  
One of America's Leading Experts on:
(Mouth Cancer) Mouth Neoplasms
Head and Neck Cancer (Head and Neck Neoplasm)
Inverted Papilloma
Laryngectomy
Oral Cavity and the Oropharynx Cancer (Oropharyngeal Neoplasm)
Squamous Cell Carcinoma
Throat Cancer (Laryngeal Neoplasm)
Castle Connolly America's Top Doctors® (2006 - 2008, 2010 - 2015)
Castle Connolly America's Top Doctors® for Cancer (2005 - 2007, 2009 - 2012, 2014 - 2015)
Compassionate Doctor Recognition (2015)
On-Time Doctor Award (2015)
Associations
American Board of Otolaryngology
American College of Surgeons
American Society of Clinical Oncology
American Academy of Otolaryngology: Head and Neck Surgery

Affiliations ?

Dr. Bradford is affiliated with 5 hospitals.

Hospital Affiliations

Score

Rankings

  • University of Michigan Hospitals & Health Centers *
    Otolaryngology
    1500 E Medical Center Dr, Ann Arbor, MI 48109
    •  
    Top 25%
  • C.S. Mott Children's Hospital
    1500 E Medical Center Dr, Ann Arbor, MI 48109
  • Ann Arbor Veterans Affairs Medical Center
    2215 Fuller Rd, Ann Arbor, MI 48105
  • University of Michigan Health System
  • San Juan Regional Medical Center
  • * This information was reported to Vitals by the doctor or doctor's office.

    Publications & Research

    Dr. Bradford has contributed to 153 publications.
    Title Sentinel Lymph Node Biopsy is Accurate and Prognostic in Head and Neck Melanoma.
    Date April 2012
    Journal Cancer
    Excerpt

    Sentinel lymph node biopsy (SLNB) has emerged as a widely used staging procedure for cutaneous melanoma. However, debate remains around the accuracy and prognostic implications of SLNB for cutaneous melanoma arising in the head and neck, as previous reports have demonstrated inferior results to those in nonhead and neck regions. Through the largest single-institution series of head and neck melanoma patients, the authors set out to demonstrate that SLNB accuracy and prognostic value in the head and neck region are comparable to other sites.

    Title Clinical and Pathologic Predictors of Recurrence and Survival in Spindle Cell Squamous Cell Carcinoma.
    Date November 2011
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    To determine clinicopathologic predictors of recurrence and survival in patients with spindle cell squamous cell carcinoma (SpSCC).

    Title Features Predicting Sentinel Lymph Node Positivity in Merkel Cell Carcinoma.
    Date May 2011
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    Merkel cell carcinoma (MCC) is a relatively rare, potentially aggressive cutaneous malignancy. We examined the clinical and histologic features of primary MCC that may correlate with the probability of a positive sentinel lymph node (SLN).

    Title Copy Number Variations and Clinical Outcome in Atypical Spitz Tumors.
    Date February 2011
    Journal The American Journal of Surgical Pathology
    Excerpt

    Atypical Spitz tumors (ASTs) are rare spitzoid neoplasms of uncertain biological behavior. Our study was designed to characterize genetic abnormalities that may help to differentiate ASTs from melanoma or Spitz nevi. We examined copy number variation in formalin-fixed, paraffin-embedded samples using an Agilent 44k array comparative genomic hybridization platform. Sixteen patients with AST (8 with positive sentinel lymph node biopsy, 1 with distant metastasis), 8 patients with Spitz nevi, and 3 patients with melanoma (2 spitzoid, 1 superficial spreading) were evaluated. Chromosomal aberrations were found in 7 of 16 ASTs, 1 with fatal outcome, 2 spitzoid melanomas, and 1 conventional melanoma. We found no difference in chromosomal instability between AST patients with positive and negative sentinel lymph node biopsies. Our patient with widely metastatic AST lacked the most frequent aberrations in melanoma involving chromosomes 6 and 11q that are loci targeted by fluorescence in situ hybridization (FISH) probes developed to distinguish malignant melanoma from benign melanocytic lesions. The vast majority of chromosomal abnormalities observed in ASTs are not commonly found in melanomas, suggesting that AST may be a distinct clinical entity and raising additional questions regarding their malignant potential, prognosis, and clinical management. The current FISH probes failed to detect 1 spitzoid melanoma, 1 fatal metastatic AST case, and the other chromosomally aberrant ASTs in our series, but detected 1 spitzoid melanoma and 1 conventional melanoma. Thus, a comprehensive, genome-wide approach to chromosomal abnormalities offered greater sensitivity and specificity than current FISH probes in identifying spitzoid lesions of uncertain malignant potential in this series.

    Title Single-marker Identification of Head and Neck Squamous Cell Carcinoma Cancer Stem Cells with Aldehyde Dehydrogenase.
    Date December 2010
    Journal Head & Neck
    Excerpt

    In accord with the cancer stem cell (CSC) theory, only a small subset of cancer cells are capable of forming tumors. We previously reported that CD44 isolates tumorigenic cells from head and neck squamous cell cancer (HNSCC). Recent studies indicate that aldehyde dehydrogenase (ALDH) activity may represent a more specific marker of CSCs.

    Title Chemotherapy Alone for Organ Preservation in Advanced Laryngeal Cancer.
    Date December 2010
    Journal Head & Neck
    Excerpt

    For patients with advanced laryngeal cancer, a trial was designed to determine if chemotherapy alone, in patients achieving a complete histologic complete response after a single neoadjuvant cycle, was an effective treatment with less morbidity than concurrent chemoradiotherapy.

    Title Ethics of Frey Syndrome: Ensuring That Consent is Truly Informed.
    Date December 2010
    Journal Head & Neck
    Excerpt

    Frey syndrome is a widely recognized sequela of parotidectomy with a variable prevalence dependent upon diagnostic criteria. There exists a multitude of strategies for both prevention and treatment. Surgeons are obligated to engage patients in a frank and open discussion of the operative risks, benefits, and alternatives. Due to uncertainty regarding the significance of Frey syndrome postoperatively, the process of informed consent and preoperative decision-making pose a potential ethical quandary. This commentary is designed to heighten the awareness of the preoperative informed consent process by dissecting the ethical tenets underlying these patient encounters using Frey syndrome as an example, ensuring that patients are granted the opportunity to participate in their own care in accordance with the concept of individual autonomy.

    Title Intensity-modulated Chemoradiotherapy Aiming to Reduce Dysphagia in Patients with Oropharyngeal Cancer: Clinical and Functional Results.
    Date July 2010
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    To assess clinical and functional results of chemoradiotherapy for oropharyngeal cancer (OPC), utilizing intensity-modulated radiotherapy (IMRT) to spare the important swallowing structures to reduce post-therapy dysphagia.

    Title Hpv-positive/p16-positive/ebv-negative Nasopharyngeal Carcinoma in White North Americans.
    Date July 2010
    Journal Head & Neck
    Excerpt

    Human papillomavirus (HPV) has been detected in keratinizing nasopharyngeal carcinomas (NPCs); however, the relationship between HPV and Epstein-Barr virus (EBV) among whites with nonkeratinizing NPCs remains unclear. The HPV, p16, and EBV status was examined in current University of Michigan patients with NPC.

    Title Genotyping of 73 Um-scc Head and Neck Squamous Cell Carcinoma Cell Lines.
    Date June 2010
    Journal Head & Neck
    Excerpt

    We established multiple University of Michigan Squamous Cell Carcinoma (UM-SCC) cell lines. With time, these have been distributed to other labs all over the world. Recent scientific discussions have noted the need to confirm the origin and identity of cell lines in grant proposals and journal articles. We genotyped the UM-SCC cell lines in our collection to confirm their unique identity.

    Title Tobacco Use in Human Papillomavirus-positive Advanced Oropharynx Cancer Patients Related to Increased Risk of Distant Metastases and Tumor Recurrence.
    Date April 2010
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    The goal of this study was to examine the effect of tobacco use on disease recurrence (local/regional recurrence, distant metastasis, or second primary) among patients with human papillomavirus (HPV)-positive squamous cell carcinoma of the oropharynx (SCCOP) following a complete response to chemoradiation therapy.

    Title Neuroendocrine Neoplasms of the Larynx: an Overview.
    Date February 2010
    Journal Head & Neck
    Excerpt

    Neuroendocrine neoplasms of the larynx are rare but are the most common nonsquamous tumors of this organ. In the past, there has been considerable confusion about the nature and classification of these neoplasms, but the current consensus is that there are 4 different types of laryngeal neuroendocrine tumors composed of paraganglioma, typical carcinoid, atypical carcinoid tumor, and small cell neuroendocrine carcinoma. Carcinoids and small cell neuroendocrine carcinomas are epithelial neoplasms, whereas paragangliomas are of neural origin. Diagnosis is based primarily on light microscopy and confirmed by immunohistochemistry and electron microscopy. Precise diagnosis is essential because the natural history, treatment, and prognosis vary widely for the different neoplastic categories. Typical carcinoids are very rare and are treated by wide local excision, usually partial laryngectomy, without elective neck dissection. Atypical carcinoid tumors are more common and more aggressive. They are treated by partial or total laryngectomy with elective or therapeutic neck dissection. Adjuvant chemo/radiotherapy may be of benefit in some cases. Small cell neuroendocrine carcinomas are highly aggressive and should be considered disseminated at initial diagnosis. The treatment is by irradiation and chemotherapy as surgery has proven to be of a little benefit. Paragangliomas are treated by local excision or partial laryngectomy. It is difficult to determine the valid survival statistics for typical carcinoids because of their rarity and confusion in the literature with their atypical counterparts. They have a greater tendency to metastasize, and thus a worse prognosis than was previously believed. Atypical carcinoid tumors have a 5-year survival rate of approximately 50%, which decreases with time. The prognosis of small cell neuroendocrine carcinoma of the larynx is dismal, with 5-year survival rates of 5%. The biological behavior of laryngeal paraganglioma is generally benign and the prognosis is excellent.

    Title Is There a Benefit to Sentinel Lymph Node Biopsy in Patients with T4 Melanoma?
    Date February 2010
    Journal Cancer
    Excerpt

    Controversy exists as to whether patients with thick (Breslow depth>4 mm), clinically lymph node-negative melanoma require sentinel lymph node (SLN) biopsy. The authors examined the impact of SLN biopsy on prognosis and outcome in this patient population.

    Title Prognostic Significance of a Positive Nonsentinel Lymph Node in Cutaneous Melanoma.
    Date January 2010
    Journal Annals of Surgical Oncology
    Excerpt

    Sentinel lymph node (SLN) biopsy provides important prognostic information for patients with cutaneous melanoma. There may be additional prognostic significance to melanoma spreading from the SLN to nonsentinel lymph nodes (NSLN). We examined the implications of a positive NSLN for overall and distant disease-free survival.

    Title Oropharyngoplasty with Template-based Reconstruction of Oropharynx Defects.
    Date October 2009
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    To determine if oropharyngoplasty using a Gehanno technique of superior constrictor velopharyngoplasty, base of tongue mounding, and primary hypopharyngeal closure in combination with template-based revascularized free tissue transfer is effective for reconstruction of the oropharyngeal defect.

    Title Chemoselection As a Strategy for Organ Preservation in Patients with T4 Laryngeal Squamous Cell Carcinoma with Cartilage Invasion.
    Date August 2009
    Journal The Laryngoscope
    Excerpt

    High rates of overall survival (OS) and laryngeal preservation were achieved in two sequential phase II clinical trials in patients with stage III/IV laryngeal squamous cell carcinoma (SCC). Patients were treated with chemoradiation after a >50% primary tumor response to one cycle of neoadjuvant chemotherapy (IC). We analyzed outcomes for T4 patients with cartilage invasion from both studies.

    Title Diagnosis and Management of Hereditary Paraganglioma Syndrome Due to the F933>x67 Sdhd Mutation.
    Date August 2009
    Journal Head & Neck
    Excerpt

    The hereditary paraganglioma syndromes (PGLs) are autosomal dominant conditions with an increased risk for tumors of the sympathetic and parasympathetic neuroendocrine systems. The recognition of patients with hereditary PGL and identification of the responsible gene are important for the management of index patients and family members.

    Title The Pattern of Failure After Reirradiation of Recurrent Squamous Cell Head and Neck Cancer: Implications for Defining the Targets.
    Date August 2009
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    Reirradiation (re-RT) of recurrent head and neck cancer (HNC) may achieve long-term disease control in some patients, at the expense of high rates of late sequelae. Limiting the re-RT targets to the recurrent gross tumor volume (rGTV) would reduce the volumes of reirradiated tissues; however, its effect on tumor recurrence pattern is unknown.

    Title Advanced Squamous Cell Carcinoma of the Oropharynx: Efficacy of Positron Emission Tomography and Computed Tomography for Determining Primary Tumor Response During Induction Chemotherapy.
    Date July 2009
    Journal Head & Neck
    Excerpt

    To evaluate the efficacy of fluorine-18-fluorodeoxyglucose emission tomography (FDG-PET) and CT versus endoscopy with biopsy under general anesthesia for estimating tumor volume reduction among patients treated with induction chemotherapy for advanced squamous cell carcinoma (SCC) of the oropharynx.

    Title Primary Versus Secondary Tracheoesophageal Puncture in Salvage Total Laryngectomy Following Chemoradiation.
    Date April 2009
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    To compare the rate of postoperative wound-healing complications and voice fluency in primary vs secondary tracheoesophageal puncture (TEP) following chemoradiation.

    Title Lateral Oromandibular Defect: when is It Appropriate to Use a Bridging Reconstruction Plate Combined with a Soft Tissue Revascularized Flap?
    Date October 2008
    Journal Head & Neck
    Excerpt

    BACKGROUND: A quasi-experimental retrospective study was undertaken to evaluate a new concept of free tissue volume restoration combined with bridging reconstruction plate (compartment approach) to reduce plate-related complication rates. METHODS: We evaluated 40 patients with large lateral mandible defects and associated complex soft tissue defects reconstructed with a revascularized soft tissue flap and titanium hollow screw reconstruction plates. A case-control comparison was performed based on reconstruction type: restoration of soft tissue defect (conventional approach-group 1) versus over-reconstruction of soft tissue defect (compartment approach-group 2). RESULTS: Plate exposure rate was 6 of 16 (38%) in group 1 versus 2 of 24 (8%) in group 2, and the difference was statistically significant (p = .04). The mean time to exposure was 10 months. Plate fracture rate was 6 of 23 (26.1%) in dentulous patients versus 1 of 17 (5.9%) in edentulous patients. Gastrostomy tube dependence was 6 of 16 (38%) in group 1 versus 6 of 24 (25%) in group 2. CONCLUSION: The "compartment approach" reduces plate exposure rate and gastrostomy tube dependence. Revascularized osseocutaneous reconstruction is still required in dentulous patients.

    Title Rectangle Tongue Template for Reconstruction of the Hemiglossectomy Defect.
    Date October 2008
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To determine if a rectangular template free tissue transfer is effective for the reconstruction of the hemiglossectomy defect. DESIGN: Prospective case series. SETTING: Tertiary care academic medical center. PATIENTS: A total of 13 patients (male to female ratio, 8:5; mean age, 55 years) presenting with squamous cell carcinoma of the oral tongue from May 2000 to December 2002. INTERVENTIONS: Of the 13 patients, 7 received postoperative radiotherapy and 2 received prior radiotherapy. The radial forearm was the donor site in 11 patients and the lateral arm and anterolateral thigh in 1 patient each. The mean flap area was 50 cm(2) (range, 24-80 cm(2)). MAIN OUTCOME MEASURES: Major and minor complications, speech and swallowing assessment, oral cavity obliteration, premaxillary contact, tongue elevation, and tongue protrusion. RESULTS: There were no major complications, and 2 of the 13 patients experienced minor complications. Of the 13 patients, 12 achieved the goals of oral cavity obliteration and premaxillary contact and resumed solid oral intake. One patient remained G-tube dependent owing to toxic effects from previous chemoradiation treatment. The mean tongue tip protrusion was 0.7 cm (range, 0-1.7 cm), and the mean elevation was 1.7 cm (range, 1-3 cm). Patients with protrusion greater than 0.8 cm had better swallowing scores for "range of solids" (5.8 of 6 vs 3.9 of 6; P = .045) and "eating in public" (4.6 of 5 vs 3.5 of 5; P = .10). The average patient resumed a full range of liquid and solid intake with minimal restrictions and believed that their speech was mostly understandable with occasional repetition. CONCLUSIONS: The template-based rectangle tongue flap effectively restored speech and swallowing function in this group of patients. Tongue protrusion greater than 0.8 cm is associated with better swallowing results.

    Title Improved Outcomes in Patients with Head and Neck Cancer Using a Standardized Care Protocol for Postoperative Alcohol Withdrawal.
    Date August 2008
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To show clinical benefit in the main outcome measures by the use of a standardized protocol for identification, characterization, and treatment of alcohol withdrawal syndrome (AWS) in postoperative patients with head and neck cancer. DESIGN: Prospective cohort study with a retrospective cohort control. SETTING: Tertiary care university. PATIENTS: A total of 26 consecutive postoperative patients with AWS were selected from among 652 patients with head and neck cancer to be enrolled in the protocol from March 2003 through March 2005. Controls consisted of 14 of 981 consecutive patients with AWS from March 2000 through December 2002. INTERVENTION: Application of a standardized care protocol. MAIN OUTCOME MEASURES: Sensitivity and specificity of preoperative screening for AWS risk, predictability of outcomes, length of stay, transfers to the intensive care unit (ICU), AWS symptoms, postoperative morbidity and mortality, doses of pharmacotherapy required, and charges. RESULTS: Protocol patients demonstrated significantly fewer AWS-related ICU transfers and less delirium and violence than preprotocol patients. Mortality, wound complications, hospital charges, and doses of benzodiazepines, clonidine, and haloperidol were not significantly different between these 2 groups. Preoperative medical history correlated poorly with AWS outcomes. Screening was 87.5% sensitive and 99.7% specific. Late enrollees to the protocol (false-negative screening results) showed many significantly worse outcomes than immediate enrollees. CONCLUSION: Use of the standardized AWS symptom-triggered protocol decreased delirium, violence, and AWS-related ICU transfers without significantly increasing hospital charges.

    Title Reactivation of P53 by a Specific Mdm2 Antagonist (mi-43) Leads to P21-mediated Cell Cycle Arrest and Selective Cell Death in Colon Cancer.
    Date August 2008
    Journal Molecular Cancer Therapeutics
    Excerpt

    MDM2 oncoprotein binds directly to the p53 tumor suppressor and inhibits its function in cancers retaining wild-type p53. Blocking this interaction using small molecules is a promising approach to reactivate p53 function and is being pursued as a new anticancer strategy. The spiro-oxindole MI-43, a small-molecule inhibitor of the MDM2-p53 interaction, was designed and examined for its cellular mechanism of action and therapeutic potential in colon cancer. MI-43 binds to MDM2 protein with a K(i) value of 18 nmol/L and is 300 times more potent than a native p53 peptide. MI-43 blocks the intracellular MDM2-p53 interaction and induces p53 accumulation in both normal and cancer cells, with wild-type p53 without causing p53 phosphorylation. Induction of p53 leads to modulation of the expression of p53 target genes, including up-regulation of p21 and MDM2 in normal primary human cells and in colon cancer cells with wild-type p53. Using HCT-116 isogenic colon cancer cell lines differing only in p53 status or RNA interference to knockdown expression of p53 in the RKO colon cancer cell line, we show that the cell growth inhibition and cell death induction by MI-43 is p53 dependent. Furthermore, induction of cell cycle arrest by MI-43 is dependent on p53 and p21. In normal cells, MI-43 induces cell cycle arrest but not apoptosis. This study suggests that p53 activation by a potent and specific spiro-oxindole MDM2 antagonist may represent a promising therapeutic strategy for the treatment of colon cancer and should be further evaluated in vivo and in the clinic.

    Title Egfr, P16, Hpv Titer, Bcl-xl and P53, Sex, and Smoking As Indicators of Response to Therapy and Survival in Oropharyngeal Cancer.
    Date August 2008
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: To prospectively identify markers of response to therapy and outcome in an organ-sparing trial for advanced oropharyngeal cancer. PATIENTS AND METHODS: Pretreatment biopsies were examined for expression of epidermal growth factor receptor (EGFR), p16, Bcl-xL, and p53 as well as for p53 mutation. These markers were assessed for association with high-risk human papillomavirus (HPV), response to therapy, and survival. Patient variables included smoking history, sex, age, primary site, tumor stage, and nodal status. RESULTS: EGFR expression was inversely associated with response to induction chemotherapy (IC) (P = .01), chemotherapy/radiotherapy (CRT; P = .055), overall survival (OS; P = .001), and disease-specific survival (DSS; P = .002) and was directly associated with current smoking (P = .04), female sex (P = .053), and lower HPV titer (P = .03). HPV titer was significantly associated with p16 expression (P < .0001); p16 was significantly associated with response to IC (P = .008), CRT (P = .009), OS (P = .001), and DSS (P = .003). As combined markers, lower HPV titer and high EGFR expression were associated with worse OS (rho(EGFR) = 0.008; rho(HPV) = 0.03) and DSS (rho(EGFR) = 0.01; rho(HPV) = 0.016). In 36 of 42 biopsies, p53 was wild-type, and only one HPV-positive tumor had mutant p53. The combination of low p53 and high Bcl-xL expression was associated with poor OS (P = .005) and DSS (P = .002). CONCLUSION: Low EGFR and high p16 (or higher HPV titer) expression are markers of good response to organ-sparing therapy and outcome, whereas high EGFR expression, combined low p53/high Bcl-xL expression, female sex, and smoking are associated with a poor outcome. Smoking cessation and strategies to target EGFR and Bcl-xL are important adjuncts to the treatment of oropharyngeal cancer.

    Title Chemoselection As a Strategy for Organ Preservation in Advanced Oropharynx Cancer: Response and Survival Positively Associated with Hpv16 Copy Number.
    Date August 2008
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: To test induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) or surgery/radiotherapy (RT) for advanced oropharyngeal cancer and to assess the effect of human papilloma virus (HPV) on response and outcome. PATIENTS AND METHODS: Sixty-six patients (51 male; 15 female) with stage III to IV squamous cell carcinoma of the oropharynx (SCCOP) were treated with one cycle of cisplatin (100 mg/m(2)) or carboplatin (AUC 6) and with fluorouracil (1,000 mg/m(2)/d for 5 days) to select candidates for CRT. Those achieving a greater than 50% response at the primary tumor received CRT (70 Gy; 35 fractions with concurrent cisplatin 100 mg/m(2) or carboplatin (AUC 6) every 21 days for three cycles). Adjuvant paclitaxel was given to patients who were complete histologic responders. Patients with a response of 50% or less underwent definitive surgery and postoperative radiation. Pretreatment biopsies from 42 patients were tested for high-risk HPV. RESULTS: Fifty-four of 66 patients (81%) had a greater than 50% response after IC. Of these, 53 (98%) received CRT, and 49 (92%) obtained complete histologic response with a 73.4% (47 of 64) rate of organ preservation. The 4-year overall survival (OS) was 70.4%, and the disease-specific survival (DSS) was 75.8% (median follow-up, 64.1 months). HPV16, found in 27 of 42 (64.3%) biopsies, was associated with younger age (median, 55 v 63 years; P = .016), sex (22 of 30 males [73.3%] and five of 12 females [41.7%]; P = .08), and nonsmoking status (P = .037). HPV titer was significantly associated with IC response (P = .001), CRT response (P = .005), OS (P = .007), and DSS (P = .008). CONCLUSION: Although the numbers in this study are small, IC followed by CRT is an effective treatment for SCCOP, especially in patients with HPV-positive tumors; however, for patients who do not respond to treatment, alternative treatments must be developed.

    Title Rap1gap Promotes Invasion Via Induction of Matrix Metalloproteinase 9 Secretion, Which is Associated with Poor Survival in Low N-stage Squamous Cell Carcinoma.
    Date June 2008
    Journal Cancer Research
    Excerpt

    The objective of the current study was to investigate the effects of Rap1GAP on invasion and progression of head and neck squamous cell carcinoma (SCC) and the role of matrix metalloproteinase (MMP) 9 and MMP2 in this process. Rap1GAP functions by switching off Rap1, the Ras-like protein that has been associated with carcinogenesis. Previous findings suggest that Rap1GAP acts as a tumor suppressor protein in SCC by delaying the G(1)-S transition of the cell cycle. However, cells transfected with Rap1GAP exhibit a more invasive phenotype than corresponding vector-transfected control cells. MMP2 and MMP9 are enzymes that mediate SCC invasion via degradation of the extracellular matrix. Using SCC cells transfected with empty vector or Rap1GAP, cell invasion and MMP secretion were determined by Matrigel assays and gelatin zymography, respectively. Rap1GAP up-regulated transcription and secretion of MMP2 and MMP9, as assayed by quantitative reverse transcription-PCR and zymography. Furthermore, chemical and RNA interference blockade of MMP2/MMP9 inhibited invasion by Rap1GAP-transfected cells. Immunohistochemical staining of a human oropharyngeal SCC tissue microarray showed that Rap1GAP and MMP9 expression and staining intensity are correlated (P < 0.0001) and that, in early N-stage lesions of SCC, high MMP9 is prognostic of poor disease-specific survival (P < 0.05). Furthermore, Rap1GAP staining is correlated with MMP2 (P < 0.03). MMP2 in combination with N stage has a prognostic effect on time to indication of surgery at primary site. MMP2 intensity is also positively correlated with T stage (P < 0.015). In conclusion, Rap1GAP inhibits tumor growth but induces MMP2- and MMP9-mediated SCC invasion and tumor progression, suggesting a role for this protein as a biomarker for early N-stage, aggressive SCCs.

    Title Expression of P53 and Bcl-xl As Predictive Markers for Larynx Preservation in Advanced Laryngeal Cancer.
    Date June 2008
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To assess tumor markers in advanced laryngeal cancer. DESIGN: Marker expression and clinical outcome. PATIENTS: Pretreatment tumor biopsy specimens were analyzed from patients enrolled in the Department of Veterans Affairs Laryngeal Cancer Study. MAIN OUTCOME MEASURES: Expression of p53 (OMIM TP53) and Bcl-xL (OMIM 600039) in pretreatment biopsy specimens was assessed for correlation with chemotherapy response, laryngeal preservation, and survival. RESULTS: Higher rates of larynx preservation were observed in patients whose tumors expressed p53 vs those that did not (80% [36 of 45 patients] vs 59% [24 of 41 patients], P =.03). Higher rates of larynx preservation were also observed in patients whose tumors expressed low levels of Bcl-xL vs high levels of Bcl-xL (90% [18 of 20 patients] vs 60% [30 of 50 patients], P =.02). Patients were categorized into 3 risk groups (low, intermediate, and high) based on their tumor p53 and Bcl-xL expression status. Patients whose tumors had the high-risk biomarker profile (low p53 expression and high Bcl-xL expression) were less likely to preserve their larynx than patients whose tumors had the intermediate-risk biomarker profile (high p53 expression and low or high Bcl-xL expression) or the low-risk biomarker profile (low p53 expression and low Bcl-xL expression). The larynx preservation rates were 100% (10 of 10 patients), 77% (26 of 34 patients), and 54% (7 of 13 patients) for the low-risk, intermediate-risk, and high-risk groups, respectively (P =.04, Fisher exact test). CONCLUSION: Tumor expression of p53 and Bcl-xL is a strong predictor of successful larynx preservation in patients treated with induction chemotherapy and followed by radiation therapy in responding tumors.

    Title Targeting Apoptosis to Overcome Cisplatin Resistance: a Translational Study in Head and Neck Cancer.
    Date November 2007
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: Cisplatin resistance remains a barrier to organ-sparing and survival of patients with advanced head and neck squamous cell carcinoma (HNSCC). Targeted therapies to overcome cisplatin-resistant HNSCC are being developed. METHODS AND MATERIALS: Cisplatin-sensitive parental HNSCC cell lines and cisplatin-resistant progeny were studied. Pretreatment HNSCC biopsies were used to construct tissue microarrays which were stained for p53 and Bcl-xL. RESULTS: HNSCC cell lines selected for cisplatin resistance had wild-type p53 and high levels of Bcl-xL. Expression of wild-type p53 in cell lines with low Bcl-xL enhanced cisplatin sensitivity. Expression of both Bcl-xL and wild-type p53 caused tumor cells to become cisplatin resistant. Patients whose tumors expressed low levels of p53 and Bcl-xL enjoyed the best organ preservation and disease-free survival whereas patients whose tumors expressed low levels of p53 and high levels of Bcl-xL had the worst outcome. Novel agents that inhibit Bcl-xL or activate p53 function may target cisplatin-resistant HNSCC. CONCLUSION: Cisplatin resistance in HNSCC is mediated, at least in part, by high Bcl-xL and functional p53.

    Title Response to Therapy and Outcomes in Oropharyngeal Cancer Are Associated with Biomarkers Including Human Papillomavirus, Epidermal Growth Factor Receptor, Gender, and Smoking.
    Date November 2007
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    Induction chemotherapy and concurrent chemoradiation for responders or immediate surgery for non-responders is an effective treatment strategy head and neck squamous cell carcinoma (HNSCC) of the larynx and oropharynx. Biomarkers that predict outcome would be valuable in selecting patients for therapy. In this study, the presence and titer of high risk human papilloma virus (HPV) and expression of epidermal growth factor receptor (EGFR) in pre-treatment biopsies, as well as smoking and gender were examined in oropharynx cancer patients enrolled in an organ sparing trial. HPV16 copy number was positively associated with response to therapy and with overall and disease specific survival, whereas EGFR expression, current or former smoking behavior, and female gender (in this cohort) were associated with poor response and poor survival in multivariate analysis. Smoking cessation and strategies to target EGFR may be useful adjuncts for therapy to improve outcome in the cases with the poorest biomarker profile.

    Title Merkel Cell Carcinoma: Critical Review with Guidelines for Multidisciplinary Management.
    Date August 2007
    Journal Cancer
    Excerpt

    Merkel cell carcinoma (MCC) is a relatively rare cutaneous malignancy that occurs predominantly in the older white population. The incidence of MCC appears to have tripled during the past 20 years; an increase that is likely to continue because of the growing number of older Americans. The pathogenesis of MCC remains largely unknown. However, ultraviolet radiation and immunosuppression are likely to play a significant pathogenetic role. Many questions currently remain unanswered regarding the biologic behavior and optimal treatment of MCC. Large, prospective, randomized studies are not available and are unlikely to be performed because of the rarity of the disease. The objective of this review was to provide a comprehensive reference for MCC based on a critical evaluation of the current data. The authors investigated the importance of sentinel lymph node biopsy as a staging tool for MCC to assess the status of the regional lymph node basin and to determine the need for additional therapy to the lymph node basin. In an attempt to standardize prospective data collection with the intention to define prognostic indicators, the authors also present histopathologic profiles for primary MCC and sentinel lymph nodes. The controversies regarding the appropriate surgical approach to primary MCC, the use of adjuvant radiation therapy, and the effectiveness of adjuvant chemotherapy were examined critically. Finally, the authors have provided treatment guidelines based on the available evidence and their multidisciplinary experience.

    Title Acceleration of Hyperfractionated Chemoradiation Regimen for Advanced Head and Neck Cancer.
    Date June 2007
    Journal Head & Neck
    Excerpt

    BACKGROUND: Our aim was to evaluate the acceleration of a hyperfractionated, concurrent chemoradiation regimen (HxCRT) for advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Patients with unresectable HNSCC were treated based on a previously published HxCRT regimen: 1.25 Gy twice daily to 70 Gy concurrent with cisplatin 12 mg/m(2)/day and 5-fluorouracil 600 mg/m(2)/day for 5 days, weeks 1, 5. This regimen was accelerated in this series by shortening the treatment from 7 to 6 weeks by omitting the planned mid-treatment 1-week break. RESULTS: Forty-six patients with T3-4/N3 disease were treated. The main acute toxicity was pharyngeal. Median weight change during therapy in patients with and without enteral feeding tubes was -3.8% and -7.9%, respectively (p = .08). Fifteen percent had late grade III pharyngeal toxicity. Local/regional and distant failure rates were 28% and 17%, respectively; 52% are alive without evidence of disease. CONCLUSIONS: In nonresectable HNSCC, acceleration of the HxCRT regimen is feasible, requiring enteral feeding tubes during therapy in most patients.

    Title Incidence and Prognosis of Cutaneous Melanoma Involving the Head and Neck.
    Date June 2007
    Journal Jama : the Journal of the American Medical Association
    Title Tissue-preserving Approach to Extracting Dna from Paraffin-embedded Specimens Using Tissue Microarray Technology.
    Date June 2007
    Journal Head & Neck
    Excerpt

    BACKGROUND: DNA extracted from tumor cells or normal cells contained in formalin-fixed, paraffin-embedded tissues is widely used in many laboratories. The 2 most common procedures to isolate cells for DNA extraction from paraffin-embedded tissues are scalpel microdissection and laser capture microdissection. A new tissue- and time-conserving method for rapid DNA isolation from small cores taken from paraffin-embedded tissue blocks is described in this report. METHODS: DNA was extracted from small tissue cores collected from paraffin-embedded tissue blocks at the time of tissue microarray construction. The quality and quantity of the DNA extracted was compared to DNA collected by scalpel microdissection. DNA collected from tissue cores was used in polymerase chain reaction (PCR) and loss of heterozygosity (LOH) analysis. RESULTS: The quality and quantity of DNA obtained using tissue cores was comparable to DNA obtained by traditional methods. The tissue core method of DNA extraction preserves the tissue blocks from which the cores are extracted for future use. Adequate quantities of DNA can be successfully extracted from small segments of tissue cores and used for PCR. DNA isolated by tissue microdissection and the tissue core method were comparable when used to assess allelic heterozygosity on chromosome arm 18q. CONCLUSION: The tissue core method of DNA isolation is reliable, tissue conserving, and time effective. Tissue cores for DNA extraction can be harvested at the same time as tissue microarray construction. The technique has the advantage of preserving the original tissue blocks for additional study as only tiny cores are removed.

    Title Prevention of Wound Complications Following Salvage Laryngectomy Using Free Vascularized Tissue.
    Date June 2007
    Journal Head & Neck
    Excerpt

    BACKGROUND: Total laryngectomy following radiation therapy or concurrent chemoradiation therapy is associated with unacceptably high complication rates because of wound healing difficulties. With an ever increasing reliance on organ preservation protocols as primary treatment for advanced laryngeal cancer, the surgeon must develop techniques to minimize postoperative complications in salvage laryngectomy surgery. We have developed an approach using free tissue transfer in an effort to improve tissue vascularity, reinforce the pharyngeal suture line, and minimize complications in this difficult patient population. The purpose of this study was to outline our technique and determine the effectiveness of this new approach. METHODS: We conducted a retrospective review of a prospective cohort and compared it with a historical group (surgical patients of Radiation Therapy Oncology Group (RTOG)-91-11 trial). Eligibility criteria for this study included patients undergoing salvage total laryngectomy following failed attempts at organ preservation with either high-dose radiotherapy or concurrent chemo/radiation therapy regimen. Patients were excluded if the surgical defect required a skin paddle for pharyngeal closure. The prospective cohort consisted of 14 consecutive patients (10 males, 4 females; mean age, 58 years) who underwent free tissue reinforcement of the pharyngeal suture line following total laryngectomy. The historical comparison group consisted of 27 patients in the concomitant chemoradiotherapy arm of the RTOG-91-11 trial who met the same eligibility criteria (26 males, 1 female; mean age, 57 years) but did not undergo free tissue transfer or other form of suture line reinforcement. Minimum follow-up in both groups was 12 months. RESULTS: The overall pharyngocutaneous fistula rate was similar between groups-4/14 (29%) in the flap group, compared with 8/27 (30%) in the RTOG-91-11 group. There were no major wound complications in the flap group, compared with 4 (4/27, 14.8%) in the RTOG-91-11 group. There were no major fistulas in the flap group, compared with 3/27 (11.1%) in the RTOG-91-11 group. The rate of pharyngeal stricture requiring dilation was 6/14 (42%) in the flap group, compared with 7/27 (25.9%) in the RTOG-91-11 group. In our patients, the rate of tracheoesophageal speech was 14/14 (100%), and complete oral intake was achieved in 13/14 (93%) patients. Voice-Related Quality of Life Measure (V-RQOL) and Performance Status Scale for Head and Neck Cancer Patients (PSS-HN) scores suggest that speech and swallowing functions are reasonable following free flap reinforcement. CONCLUSIONS: Free vascularized tissue reinforcement of primary pharyngeal closure in salvage laryngectomy following failed organ preservation is effective in preventing major wound complications but did not reduce the overall fistula rate. Fistulas that developed following this technique were relatively small, did not result in exposed major vessels, and were effectively treated with outpatient wound care rather than readmission to the hospital or return to operating room. Speech and swallowing results following this technique were comparable to those following total laryngectomy alone.

    Title Bcl-2 Protects Endothelial Cells Against Gamma-radiation Via a Raf-mek-erk-survivin Signaling Pathway That is Independent of Cytochrome C Release.
    Date February 2007
    Journal Cancer Research
    Excerpt

    The Bcl-2 oncoprotein is a potent inhibitor of apoptosis and is overexpressed in a wide variety of malignancies. Until recently, it was generally accepted that Bcl-2 primarily mediates its antiapoptotic function by regulating cytochrome c release from mitochondria. However, more recent studies have shown that Bcl-2 is present on several intracellular membranes and mitochondria may not be the only site where Bcl-2 exercises its survival function. In this study, we investigated if Bcl-2 can protect endothelial cells against gamma-radiation by a cytochrome c-independent signaling pathway. Human dermal microvascular endothelial cells (HDMEC), when exposed to gamma-radiation, exhibited a time-dependent activation of caspase-3 that was associated with increased cytochrome c release from mitochondria. Bcl-2 expression in endothelial cells (HDMEC-Bcl-2) significantly inhibited irradiation-induced caspase-3 activation. However, Bcl-2-mediated inhibition of caspase-3 was significantly reversed by inhibition of the Raf-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway. Interestingly, caspase-3 activation in HDMEC-Bcl-2 cells was not associated with cytochrome c release. We also observed that endothelial cell Bcl-2 expression significantly increased the expression of survivin and murine double minute-2 (Mdm2) via the Raf-MEK-ERK pathway. Endothelial cells expressing Bcl-2 also inhibited gamma-radiation-induced activation of p38 MAPK and p53 accumulation. Inhibition of p53 accumulation in HDMEC-Bcl-2 could be due to the enhanced expression of Mdm2 in these cells. Taken together, these results show three mechanisms by which Bcl-2 may mediate endothelial cell cytoprotection independently of cytochrome c release: (a) increased survivin expression, (b) inhibition of p53 accumulation, and (c) inhibition of p38 MAPK.

    Title The Impact of Factors Beyond Breslow Depth on Predicting Sentinel Lymph Node Positivity in Melanoma.
    Date January 2007
    Journal Cancer
    Excerpt

    BACKGROUND: In addition to Breslow depth, the authors previously described how increasing mitotic rate and decreasing age predicted sentinel lymph node (SLN) metastases in patients with melanoma. The objectives of the current study were to verify those previous results and to create a prediction model for the better selection of which patients with melanoma should undergo SLN biopsy. METHODS: The authors reviewed 1130 consecutive patients with melanoma in a prospective database who underwent successful SLN biopsy. After eliminating patients aged <16 years and patients who had melanomas that measured <1 mm, 910 remaining patients were reviewed for clinical and pathologic features and positive SLN status. Univariate association of patient and tumor characteristics with positive SLN status was explored by using standard logistic regression techniques, and the best multivariate model that predicted lymph node metastases was constructed by using a backward stepwise-elimination technique. RESULTS: The characteristics that were associated significantly with lymph node metastasis were angiolymphatic invasion, the absence of regression, increasing mitotic rate, satellitosis, ulceration, increasing Breslow depth, decreasing age, and location (trunk or lower extremity compared with upper extremity or head/neck). Previously reported interactions between mitotic rate and age and between Breslow depth and age were confirmed. The best multivariate model included patient age (linear), angiolymphatic invasion, the number of mitoses (linear), the interaction between patient age and the number of mitoses, Breslow depth (linear), the interaction between patient age and Breslow depth, and primary tumor location. CONCLUSIONS: Younger age, increasing mitotic rate (especially in younger patients), increasing Breslow depth (especially in older patients), angiolymphatic invasion, and trunk or lower extremity location of the primary tumor were associated with a greater likelihood of positive SLN status. The current results support the use of factors beyond Breslow depth to determine the risk of positive SLN status in patients with cutaneous melanoma.

    Title A Novel Bh3 Mimetic Reveals a Mitogen-activated Protein Kinase-dependent Mechanism of Melanoma Cell Death Controlled by P53 and Reactive Oxygen Species.
    Date January 2007
    Journal Cancer Research
    Excerpt

    The RAS/BRAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway is emerging as a key modulator of melanoma initiation and progression. However, a variety of clinical studies indicate that inhibiting the MAPK pathway is insufficient per se to effectively kill melanoma cells. Here, we report on a genetic and pharmacologic approach to identify survival factors responsible for the resistance of melanoma cells to MEK/ERK antagonists. In addition, we describe a new tumor cell-selective means to bypass this resistance in vitro and in vivo. By generating a panel of isogenic cell lines with specific defects in the apoptotic machinery, we found that the ability of melanoma cells to survive in the absence of functional MEK relies on an ERK-independent expression of the antiapoptotic factor Mcl-1 (and to a lesser extent, Bcl-x(L) and Bcl-2). Using computer-based modeling, we developed a novel Bcl-2 homology domain 3 (BH3) mimetic. This compound, named TW-37, is the first rationally designed small molecule with high affinity for Mcl-1, Bcl-x(L), and Bcl-2. Mechanistic analyses of the mode of action of TW-37 showed a synergistic tumor cell killing in the presence of MEK inhibitors. Importantly, TW-37 unveiled an unexpected role of the MAPK pathway in the control of reactive oxygen species (ROS). This function was critical to prevent the activation of proapoptotic functions of p53 in melanoma cells, but surprisingly, it was dispensable for normal melanocytes. Our results suggest that this MAPK-dependent ROS/p53 feedback loop is a point of vulnerability of melanoma cells that can be exploited for rational drug design.

    Title In Brief.
    Date December 2006
    Journal Current Problems in Surgery
    Title The Management of Head and Neck Melanoma.
    Date December 2006
    Journal Current Problems in Surgery
    Title (-)-gossypol Inhibits Growth and Promotes Apoptosis of Human Head and Neck Squamous Cell Carcinoma in Vivo.
    Date August 2006
    Journal Neoplasia (new York, N.y.)
    Excerpt

    Resistance to chemotherapy is a common problem encountered in the treatment of head and neck squamous cell carcinoma (HNSCC). Chemoresistant HNSCC tumors frequently overexpress antiapoptotic proteins, such as Bcl-x(L). (-)-gossypol, the negative enantiomer of a cottonseed polyphenol, binds to Bcl-x(L) and was recently been shown to inhibit HNSCC proliferation in vitro. In this study, we assessed the in vivo efficacy of (-)-gossypol in an orthotopic xenograft model of HNSCC, using two human HNSCC cell lines with high Bcl-x(L) expression levels. Both produced tumors in a murine floor-of-mouth model that mimics human HNSCC, exhibiting growth and invasion into adjacent tissues. Mice were randomized into three groups: vehicle control and two daily intraperitoneal (-)-gossypol treatment groups (5 and 15 mg/kg). Tumors were measured twice weekly. In the control group, tumors grew progressively, whereas in (-)-gossypol treatment groups, tumor growth was significantly suppressed. The mitotic rate in tumors from (-)-gossypol-treated animals was significantly lower than that in controls, and an increase in the percentage of apoptotic cells was observed in treated tumors versus controls. Residual tumors remained growth-suppressed for 2 weeks after cessation of (-)-gossypol treatment. Our results demonstrate that (-)-gossypol can inhibit tumor growth in an orthotopic model of aggressive HNSCC.

    Title Variables Associated with Feeding Tube Placement in Head and Neck Cancer.
    Date July 2006
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To identify clinical factors associated with enteral feeding tube placement in a head and neck cancer population. DESIGN: A self-administered survey was given to patients being treated for head and neck cancer while they were waiting to be seen in 1 of 4 otolaryngology clinics. The post hoc analysis presented here combines survey and chart review data to determine clinical and demographic variables associated with feeding tube placement. SETTING: Four otolaryngology clinics. PATIENTS: Otolaryngology clinic patients being treated for head and neck cancer. MAIN OUTCOME MEASURE: Enteral feeding tube placement. RESULTS: Of the 724 patients eligible for this study, 14% (n = 98) required enteral feeding tube placement. Multivariate analysis found the following variables to be independently associated with feeding tube placement: oropharynx/hypopharynx tumor site (odds ratio [OR], 2.4; P = .01), tumor stage III/IV (OR, 2.1; P = .03), flap reconstruction (OR, 2.2; P = .004), current tracheotomy (OR, 8.0; P<.001), chemotherapy (OR, 2.6; P<.001), and increased age (OR, 1.3; P = .02). In addition, there was a curvilinear relationship between time since treatment and feeding tube placement, with about 30% having a feeding tube at 1 month posttreatment, tapering down during the first 3 years to about 8% and leveling off thereafter. CONCLUSIONS: Identification of factors associated with an increased risk of feeding tube placement may allow physicians to better counsel patients regarding the possibility of feeding tube placement during treatment. Since feeding tube placement has been linked to decreased quality of life in head and neck cancer, such counseling is an integral part of the clinical management of these patients.

    Title Controversies: is There a Role for Positron-emission Tomographic Ct in the Initial Staging of Head and Neck Squamous Cell Carcinoma?
    Date April 2006
    Journal Ajnr. American Journal of Neuroradiology
    Title Correlation Between Initial and Early Follow-up Ct Perfusion Parameters with Endoscopic Tumor Response in Patients with Advanced Squamous Cell Carcinomas of the Oropharynx Treated with Organ-preservation Therapy.
    Date February 2006
    Journal Ajnr. American Journal of Neuroradiology
    Excerpt

    BACKGROUND AND PURPOSE: Current organ-preservation regimens for upper aerodigestive tract squamous cell carcinoma (SCCA) require endoscopic procedures under general anesthesia to evaluate the tumor response. The purpose of our study was to determine whether CT perfusion (CTP) parameters correlate with response to induction chemotherapy as assessed by endoscopy under general anesthesia. METHODS: Nine patients with advanced (stage 3 or 4) SCCA of the oropharynx were enrolled in a nested phase 2 prospective trial in which induction chemotherapy was used to assess the tumor response. Patients underwent direct laryngoscopy and CTP before and 3 weeks after one cycle of induction chemotherapy. The outcome variables were the surgeon's estimate of tumor volume during endoscopy with biopsy under anesthesia and CTP parameters (capillary permeability (CP), blood volume (BV), blood flow (BF), and mean transit time (MTT)). Wilcoxon rank sum analysis was used to correlate the baseline values of BF and BV with response to induction chemotherapy. Comparison of agreement between the reduction in tumor volume and change in CTP parameters was performed by using kappa estimates. RESULTS: Seven of 9 patients demonstrated > or =50% tumor volume reduction, representing positive response to induction chemotherapy. In the responder group, the following changes in mean pre- and postinduction chemotherapy values were noted: mean BF, 114.2 mL/100 g /min (preinduction) to 45.1 mL/100 g/min (postinduction); mean BV, 5.11 mL/100 g to 3.1 mL/100 g; mean CP, 25.6 mL/100 g /min (preinduction) to 18.3 mL/100 g / min (postinduction); mean MTT, 4.9 seconds (preinduction) to 8.0 seconds (postinduction). In the nonresponder group, the following changes were noted: mean BF, 56.9 mL/100 g/min to 75.9 mL/100 g/min; mean, BV 2.7 mL/100 g to 4.71 mL/100 g; mean CP, 24.1 mL/100 g/min to 23.7 mL/100 g/min; mean MTT, 4.3 seconds to 5.34 seconds. Higher baseline (pretherapy) values of BV showed significant correlation with endoscopic tumor response (P < .05). Reduction in the BV (by >/=20%) on follow-up studies also showed substantial agreement with clinical response as assessed with endoscopy (kappa = 0.73). The agreement between decreased BF, decreased CP, and increased MTT and clinical response was fair (kappa = 0.37). CONCLUSION: These preliminary results show that deconvolution-based CTP technique offers potential for noninvasive monitoring of response to induction chemotherapy in patients with oropharyngeal cancers. Percentage reduction of BV is significantly correlated to endoscopic response to induction chemotherapy, though we acknowledge that the data correspond to short-term outcomes and long-term durability of response cannot be established. Nevertheless, validation of the use of deconvolution CTP parameters as predictors of tumor response may permit replacement of an invasive diagnostic procedure conducted under anesthesia currently used to assess response with noninvasive perfusion CT imaging.

    Title Predictive Factors of Local-regional Recurrences Following Parotid Sparing Intensity Modulated or 3d Conformal Radiotherapy for Head and Neck Cancer.
    Date January 2006
    Journal Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology
    Excerpt

    BACKGROUND AND PURPOSE: Predictive factors for local-regional (LR) failures after parotid-sparing, Intensity modulated (IMRT) or 3D conformal radiotherapy for head and neck (HN) cancers were assessed. PATIENTS AND METHODS: One hundred and fifty-eight patients with mostly stages III-IV HN squamous cell carcinoma underwent curative bilateral neck irradiation aimed at sparing the parotid glands. Patient, tumor, and treatment factors were analyzed as predictive factors for LR failure. RESULTS: Twenty-three patients had LR recurrence (19 in-field and four marginal). No differences were found in the doses delivered to the PTVs of patients with or without in-field recurrences. In univariate analysis, tumor site was highly predictive for LR failure in both postoperative and definitive RT patients. In postoperative RT patients, pathologic tumor size, margin status, extracapsular extension (ECE) and number of lymph node metastases, were also significantly predictive. Multivariate analysis showed tumor site (oropharynx vs. other sites) to be a significant predictor in all patients, and involved margins and number of involved lymph nodes in postoperative patients. CONCLUSIONS: Clinical rather than dosimetric factors predicted for LR failures in this series, and were similar to those reported following standard RT. These factors may aid in the selection of patients for studies of treatment intensification using IMRT.

    Title Voice and Swallowing Outcomes of an Organ-preservation Trial for Advanced Laryngeal Cancer.
    Date January 2006
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    INTRODUCTION: Organ-preservation treatment approaches for advanced laryngeal cancer patients that use combination chemoradiotherapy result in cure rates similar to primary laryngectomy with postoperative radiotherapy. In the national VA Larynx Cancer Trial, successful organ preservation was associated with an overall improvement in quality of life but not in subjective speech compared with long-term laryngectomy survivors. As part of a Phase II clinical trial, a prospective study of speech and swallowing results was conducted to determine if larynx preservation is associated with improved voice and swallowing compared with results in patients who require salvage laryngectomy. SUBJECTS: A total of 97 patients with advanced laryngeal cancer (46 Stage III, 51 Stage IV) were given a single course of induction chemotherapy (cisplatin 100 mg/m2 on Day 1 and 5-FU 1,000 mg/m2/day x 5 days), followed by assessment of response. Patients with less than 50% response underwent early salvage laryngectomy, and patients with 50% or better response underwent concurrent chemoradiation (72 Gy and cisplatin 100 mg/m2 on Days 1, 22, and 43), followed by two cycles of adjuvant chemotherapy (DDP/5-FU). Direct laryngoscopy and biopsy were performed 8 weeks after radiation therapy to determine final tumor response. Late salvage surgery was performed on patients with persistent or recurrent disease. METHODS: Completed survey data on voice and swallowing utilizing the Voice-Related Quality of Life Measure (V-RQOL) and the List Performance Status Scale for Head and Neck Cancer Patients (PSS-HN) were obtained from 56 patients who were alive and free of disease at the time of survey, with a minimum follow-up of 8 months. Comparisons were made between patients with an intact larynx (n = 37) vs. laryngectomy (n = 19), as well as early (n = 12) vs. late salvage laryngectomy (n = 7). Multivariate analysis was performed to determine factors predictive of voice and swallowing outcomes. Overall 3-year determinant survival was 87%, with median follow-up of 40 months. RESULTS: Patients with an intact larynx demonstrated significantly higher (p = 0.02) mean V-RQOL scores (80.3) than did laryngectomy patients (65.4). This finding was consistent in the social-emotional (p = 0.007) and physical functioning domains (p = 0.03). No differences in V-RQOL scores were found in comparisons between early and late salvage laryngectomy. Multiple linear regression revealed that predictors of higher total V-RQOL scores include lower T stage (p = 0.03), organ preservation (p = 0.0007), and longer duration since treatment (p = 0.01). Understandability of speech was better in patients with an intact larynx (p = 0.001). Overall swallowing function was comparable between groups. Multiple logistic regression revealed that longer duration since treatment (p = 0.03, odds ratio = 1.1) and lower maximal mucositis grade (p = 0.03, odds ratio = 0.3) were predictive of higher likelihood of eating in public. Nutritional mode consisting of oral intake alone without nutritional supplements was achieved in 88.9% of patients with an intact larynx compared with 64.3% of laryngectomees (p = 0.09). CONCLUSIONS: Voice-related quality of life is better in patients after chemoradiation therapy compared with salvage laryngectomy. Earlier salvage, although known to be associated with fewer surgical complications, did not result in improved voice; however, the number of patients analyzed is small. Overall swallowing function is good in all patients; however, patients with an intact larynx are more likely to obtain nutrition with oral intake alone without supplements. Such measures of function and quality of life are important endpoints to help judge overall effectiveness as newer, more aggressive treatment protocols with added toxicities are developed and evaluated.

    Title Metabolic Abnormalities Associated with Weight Loss During Chemoirradiation of Head-and-neck Cancer.
    Date January 2006
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: Weight loss caused by acute mucositis and dysphagia is common during concurrent chemoirradiation (chemo-RT) of head-and-neck (HN) cancer. The metabolic consequences of weight loss during chemo-RT were investigated. PATIENTS AND METHODS: Ninety-six patients with locally advanced HN cancer were treated from 1995 to 2001 on protocols that consisted of 1 to 2 cycles of induction cisplatin/5-fluorouracil followed by irradiation (70 Gy over 7 weeks) concurrent with cisplatin (100 mg/m2 every 3 weeks). Body weights and metabolic evaluations were obtained before and during induction chemotherapy and chemo-RT. Greatest percent changes in weight and in the laboratory values were calculated for each phase of therapy. RESULTS: During induction chemotherapy, significant changes were found in BUN, BUN:creatinine ratio, HCO3, Mg, and albumin, but not in creatinine, Na, K, or weight. During chemo-RT, significant additional changes were observed in all parameters measured, including increases in BUN, creatinine, BUN: creatinine ratio, and HCO3 and decreases in Mg, albumin, Na, K, and weight. The magnitude of most of these changes was significantly greater during chemo-RT than during induction chemotherapy. During chemo-RT, 35% of the patients had more than 10% body weight loss and 6 patients had an increase in creatinine of more than 100%, including 5 patients with Grade 2 nephrotoxicity, all of whom had weight loss 10% or more. Significant correlations were found between weight loss and creatinine (p < 0.0001) or BUN (p = 0.0002) rises, but not with BUN:creatinine ratio or other metabolic changes. Age, gender, tobacco history, hypertension, and diabetes mellitus were not significant predictors of nephrotoxicity. CONCLUSIONS: Weight loss during cisplatin-containing chemo-RT was found to be associated with reduced kidney function. These findings do not establish cause-effect relationships; however, they highlight the importance of intensive supportive measures of nutrition and hydration beyond standard hydration during cisplatin administration. These intensive measures should be enacted before a 10% weight loss is reached.

    Title Reversal of Cisplatin Resistance with a Bh3 Mimetic, (-)-gossypol, in Head and Neck Cancer Cells: Role of Wild-type P53 and Bcl-xl.
    Date December 2005
    Journal Molecular Cancer Therapeutics
    Excerpt

    Organ preservation protocols in head and neck squamous cell carcinoma (HNSCC) are limited by tumors that fail to respond. We observed that larynx preservation and response to chemotherapy is significantly associated with p53 overexpression, and that most HNSCC cell lines with mutant p53 are more sensitive to cisplatin than those with wild-type p53. To investigate cisplatin resistance, we studied two HNSCC cell lines, UM-SCC-5 and UM-SCC-10B, and two resistant sublines developed by cultivation in gradually increasing concentrations of cisplatin. The cisplatin-selected cell lines, UM-SCC-5PT and UM-SCC-10BPT, are 8 and 1.5 times more resistant to cisplatin than the respective parental cell lines, respectively. The parental lines overexpress p53 and contain p53 mutations but the cisplatin-resistant cell lines do not, indicating that cells containing mutant p53 were eliminated during selection. Bcl-x(L) expression increased in the cisplatin-resistant lines relative to the parental lines, whereas Bcl-2 expression was high in the parental lines and decreased in the cisplatin-resistant lines. Thus, cisplatin selected for wild-type p53 and high Bcl-x(L) expression in these cells. We tested a small-molecule BH3 mimetic, (-)-gossypol, which binds to the BH3 domain of Bcl-2 and Bcl-x(L), for activity against the parental and cisplatin-resistant cell lines. At physiologically attainable levels, (-)-gossypol induces apoptosis in 70% to 80% of the cisplatin-resistant cells but only in 25% to 40% of the parental cells. Thus, cisplatin-resistant cells seem to depend on wild-type p53 and Bcl-x(L) for survival and BH3 mimetic agents, such as (-)-gossypol, may be useful adjuncts to overcome cisplatin resistance in HNSCC.

    Title Spinal Epidural Abscess After Cervical Pharyngoesophageal Dilation.
    Date October 2005
    Journal Head & Neck
    Excerpt

    BACKGROUND: Esophageal perforation is an uncommon but known complication of esophageal dilation. Abscess after esophageal tear is rare, especially in the spinal epidural space. This is one case report of such an abscess. METHODS: We present a case of a spinal epidural abscess after cervical pharyngoesophageal dilation. RESULTS: After surgical decompression and abscess drainage, long-term intravenous antibiotics, and physical therapy, the patient has regained some functional use of her left upper extremity. CONCLUSIONS: Early diagnosis with a gadolinium-enhanced MRI and aggressive surgical treatment are keys to successful management with a good functional outcome after this unfortunate complication.

    Title Predictors of Nonsentinel Lymph Node Positivity in Patients with a Positive Sentinel Node for Melanoma.
    Date August 2005
    Journal Journal of the American College of Surgeons
    Excerpt

    BACKGROUND: Patients found to harbor melanoma micrometastases in the sentinel lymph node (SLN) are recommended to proceed to complete lymph node dissection (CLND), although the majority of patients will have no additional disease identified in the nonsentinel lymph nodes (NSLNs). We sought to assess predictive factors associated with finding positive NSLNs, and identify a subset of patients with low likelihood of finding additional disease on CLND. STUDY DESIGN: We queried our prospective melanoma database for patients from January 1996 to August 2003 with a positive SLN. Univariable logistic regression models were fit for multiple factors and a positive NSLN. To derive a probabilistic model for occurrence of one or more positive NSLN(s), a multivariable logistic model was fit using a stepwise variable selection method. RESULTS: Of 980 patients who underwent SLN biopsy for cutaneous melanoma, 232 (24%) had a positive SLN; 221 (23%) followed by CLND. Of these patients, 34 (15%) had one or more positive NSLN(s). In multivariable analysis, male gender (odds ratio [OR] 3.6 [95% CI 1.33, 9.71]; p = 0.01), Breslow thickness (OR 4.58 [95% CI 1.28, 16.36]; p = 0.019), extranodal extension (OR 3.2 [95% CI 1.0, 10.5]; p = 0.05), and three or more positive sentinel nodes (OR 65.81 [95% CI 5.2, 825.7]; p = 0.001) were all associated with the likelihood of finding additional positive nodes on CLND. Of 47 patients with minimal tumor burden in the SLN, only 1 (2%) had additional disease in the NSLN. CONCLUSIONS: These results provide additional data to plan clinical trials to answer the question of who can safely avoid CLND after a positive SLN. Patients with minimal tumor burden in the SLN might be the most likely group, although defining "minimal tumor burden" must be standardized. Serial sectioning and immunohistochemistry on the NSLN in any "low-risk" group must be performed in a clinical trial to confirm that residual disease is unlikely before avoiding CLND can be recommended.

    Title Reliability of Sentinel Lymph Node Biopsy for Regional Staging of Head and Neck Merkel Cell Carcinoma.
    Date August 2005
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To determine (1) the reliability of sentinel lymph node (SLN) biopsy and (2) the need for cytokeratin 20 (CK-20) immunostaining in the staging of head and neck Merkel cell carcinoma (MCC). DESIGN: Retrospective cohort study (median follow-up of 34.5 months). SETTING: Tertiary care center. PATIENTS: Ten patients with head and neck MCC who underwent regional staging with SLN biopsy (SLNB) and CK-20 immunostaining. INTERVENTIONS: Sentinel lymph nodes were identified using preoperative lymphoscintigraphy, intraoperative gamma probe, and isosulfan blue dye. The SLNs were evaluated with hematoxylin-eosin and CK-20 immunostaining. Patients with negative SLNB results were followed up clinically. MAIN OUTCOME MEASURES: Percentage of positive SLNs, regional recurrence in the setting of a negative finding from SLNB, and percentage of positive SLNs requiring CK-20 immunostaining for diagnosis of micrometastatic MCC. RESULTS: At least 1 SLN was identified in every patient. Of 24 nodes, 19 (79%) were from the neck region and 5 (21%) were from the parotid basin. Two of the 24 SLNs, in 2 (20%) of 10 patients, were positive for metastatic disease. Both positive SLNs appeared negative on hematoxylin-eosin-stained sections, but small foci of micrometastatic MCC were identified with CK-20 immunostaining. No cranial nerve complications occurred. Regional failure in the setting of a negative finding on SLNB was observed in 1 (12%) of 8 patients. CONCLUSIONS: Biopsy of SLNs represents a safe and reliable technique for regional staging of MCC of the head and neck. It provides pathologists with a limited number of SLNs for focused analysis, which is imperative because hematoxylin-eosin immunostaining is often insufficient for identifying micrometastatic MCC. The use of anti-CK-20 antibody allows accurate identification of micrometastatic MCC.

    Title Osseocutaneous Radial Forearm Free Tissue Transfer for Repair of Complex Midfacial Defects.
    Date July 2005
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To evaluate the resulting aesthetics, function, and donor site morbidity of the osseocutaneous radial forearm free flap (OCRFFF) used for midface reconstruction. DESIGN: Prospective case series and a retrospective review of results. PATIENTS: Ten patients from an academic practice who underwent reconstruction at the University of Michigan Hospitals between 1995 and 2001. INTERVENTIONS: All patients had maxillectomy defects in which the entire infraorbital rim was reconstructed with an OCRFFF. Of the 10 patients included in the study, 3 underwent a total maxillectomy with orbital exenteration, 4 had a total maxillectomy without orbital exenteration, and 3 had a limited maxillectomy that did not involve the palate. Patients with palatal defects underwent reconstruction with a prosthetic palatal obturator. MAIN OUTCOME MEASURES: Facial contour and aesthetic results, speech understandability, ability to eat solid foods, oronasal separation, socializing outside the home, and return-to-work status. Flap success, donor site morbidity, and orbital complications were also studied. RESULTS: Mean +/- SEM follow-up was 23.2 +/- 5.0 months. A modified Funk facial deformity scale was used, and 7 of the 10 patients had either no deformity or minimal deformity. The mean aesthetic score for these reconstructions was 2.1 +/- 0.3 on a scale of 1 to 4, with 1 representing no deformity and 4 representing a severe deformity. All patients returned to a solid diet and had understandable speech, although patients who had an orbital exenteration trended to poorer scores. All patients socialized either frequently or occasionally outside the home, and all patients not retired or disabled prior to surgery returned to work. CONCLUSION: The OCRFFF reconstruction of the infraorbital rim in patients with total maxillectomy defects and obturator of the palatal defect controls orbital complications and optimizes aesthetic outcome while achieving nearly normal palatal function.

    Title The Use of a Bovine Collagen Construct for Reconstruction of Full-thickness Scalp Defects in the Elderly Patient with Cutaneous Malignancy.
    Date June 2005
    Journal Annals of Plastic Surgery
    Excerpt

    Full-thickness defects of the scalp following cancer resection are reconstructive challenges when bone is exposed. Local, regional, and/or free tissue transfer have all been described for reconstruction when the pericranium is exposed. We examined the surgical outcomes from 23 patients who underwent placement of bovine collagen constructs. Thereafter, delayed skin grafting was performed. The average age of the patients was 70 years. All patients had one of the following: melanoma (n = 13) squamous cell carcinoma (n = 5), angiosarcoma (n = 2), basal cell carcinoma (n = 1), spindle cell carcinoma (n = 1), or malignant pilar tumor (n = 1). The average defect size was 51 cm, with a range of 9 cm to 169 cm. Average time between bovine construct placement and skin grafting was 30 days. Histologic studies demonstrated persistence of the construct and infiltration of nascent fibroblasts. Six patients had delayed healing due to microabscesses in the constructs. All wounds eventually healed. In the elderly, this is a simple method to treat full-thickness scalp defects.

    Title In Vitro Effects of the Bh3 Mimetic, (-)-gossypol, on Head and Neck Squamous Cell Carcinoma Cells.
    Date May 2005
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: Bcl-xL overexpression is common in head and neck squamous cell carcinomas (HNSCC) and correlates with resistance to chemotherapy. Thus, a nonpeptidic, cell-permeable small molecule that mimics the BH3 domain of proapoptotic proteins may inhibit Bcl-xL function and have therapeutic potential for HNSCC by overcoming drug-resistance. (-)-Gossypol, the levorotatory isomer of a natural product isolated from cottonseeds and roots, was recently discovered to bind to the BH3 binding groove of Bcl-xL and Bcl-2. EXPERIMENTAL DESIGN: We investigated the in vitro effects of (-)-gossypol on HNSCC cell lines as well as on fibroblast and keratinocyte cultures by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell survival assays and assessed the results with respect to Bcl-2 family protein expression. RESULTS: We observed dose-dependent growth inhibition of 10 HNSCC cell lines at biologically achievable doses (2.5-10 micromol/L). (-)-Gossypol doses required to inhibit the growth of human fibroblast cell lines by 50% were 2- to 10-fold higher than for HNSCC cell lines. To inhibit human oral keratinocyte growth by 50%, (-)-gossypol concentrations were 2-to 3-fold higher than for HNSCC cell lines. CONCLUSIONS: There is a direct correlation between Bcl-xL-to-Bcl-xS ratios and sensitivity to (-)-gossypol. This agent induced apoptosis in a much higher proportion of cells with wild-type p53. Importantly, cell lines resistant to cisplatin were very sensitive to (-)-gossypol. These results demonstrate that (-)-gossypol has potent antitumor activity in HNSCC in vitro. This agent may be developed as a novel therapeutic agent for HNSCC, either alone or in combination with existing chemotherapeutic agents.

    Title Laryngeal Paraganglioma in a Patient with Multiple Head and Neck Paragangliomas.
    Date April 2005
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    Paragangliomas of the larynx are rare neuroendocrine tumors, with fewer than 70 cases reported in the literature. 1 Typically, laryngeal paragangliomas are not found in patients with multicentric or familial paragangliomas. Only 1 case of laryngeal paraganglioma has been reported in a patient with a synchronous lesion elsewhere (carotid body tumor). 2 We report an additional case of a patient with a laryngeal and multiple other paragangliomas.

    Title Use of Cross-sectional Imaging in Predicting Facial Nerve Sacrifice During Surgery for Parotid Neoplasms.
    Date March 2005
    Journal Orl; Journal for Oto-rhino-laryngology and Its Related Specialties
    Excerpt

    BACKGROUND: Neoplasms of the parotid gland are difficult management issues because of the wide variation in their biological behavior and the potential for sacrifice of the facial nerve during resection. Because of the significant associated morbidity, prediction of facial nerve sacrifice is critically important for planning surgical procedures and preoperative counseling of patients. We hypothesize that along with the knowledge of the tumor type we would be able to accurately predict the likelihood of facial nerve sacrifice using cross-sectional imaging. METHODS: All patients included in this study were previously untreated patients with parotid neoplasms operated on between January 1997 and July 2002. Only those patients with an available preoperative imaging were included and this resulted in 44 patients for review. Nine patients with preoperative deficits in facial nerve function were excluded from this study since these patients would require facial nerve sacrifice regardless of the radiological prediction. The prediction of facial nerve sacrifice was determined using a prediction of tumor location and an algorithm. The predicted results were compared to the operative record. RESULTS: For all lesions, cross-sectional imaging predicted the need for sacrifice of the facial nerve with a sensitivity of 0.83 (95% CI, 0.36-0.99), specificity of 0.90 (95% CI, 0.72-0.97), PPV of 0.63 (95% CI, 0.26-0.90), and NPV of 0.96 (95% CI, 0.79-0.99). For malignant lesions only, prediction of sacrifice of the facial nerve had a sensitivity of 0.83 (95% CI, 0.36-0.99), specificity of 0.80 (95% CI, 0.51-0.95), PPV of 0.63 (95% CI, 0.26-0.90), and NPV of 0.92 (95% CI, 0.62-0.99). CONCLUSION: Cross-sectional imaging and application of our algorithm is a sensitive method for identifying patients with parotid neoplasms who require facial nerve sacrifice. CT and MRI have a high negative predictive value for facial nerve sacrifice.

    Title Selective Neck Dissection is an Option for Early Node-positive Disease.
    Date January 2005
    Journal Archives of Otolaryngology--head & Neck Surgery
    Title Overexpression of Cyclin D1 Correlates with Sensitivity to Cisplatin in Squamous Cell Carcinoma Cell Lines of the Head and Neck.
    Date January 2005
    Journal Acta Oto-laryngologica
    Excerpt

    OBJECTIVE: Treatment strategies for squamous cell carcinoma of the head and neck (SCCHN) are based on the TNM classification. Biological markers that can predict the response to therapy have so far not been introduced. The objective of this study was to investigate cyclin D1 deregulation relative to sensitivity to cisplatin.MATERIAL AND METHODS: This was a laboratory study of 23 established University of Michigan SCC cell lines. Chemosensitivity was assessed by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cyclin D1 amplification status was evaluated by real-time polymerase chain reaction (PCR; data were verified by differential and conventional PCR) using a chromosome 18q microsatellite marker probe (D18S70) as an internal control. Cyclin D1 protein expression was tested using Western blotting.RESULTS: Cyclin D1 amplification was seen in 9/23 (39%) and cyclin D1 overexpression in 12/19 (63%) of the cell lines. As expected, all cell lines showing amplification also showed overexpression of cyclin D1 (p=0.004; Fisher's exact test). The mean cisplatin concentration inhibiting growth of 50% of the cells (ID50) was 9.8 microM in all cell lines (range 2.7-36.7 microM). Five of nine cell lines showing cyclin D1 amplification were highly sensitive to cisplatin (ID50 3-4.8 microM) and the remaining four revealed intermediate sensitivity. Five cell lines that strongly overexpressed cyclin D1 protein responded better to cisplatin than cell lines that showed any other expression (ID50 5.1 vs 11.2 microM; p=0.025; Student's t-test).CONCLUSIONS: This in vitro study suggests that overexpression of cyclin D1 is associated with a good response to cisplatin in SCC cell lines. Our results support the hypothesis that overexpression of cyclin D1 is one of the molecular factors that can be used to predict sensitivity to chemotherapy, thus enabling individualization of treatment of head and neck cancer.

    Title Restoration of the Orbital Aesthetic Subunit in Complex Midface Defects.
    Date December 2004
    Journal The Laryngoscope
    Excerpt

    OBJECTIVES/HYPOTHESIS: Although various options exist for restoration of the orbital defect in complex craniofacial resections, the aesthetic appearance and functional result of the orbit are optimized when the bony orbital architecture, orbital volume, and facial contour are specifically addressed. The study describes an approach using free tissue transfer for restoration of the native orbital aesthetic subunit. STUDY DESIGN: Retrospective case series. METHODS: Nineteen patients (male-to-female ratio, 14:5; mean age, 52 y [age range, 8-79 y]) in the study period between 1997 and 2001 had orbital defects that could be classified into one of the following categories: 1) orbital exenteration cavities only, 2) orbital exenteration cavities with resection of less than 30% of the bony orbital rim, or 3) radical orbital exenteration cavities with resection of overlying skin and bony malar eminence. Group 1 had reconstructions with fasciocutaneous forearm flaps; group 2, with osseocutaneous forearm flaps; and group 3, with osseocutaneous scapula flaps. RESULTS: Eighteen of 19 patients achieved a closed orbital reconstruction with restoration of the orbital aesthetic subunit. Among 16 patients with more than 4 months of follow-up, 10 patients had minimal or no resulting facial contour deformity and 8 patients engaged in social activities outside the home on a frequent basis. Five of the nine patients who were working before their surgery were able to return to work. CONCLUSION: Patients with complex midface defects involving the orbit can undergo free tissue transfer and have successful restoration of the native orbital aesthetic subunit without an orbital prosthesis.

    Title Disability in Patients with Head and Neck Cancer.
    Date July 2004
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    BACKGROUND: Patients with head and neck cancer often experience debilitating speech, eating, and respiratory problems as well as the psychological effects of loss of function and change in body image. These patients often become unemployed as a result of their disease process, which adds financial burden to their already stressful lives. Yet the specific factors associated with unemployment have not been systematically studied. METHODS: This multisite study used survey and chart data to determine the predictors of work-related disability. RESULTS: Of the 384 patients who were working prior to their diagnosis of head and neck cancer, 52% (n = 201) were disabled by their cancer treatment. Multivariate analysis demonstrated significant links between disability and chemotherapy (odds ratio [OR], 3.4; P <.001), neck dissection status (OR, 2.3; P =.01), pain scores (OR, 1.2; P =.01), and time since diagnosis (OR, 0.9; P =.04). CONCLUSIONS: More than half of the patients in this study were disabled by their head and neck cancer or treatment. Patients with head and neck cancer who have undergone chemotherapy or neck dissection or have high pain scores are at increased risk for disability from their cancer or their treatment. Efforts to prevent (if possible), better assess, and treat pain and other adverse effects of head and neck cancer treatments may also have the potential to reduce patient disability.

    Title Current Thoughts on the Role of Chemotherapy and Radiation in Advanced Head and Neck Cancer.
    Date June 2004
    Journal Current Opinion in Otolaryngology & Head and Neck Surgery
    Excerpt

    PURPOSE OF REVIEW: The management of advanced malignancies of the head and neck continues to be a challenging clinical problem. During the last three decades, the traditional treatments of surgery and/or radiation have not yielded significant improvements in survival in this patient population. In addition, surgery for advanced disease can create significant functional and cosmetic defects that adversely impact a patient's quality of life. Newer "organ preservation" approaches using chemotherapy and radiation are currently being studied in an attempt to improve survival while maintaining the functional integrity of the disease site. RECENT FINDINGS: Recent studies have demonstrated that for advanced head and neck squamous cell cancers, concurrent chemoradiation is superior to radiation alone for local tumor control and perhaps overall survival. With the exception of laryngeal cancer, phase III data comparing chemoradiation with surgery is lacking for most head and neck subsites. However, comparisons with historical controls suggest that chemoradiation strategies may offer improved outcomes when compared with more traditional treatment regimens. SUMMARY: This review emphasizes recent phase III trials that support the use of chemoradiation strategies in the treatment of advanced head and neck squamous cell cancers.

    Title Recurrences Near Base of Skull After Imrt for Head-and-neck Cancer: Implications for Target Delineation in High Neck and for Parotid Gland Sparing.
    Date May 2004
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: Locoregional (LR) failures near the base of the skull, and their relationships to the targets in the high neck, were examined in a series of patients who underwent intensity-modulated radiotherapy (IMRT) for head-and-neck cancer. METHODS AND MATERIALS: Between 1994 and 2002, 133 patients with non-nasopharyngeal head-and-neck squamous cell carcinoma completed a course of curative, parotid-sparing RT. Treatment was delivered until 1996 with conformal three-dimensional techniques and thereafter with multisegmental static IMRT. Of the 133 patients, 80 had oropharyngeal, 27 oral cavity, 12 hypopharyngeal, 11 laryngeal, and 3 unknown primary cancer. The AJCC stage was I in 1, II in 6, III in 26, IVA in 83, and IVB in 12; cancer was recurrent in 5. Sixty patients received primary and 73 postoperative IMRT. 86% of patients (n = 115) had ipsilateral neck metastasis. In all patients, the contralateral neck was clinically node negative but was judged to be at high risk of subclinical disease. Delineation of the superior-most extent of the nodal targets was consistent and corresponded with Rouviere's observations. In the contralateral clinically node-negative neck, the uppermost Level II nodal target was the subdigastric (SD) nodes. To ensure coverage, the uppermost clinical target volume was delineated at the axial CT image in which the posterior belly of the digastric muscle crossed the jugular vein. In the ipsilateral neck, which was node positive in most patients, the uppermost Level II clinical target volume was delineated through the base of the skull. The uppermost retropharyngeal (RP) nodal target was delineated at the level of the top of the C1 vertebral body, accommodating Rouviere's description of the location of the lateral RP nodes. The dose prescription was 70 Gy for the primary planning target volumes (PTVs); 64 Gy and 60 Gy for PTV of the postoperative beds with and without extracapsular extension, respectively; and 50-54 Gy for PTVs of nonoperated subclinical disease, at 1.8-2.0 Gy fractions. In-field or marginal recurrences were defined as those occurring when >95% or 20-95% of the recurrence volume, respectively, had received >95% of the prescribed dose. RESULTS: At a median follow-up of 32 months (range, 6-107 months), 21 patients (16%) had locoregional recurrence. Seventeen recurrences were in-field and four were marginal. The most prevalent nodal recurrence was in Level II bilaterally, where all failures were in-field. In-field failures were observed in the ipsilateral high neck cranial to the SD nodes (all in initially node-positive neck). No recurrences occurred in the contralateral high neck, cranial to the SD nodes, which was not included in the targets. The 95% confidence interval for the risk of recurrence in that region was 0-2.7%. Three RP nodal failures were observed; two were marginal, occurring ipsilateral and contralateral to the primary tumors, and centered cranial to the top of C1. After these recurrences, the RP nodal clinical target volumes were delineated bilaterally through the base of skull, without subsequent RP recurrence. These target delineation guidelines allowed the achievement of a mean contralateral parotid dose of < or =26 Gy (found previously to preserve salivary output significantly) in 82% of the patients. The 3-year actuarial LR recurrence-free survival rate of primary and postoperative IMRT patients was similar (81% and 84%, respectively). Oropharyngeal cancer patients had the greatest LR recurrence-free survival rate (94%, p <0.001). No statistically significant differences were found in the dose delivered to the PTVs or the in-field recurrence volume between patients who had or did not have LR failure. CONCLUSION: These results suggest that when the contralateral node-negative side of the neck has a high risk of subclinical metastasis, it is adequate to include the SD nodes as the cranial-most Level II nodal target in non-nasopharyngeal head-and-neck cancer. In the node-positive side of the neck, this nodal level should be delineated more cranially. The RP nodal targets should be delineated more cranially. The RP nodal targets should be delineated bilaterally and should extend to the base of the skull, rather than to the top of C1. These guidelines allowed substantial sparing of the contralateral parotid gland. The results of this series validate a consensus for target delineation adopted recently by cooperative radiotherapy groups.

    Title Cartilaginous Tumours of the Larynx.
    Date May 2004
    Journal The Journal of Otolaryngology
    Excerpt

    Cartilaginous tumours of the larynx are rare. Chondrosarcomas represent the most common sarcoma involving this site. A series of seven patients with the diagnosis of chondrosarcoma of the larynx from the cancer registry at the University of Michigan Medical Center from 1975 to 1997 and one recent case from the Ann Arbor Department of Veterans Affairs Hospital were identified. One patient with a laryngeal chondroma was also included in the series. Pertinent clinical, pathologic, and therapeutic data were reviewed. In three of the nine patients, tumours involved the thyroid cartilage; the remainder, including the chondroma, arose from the cricoid cartilage. Four of the chondrosarcomas were histopathologic grade I, three were grade II, and one was grade III. Surgical treatment of the chondrosarcomas included five total laryngectomies, three laryngofissures with resection, and a partial cricoid resection. Six patients are alive without disease, including one patient who had direct spread to the thyroid gland and a peristomal recurrence that was excised. The patient with a grade III tumour developed pulmonary metastases 6 months after total laryngectomy and radiation therapy and died. One patient died of other causes. These findings confirm previous reports that chondrosarcomas are usually slow growing and demonstrate an indolent clinical course and that low-grade chondrosarcomas arising in the larynx may be excised with close surgical margins without compromising survival. This series suggests that local recurrence of low-grade lesions can be salvaged surgically, even after total laryngectomy, and that high-grade chondrosarcomas, although exceedingly rare, are much more aggressive neoplasms with a greater tendency to metastasize.

    Title Clinical Predictors of Quality of Life in Patients with Head and Neck Cancer.
    Date May 2004
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To identify clinical predictors of quality of life (QoL) in a head and neck cancer patient population. DESIGN, PATIENTS, AND SETTING: A convenience sample of 570 patients with upper aerodigestive tract cancers were surveyed at a tertiary care oncology clinic and Veterans Affairs otolaryngology clinic. INTERVENTIONS: A self-administered health survey was constructed to collect demographic, health, smoking, alcohol, depression symptom, and QoL information. Tumor site and tumor stage, clinical, and treatment data were abstracted from the patient medical records. MAIN OUTCOME MEASURES: Quality of life was assessed using the Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36) and the Head and Neck QoL (HNQoL) instrument. RESULTS: Of the 570 eligible respondents, the presence of a feeding tube had the most negative impact on QoL, with significant decrements in 6 of the 8 SF-36 scales and all 4 HNQoL scales (P<.01). In descending order of severity, medical comorbid conditions, presence of a tracheotomy tube, chemotherapy, and neck dissection were also associated with significant (P<.05) decrements in QoL domains. Patients who took the survey more than 1 year after diagnosis had improved QoL in 7 of 12 domains. Hospital site, age, education level, sex, race, and marital status were also significant predictors of QoL. CONCLUSION: There are at least 13 demographic and clinical characteristics that are significant predictors of QoL in patients with head and neck cancer, which should be considered when treating patients and conducting QoL studies in the future.

    Title Molecular Profiling and the Identification of Genes Associated with Metastatic Oral Cavity/pharynx Squamous Cell Carcinoma.
    Date April 2004
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To investigate differences in gene expression profiles between oral cavity/oropharynx squamous cell carcinoma (OC/OP SCC) primary tumors that have metastasized to cervical lymph nodes and nonmetastatic OC/OP SCC tumors. DESIGN: Oligonucleotide microarray analysis of primary tumors was used to produce gene expression profiles. Profile comparisons between metastatic and nonmetastatic tumors were performed using principal component analysis, t test, and fold change differences. A similar comparison between metastatic tumors and noncancer oral mucosa samples was performed to ensure tumor origin. SUBJECTS: A prospective cohort of 20 patients with previously untreated OC/OP SCC who underwent pathologic staging following surgical resection and lymphadenectomy. RESULTS: Of the approximately 9600 genes profiled, 101 demonstrated significant expression differences between the metastatic and nonmetastatic tumors (fold change > or =1.5; P<.01). Among this subset, 57 genes also exhibited significant differences between metastatic tumors and normal mucosa samples (fold change > or =1.5; P<.05). This profile included genes related to the extracellular matrix, adhesion, motility, inflammation, and protease inhibition. Collagen type 11 alpha-1 (COL11A1) demonstrated the greatest differential expression between metastatic and nonmetastatic OC/OP SCC tumors (fold change=7.61; P=.002). Tissue inhibitor of metalloproteinase 1 (TIMP-1) also demonstrated increased expression in metastatic tumors (fold change=3.3; P=.003). CONCLUSIONS: Metastatic OC/OP SCC has a distinct gene expression profile compared with nonmetastatic OC/OP SCC and normal oral mucosa. This metastatic profile includes genes related to the extracellular matrix, adhesion, motility, and protease inhibition. Knowledge gained through tumor gene expression profiling may facilitate early detection of aggressive tumors and targeted therapeutic interventions.

    Title Pectoralis Major Myocutaneous Flap Vs Revascularized Free Tissue Transfer: Complications, Gastrostomy Tube Dependence, and Hospitalization.
    Date March 2004
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To evaluate the factors related to surgical complications, rate of gastrostomy tube (G-tube) dependence, and hospitalization in patients undergoing reconstruction with a pectoralis myocutaneous flap vs a soft-tissue revascularized flap. DESIGN: Quasi-experimental case series with a historic control group. POPULATION: A total of 179 patients (138 men and 41 women) with a mean (SD) age of 58 (14) years treated between January 1, 1986, and December 31, 1995, with a pectoralis flap (108 patients) or a revascularized free flap (71 patients). METHODS: Inclusion criteria were first or second extirpation, reconstruction with soft-tissue flap, or defect including the upper aerodigestive tract. Exclusion criteria were secondary reconstruction, or reconstruction for salvage of a complication. RESULTS: Although the major complication rate was not significantly different according to reconstructive approach, hypopharyngeal defects had a significantly higher major complication rate of 30% (6/20) compared with 8% (13/159) for other defect sites (P<.003). The minor complication rate was higher in the pectoralis group, at 57% (62/108), than in the revascularized flap group, at 21% (15/71) (P<.001). G-tube dependence was higher in the pectoralis group at 42% (40/96), in contrast to the revascularized flap group at 16% (10/63) (P<.001). G-tube dependence was 25% higher in patients who underwent salvage surgery after radiation (42% [30/72]) than in patients treated with postoperative radiation (17% [12/69]) (P<.004). Revascularized flaps helped ameliorate the effects of radiation before surgery; 56% (23/41) of the patients who received pectoralis flaps were G-tube dependent, while the rate of G-tube dependence in the revascularized flap group was 23% (7/31) (P<.004). Hospitalization was longer in the pectoralis group (14 days) than the revascularized flap group (12 days) (P<.006). CONCLUSION: Patients who undergo reconstruction with a pectoralis flap have significantly higher minor complication rates, a higher rate of G-tube dependence, and longer hospitalization than patients who undergo reconstruction with a soft-tissue revascularized flap.

    Title Staging Workup, Sentinel Node Biopsy, and Follow-up Tests for Melanoma: Update of Current Concepts.
    Date February 2004
    Journal Archives of Dermatology
    Excerpt

    OBJECTIVES: To clarify and update workup and follow-up strategies based on fundamental principles and current data, and to discuss new and current concepts regarding sentinel lymph node biopsy (SLNB), particularly in relation to the staging workup. DATA SOURCES: Studies conducted from 1995 to 2003 were identified by PubMed search. Additional searches included workup for reference lists of retrieved articles when applicable, and PubMed-related articles. STUDY SELECTION: Contemporary studies with good design, conclusions based on sound methods, and results pertaining to staging workup, SLNB, and follow-up tests were critically reviewed. DATA EXTRACTION: Data and conclusions based on the above studies were incorporated into a review. DATA SYNTHESIS: Routine tests have marginal to no efficacy and are not cost-efficient for detecting occult disease in asymptomatic patients with localized melanoma. The only staging test that has relatively high sensitivity and specificity and provides tissue diagnosis is SLNB; moreover, SLNB has revolutionized our understanding of lymphatic pathways. The concepts of interval nodes and unexpected lymphatic drainage pathways have been addressed by several recent reports. There are no data that demonstrate any significant difference in overall survival for detection of asymptomatic vs symptomatic stage IV melanoma. CONCLUSIONS: An initial workup is useful for staging and prognosis to identify occult disease, with potential outcome benefit if treated early; and, by detecting distant occult disease (stage IV), to obviate the need for an extensive surgical procedure and thereby avoid associated increased morbidity. The foundation for the workup and follow-up remains thorough history taking and a physical examination, combined with a low index of suspicion for symptom-directed tests.

    Title P53 Mutation Correlates with Cisplatin Sensitivity in Head and Neck Squamous Cell Carcinoma Lines.
    Date December 2003
    Journal Head & Neck
    Excerpt

    BACKGROUND: A critical factor for successful organ preservation treatment in head and neck cancer may be selecting tumors that respond to chemotherapy and radiation. Previous results in patients indicated that tumors that overexpressed p53 were more sensitive to chemotherapy than those that did not overexpress p53. METHODS: To determine the relationship of p53 mutations to sensitivity to cisplatin in vitro, 23 head and neck squamous cell carcinoma (HNSCC) cell lines were analyzed for cisplatin sensitivity, p53 expression, and p53 mutation status. RESULTS: Mutations of the p53 gene were identified in 13 of 23 of the cell lines tested. Mutation of the p53 gene was significantly associated with high levels of expression of the p53 protein. The average ID(50) (drug dose required to inhibit 50% of cell growth) for cell lines with mutant p53 was 6.8 microM, whereas the average ID(50) for cell lines with wild-type p53 was 13.7 microM. CONCLUSIONS: These in vitro data support a role for mutation of the p53 tumor suppressor gene as a marker for response to cisplatin in HNSCC.

    Title Epstein-barr Virus Detected in a Head and Neck Squamous Cell Carcinoma Cell Line Derived from an Immunocompromised Patient.
    Date December 2003
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    BACKGROUND: DNA tumor viruses potentially play a role in the development of squamous cell carcinoma of the head and neck (SCCHN). Human papillomavirus is found in up to 50% of SCCHN specimens, and Epstein-Barr virus (EBV) has been detected in nasopharyngeal carcinoma, Burkitt lymphoma, and other lymphomas. However, the role of EBV in nonnasopharyngeal SCCHN has not been thoroughly investigated. METHODS: Twenty-one SCCHN cell lines derived from tumors of various subsites were used to screen for EBV DNA as well as latent viral protein expression. The method of EBV DNA detection was polymerase chain reaction with 3 independent primer sets from distinct regions of the genome. Expression of the viral protein EBNA-1, critical for the maintenance of the viral episome, was monitored by immunofluorescence using an antibody specific for EBNA-1. In addition, 12 paraffin-embedded tumor specimens and adjacent normal tissues were analyzed by polymerase chain reaction. These tumor specimens were further characterized by immunohistochemistry with the use of a mouse monoclonal antibody that recognizes EBNA-1. RESULTS: Little or no EBV DNA was detected in 20 of 21 cell lines or in any of the tumor specimens, while detecting approximately 40 genome copies in a control reaction. Accordingly, these cell lines and specimens were negative for EBNA-1 expression. In 1 cell line derived from an immunosuppressed patient, EBV DNA was detected, and on further examination a small percentage of cells expressed EBNA-1 as shown by immunofluorescence. CONCLUSIONS: Although EBV may not be a major cofactor contributing to the proliferation of SCCHN, the limited initial evidence suggests that EBV may be involved in development of SCCHN in immunosuppressed patients.

    Title Reconstruction of Complex Parotidectomy Defects Using the Lateral Arm Free Tissue Transfer.
    Date October 2003
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    OBJECTIVES: The study goal was to show that the lateral arm flap is a viable reconstructive option for complex parotidectomy defects.Study design and setting We studied a case series at a tertiary care medical center from March 1997 to March 2002. The lateral arm flap was used to reconstruct parotidectomy defects that included a composite resection of adjacent tissue in 30 patients. There were 19 men and 11 women (mean age, 62 years; mean follow-up, 19 months). The mean flap area was 114 cm(2), and the mean flap volume was 172 cm(3). The posterior cutaneous nerve of the forearm (PCNF) was used as a facial nerve cable graft in 14 patients. Facial disability outcomes were measured using the Facial Clinimetric Evaluation scale. RESULTS: The major and minor complication rates with use of this reconstructive approach were low: 16.7% (5 of 30) and 26.7% (8 of 30), respectively. Donor site morbidity was minimal, with no patient having a major donor site complication and 23.3% (7 of 30) having minor complications. Functional recovery of the facial nerve occurred in 6 of 8 evaluable patients who underwent facial nerve grafting using the PCNF. Controlling for degree of facial nerve paralysis, Facial Clinimetric Evaluation scale scores of our patients were not statistically different than those of a historic population with a facial paralysis and no surgical defect. CONCLUSIONS: The lateral arm free flap effectively restores facial appearance when used for reconstruction of complex parotidectomy defects. The PCNF, a nerve harvested with the lateral arm flap, can be used as a facial nerve cable graft with a high rate of success. SIGNIFICANCE: The lateral arm flap is successful as a single donor site for reconstructing facial contour and the facial nerve after major ablative defects in the parotid region.

    Title Salivary Gland Sparing and Improved Target Irradiation by Conformal and Intensity Modulated Irradiation of Head and Neck Cancer.
    Date October 2003
    Journal World Journal of Surgery
    Excerpt

    The goals of this study were to facilitate sparing of the major salivary glands while adequately treating tumor targets in patients requiring comprehensive bilateral neck irradiation (RT), and to assess the potential for improved xerostomia. Since 1994 techniques of target irradiation and locoregional tumor control with conformal and intensity modulated radiation therapy (IMRT) have been developed. In patients treated with these modalities, the salivary flow rates before and periodically after RT have been measured selectively from each major salivary gland and the residual flows correlated with glands' dose volume histograms (DVHs). In addition, subjective xerostomia questionnaires have been developed and validated. The pattern of locoregional recurrence has been examined from computed tomography (CT) scans at the time of recurrence, transferring the recurrence volumes to the planning CT scans, and regenerating the dose distributions at the recurrence sites. Treatment plans for target coverage and dose homogeneity using static, multisegmental IMRT were found to be significantly better than standard RT plans. In addition, significant parotid gland sparing was achieved in the conformal plans. The relationships among dose, irradiated volume, and the residual saliva flow rates from the parotid glands were characterized by dose and volume thresholds. A mean radiation dose of 26 Gy was found to be the threshold for preserved stimulated saliva flow. Xerostomia questionnaire scores suggested that xerostomia was significantly reduced in patients irradiated with bilateral neck, parotid-sparing RT, compared to patients with similar tumors treated with standard RT. Examination of locoregional tumor recurrence patterns revealed that the large majority of recurrences occurred inside targets, in areas that had been judged to be at high risk and that had received RT doses according to the perceived risk. Tangible gains in salivary gland sparing and target coverage are being achieved, and an improvement in some measures of quality of life is suggested by our findings. Additional reduction of xerostomia may be achieved by further sparing of the salivary glands and the non-involved oral cavity. A mean parotid gland dose of < or = 26 Gy should be a planning objective if significant parotid function preservation is desired. The pattern of recurrence suggests that careful escalation of the dose to areas judged to be at highest risk may improve tumor control.

    Title Generation of Vaccine-primed Lymphocytes for the Treatment of Head and Neck Cancer.
    Date June 2003
    Journal Head & Neck
    Excerpt

    BACKGROUND: This study was performed to assess the ability of autologous tumor vaccines to induce T-cell reactivity to squamous cell cancers (SCC). METHODS: Irradiated autologous tumor cells admixed with bacillus Calmette-Guérin (BCG) were given intradermally in patients with advanced head and neck cancers. Vaccine-primed lymph node (VPLN) cells were secondarily activated with anti-CD3 mAb and expanded in IL-2 for adoptive immunotherapy. A mean (+/- SEM) of 2 (+/-0.6) x 10(10) anti-CD3-activated cells were administered in conjunction with IL-2 in six patients. RESULTS: Anti-CD3-activated VPLN cells secreted IFN-gamma and GM-CSF in response to autologous tumor cells but not to allogeneic tumor cells in four of five patients analyzed. Both CD4(+) and CD8(+) tumor reactive cells were present in the VPLN. There were no significant tumor responses after transfer of the anti-CD3-activated VPLN. In separate experiments, costimulation of VPLN cells with anti-CD3 and anti-CD28 mAb resulted in enhanced cytokine secretion to autologous tumor compared with anti-CD3 activation alone. CONCLUSIONS: Both CD4(+) and CD8(+) responses can be induced to SCC by autologous tumor vaccination. However, additional approaches need to be identified to enhance the therapeutic efficacy of this approach.

    Title Genetic Markers of Head and Neck Cancer: Identifying New Molecular Targets.
    Date April 2003
    Journal Archives of Otolaryngology--head & Neck Surgery
    Title Elevated Serum Vascular Endothelial Growth Factor and Decreased Survival in Advanced Laryngeal Carcinoma.
    Date March 2003
    Journal Head & Neck
    Excerpt

    PURPOSE: The purpose of this study was to determine whether serum vascular endothelial growth factor (s-VEGF) levels at the time of diagnosis correlate with any known tumor variables and overall survival in patients with advanced laryngeal squamous cell carcinoma. Comparisons with a cohort of normal healthy controls were also performed to determine the potential usefulness of s-VEGF as a screening tool. EXPERIMENTAL DESIGN: Serum from patients enrolled in the VA Laryngeal Cooperative Study #258 (n = 183), as well as normal healthy controls (n = 40) was used in this analysis. Quantitative enzyme-linked immunosorbent assays (ELISA) for VEGF were performed in duplicate on each serum sample. Demographic and survival data were available for each patient enrolled in the study. Univariate analyses, multivariate Cox regression analyses, and Kaplan-Meier survival analysis were used. RESULTS: The mean serum concentration of s-VEGF for the healthy control group was 47.83 +/- 0.13 pg/mL. For all patients enrolled in the VA Cooperative Study, regardless of treatment group, the mean s-VEGF level was 317.22 +/- 25.46 pg/mL. The patients randomly assigned to the surgical arm (n = 97) had a mean value of 315.44 +/- 30.44 pg/mL. Those randomly assigned to the induction chemotherapy arm (n = 86) had a mean s-VEGF level of 319.22 +/- 42.11 pg/mL. Serum VEGF levels were significantly elevated in patients with laryngeal carcinoma compared with healthy controls (p < .001). The serum VEGF levels in each arm of the trial were also elevated versus the healthy controls (p < .001, surgery arm plus radiotherapy; p < .001, chemotherapy plus radiotherapy). In a univariate analysis, elevated s-VEGF correlated with poor Karnofsky performance status for all patients with advanced laryngeal carcinoma (p < .008). High s-VEGF levels also correlated with a poor performance score in patients on the chemotherapy arm of the VA Laryngeal Trial (p < .004). Elevated s-VEGF levels in the surgical plus radiotherapy arm correlated with node-positive disease (p = .047) and supraglottic location of the tumor (p = .022). In a multivariate analysis using all known tumor variables and s-VEGF levels, elevated s-VEGF levels and infiltrating growth pattern correlated with decreased survival for all evaluated patients with advanced laryngeal carcinoma (p = .065, and p = .018, respectively). CONCLUSIONS: Serum VEGF levels are significantly elevated in patients with advanced laryngeal carcinoma versus healthy controls. Elevated pretreatment s-VEGF levels tended to indicate a more aggressive disease state and a poorer overall survival in advanced laryngeal carcinoma.

    Title Reliability of Sentinel Lymph Node Mapping with Biopsy for Head and Neck Cutaneous Melanoma.
    Date January 2003
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVES: To determine (1) the reliability of sentinel lymph node mapping with biopsy (SLNB) in head and neck cutaneous melanoma to accurately stage nodal basins and (2) the safety of SLNB in both the neck and parotid regions. DESIGN: Retrospective cohort study with a median follow-up of 25 months. All patients had a minimum follow-up of 1 year. SETTING: Academic medical center. PATIENTS: Eighty evaluable patients diagnosed as having head and neck cutaneous melanoma and staged using SLNB. INTERVENTIONS: Sentinel lymph nodes were identified using preoperative lymphoscintigraphy and a combination of intraoperative gamma probe and isosulfan blue dye. Patients with a SLN positive for melanoma underwent therapeutic lymphadenectomy followed by an evaluation for adjuvant therapies. Patients with a negative SLNB result were followed up clinically. MAIN OUTCOME MEASURES: Percentage of positive SLNs, regional recurrence in the setting of a negative SLNB result (false-negative rate), and procedure complications. RESULTS: The mean Breslow depth was 2.35 mm. A SLN was identified in 77 (96.3%) of cases, with an average of 2.18 nodes per patient. Of the sentinel nodes identified, 74% were from the neck region. The remaining 26% were from the parotid basin. No facial nerve complications occurred. Of the patients, 14 (18%) were SLN positive for metastatic melanoma. The regional failure rate in the setting of a negative SLNB result was 4.5%. CONCLUSIONS: Sentinel lymph node mapping with biopsy is a reliable technique to diagnose regional spread from head and neck cutaneous melanoma. This procedure can be performed in both neck and parotid nodal basins with safety and accuracy similar to non-head and neck sites.

    Title Paranasal Sinus Malignancies: an 18-year Single Institution Experience.
    Date December 2002
    Journal The Laryngoscope
    Excerpt

    OBJECTIVES: To characterize a single institution experience with management of paranasal sinus malignancies during an 18-year time period, report long-term survival rates, and identify prognostic factors. STUDY DESIGN: Retrospective chart review. METHODS: Studied were 141 patients treated for a paranasal sinus malignancy at a single institution from 1980 to 1997 with a minimum 3-year follow-up. Gender, age, TNM stage, anatomic site, pathology, treatment, and recurrence rates were reviewed. Multivariate analysis was performed to determine factors affecting survival. RESULTS: The male to female ratio was 1.6:1, and the median patient age was 60 years. Most patients presented with T3/T4 or locally advanced disease (88%), N0 status (96%), and M0 status (96%). The maxillary sinus was the most commonly affected site (70%), followed by the ethmoid sinus (26%). The most common malignancy was squamous cell carcinoma (51%), followed by adenoid cystic carcinoma (12%) and adenocarcinoma (11%). Sixty-two percent of this study group underwent surgery as part of a multimodality curative treatment plan or alone as curative treatment. Eighteen patients (13%) had unresectable local disease and received non-surgical palliative treatment. Kaplan-Meier analysis revealed the 5-year and 10-year disease-specific survival was 52% and 35%, respectively. Multivariate analysis revealed T4 stage (P =.005), N-positive stage (P =.009), and M-positive stage (P =.018) negatively impacted survival. Seventy-two patients (51%) developed recurrent disease at a median time of 336 days after initial treatment. CONCLUSIONS: Most patients with paranasal sinus malignancies presented with locally advanced disease. Advanced T stage, regional, and distant metastasis are highly predictive of poor survival. Recurrence rate is high and typically occurs within the first year after treatment.

    Title Functional Assessment Using Constant's Shoulder Scale After Modified Radical and Selective Neck Dissection.
    Date November 2002
    Journal Head & Neck
    Excerpt

    BACKGROUND: Constant's Shoulder Scale is a validated and widely applied instrument for assessment of shoulder function. We used this instrument to assess which treatment and demographic variables contribute to shoulder dysfunction after neck dissection in head and neck cancer patients. METHODS: A convenience sample of 54 patients with 64 neck dissections and minimum follow-up of 11 months were evaluated. Thirty-two accessory nerve-sparing modified radical (MRND) and 32 selective neck (SND) dissections were performed. Multivariable regression analysis was used to determine the variables that were predictive for shoulder dysfunction. Clinical variables included age, time from surgery, handedness, weight, radiation therapy, neck dissection type, tumor stage, and site. RESULTS: Patients receiving MRND had significantly worse shoulder function than patients with SND (p =.0007). Radiation therapy contributed negatively, whereas weight contributed positively (p =.0001). CONCLUSIONS: The critical factors contributing to shoulder dysfunction after neck dissection were weight, radiation therapy, and neck dissection type.

    Title Human Papillomavirus and P53 Mutational Status As Prognostic Factors in Head and Neck Carcinoma.
    Date October 2002
    Journal Head & Neck
    Excerpt

    BACKGROUND: Mutations of the p53 tumor-suppressor gene are common in squamous cell carcinoma of the head and neck (SCCHN) and may portend a worse prognosis. Human papillomavirus (HPV) represents another potential prognostic factor for SCCHN. The oncogenic potential of HPV may be due to the ability of its E6 oncoprotein to promote degradation of wild-type p53 protein. We wish to determine whether there is a lower incidence of p53 mutations in HPV-positive versus HPV-negative tumors, and if HPV and/or p53 status has an impact on survival. METHODS: Thirty-two SCCHN specimens were analyzed for mutations of the p53 gene using single-strand conformational polymorphism (SSCP) analysis followed by DNA sequencing. The HPV status of all specimens was evaluated by use of polymerase chain reaction with HPV consensus primers and Southern blot hybridization. Pertinent clinical information was obtained from chart review. RESULTS: Nonsilent p53 mutations were present in 2 of 15 (13%) of HPV-positive tumors compared with 6 of 17 (35%) of HPV-negative tumors (p =.229; Fisher's exact test, odds ratio.28). A survival advantage was found between HPV-positive compared with HPV-negative specimens (p =.0264) and between p53 wild type compared with p53 mutant specimens (p =.01) by univariate log rank analysis. When stratified according to both HPV and p53 status, a statistically significant survival difference was observed largely because of a 100% survival for the HPV-positive/p53 wild-type group (p =.003). CONCLUSIONS: This preliminary study supports the notion that the presence of HPV confers a survival advantage among HNSCC patients, particularly when p53 is wild type.

    Title Immune Reactivity Does Not Predict Chemotherapy Response, Organ Preservation, or Survival in Advanced Laryngeal Cancer.
    Date September 2002
    Journal The Laryngoscope
    Excerpt

    OBJECTIVE: To determine whether pretreatment lymphocyte subpopulations correlate with tumor response to induction chemotherapy as part of an organ preservation treatment approach in patients with advanced laryngeal cancer. STUDY DESIGN: A prospective clinical trial in patients with advanced laryngeal cancer was undertaken to determine whether the frequency of late salvage laryngectomy and overall survival could be improved using one cycle of neoadjuvant chemotherapy to select patients for organ preservation. Pretreatment peripheral blood lymphocyte subpopulations for CD3, CD4, CD8, NK, and B cells were correlated with tumor response to induction chemotherapy, larynx preservation, and survival, to determine whether immune parameters could be useful in patient selection. METHODS: The study setting was a tertiary referral academic health center. Studied were 53 patients with stage III (42%) or IV (57%) larynx cancer. Most patients had supraglottic cancers (73%) and positive clinical nodes (51%). Sixty-eight percent had greater than 50% tumor response after one cycle of induction chemotherapy and then received concurrent chemoradiation and two cycles of adjuvant chemotherapy. Lymphocyte subpopulations were measured in 39 patients. Mean follow-up was 23.3 months (range, 5-61 mo). RESULTS: A total of 18 (34%) patients underwent laryngectomy. Only 4 cases were late salvage resections (13-35 mo after treatment). Fourteen cases were planned surgery after initial chemotherapy. Of the lymphocyte subpopulations measured, CD8 levels were significantly lower in stage IV patients and tended to be lower in patients with successful organ preservation. However, no significant differences in lymphocyte subpopulations were found among responders and nonresponders to chemotherapy. Overall survival was 88%. CONCLUSIONS: One cycle of neoadjuvant chemotherapy was effective in selecting patients for organ preservation. The regimen of definitive concurrent and adjuvant chemotherapy was associated with an unexpectedly high 2-year survival rate. Lymphocyte subsets were not significant predictors of responding patients or survival. Further study of other biological markers useful in selecting patients for organ preservation are needed.

    Title Selective Neck Dissection for the Treatment of Neck Metastasis from Squamous Cell Carcinoma of the Head and Neck.
    Date September 2002
    Journal The Laryngoscope
    Excerpt

    OBJECTIVE: Our objective was to determine the proportion of patients disease free in the neck, with the primary site controlled, who have been treated with a selective neck dissection (SND) for squamous cell carcinoma (SCCa) of the upper aerodigestive tract, and who had cervical metastasis less than 3 cm. STUDY DESIGN: A cohort of patients who fit the inclusion/exclusion criteria was identified retrospectively. Then all surviving patients were followed for a minimum of 2 years. METHODS: A group of 52 patients who had 58 selective neck dissections for cervical metastases from SCCa of the upper aerodigestive tract were identified. The mean age was 56 years (range, 20-85 y), there were 40 males and 12 females, and mean follow-up was 24.5 months (range, 1-64 mo). Twenty-six patients had clinically negative (cNo) neck examinations and 26 had clinically positive neck examinations. Postoperative radiation was given for extracapsular spread, greater than 2 positive nodes, T3, T4, or recurrent disease if the patient had not received radiation before surgery. These radiation criteria excluded 18 patients from postoperative radiation treatment. RESULTS: Kaplan-Meier survival analysis showed that the regional control rate with the primary site controlled was 0.94. Six patients developed recurrent neck disease. Three of these 6 patientswere surgically salvaged. Four recurrences were in the dissected field and 2 were out of the dissected field (level V). CONCLUSIONS: With similar indications for radiation therapy, the regional control rate in this cohort is comparable to control rates obtained with modified radical neck dissection.

    Title Leech Therapy for Patients with Surgically Unsalvageable Venous Obstruction After Revascularized Free Tissue Transfer.
    Date August 2002
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To assess the efficacy and associated complications of a leech therapy protocol used for patients with a head and neck free tissue transfer in whom flap viability is threatened because of surgically unsalvageable venous obstruction. DESIGN: Medical record review of a prospective protocol. SETTING: Tertiary care academic medical center. PATIENTS: Of the 450 free tissue transfers to the head and neck region performed by our microvascular program from January 1, 1995, to October 31, 2000, 8 patients (1.8%) developed venous obstruction not considered salvageable by conventional surgical or thrombolytic therapy. INTERVENTIONS: All 8 patients were placed on a protocol using leeches (Hirudo medicinalis), intensive care unit monitoring, antithrombotic pharmacotherapy, frequent hematologic evaluation, blood transfusions as needed, and antibiotic prophylaxis for Aeromonas hydrophila. MAIN OUTCOME MEASURES: Flap salvage rate, number of leeches used per patient, time needed for inosculation, duration of intensive care unit admission, transfusion requirement per patient, and complications during leech therapy. RESULTS: All 8 flaps survived with the application of this protocol. An average of 215 leeches were used per patient, and the average time needed for inosculation was 6.6 days. The average duration in the intensive care unit was 9.6 days. The morbidity of our protocol was substantial, with intensive care unit psychosis, prerenal azotemia, and large transfusion requirements being the most frequent complications. An average of 13 U of packed red blood cells per patient was necessary. CONCLUSIONS: Aggressive application of the presented leech therapy protocol can salvage free tissue transfers with venous obstruction that are otherwise unsalvageable. The associated morbidity can be marked. Thus, judicious application of this protocol for flap preservation is essential.

    Title Tumor Angiogenesis As a Predictive Marker for Organ Preservation in Patients with Advanced Laryngeal Carcinoma.
    Date August 2002
    Journal The Laryngoscope
    Excerpt

    BACKGROUND: The purpose of this study was to retrospectively investigate tumor angiogenesis as a predictive marker for response to neoadjuvant chemotherapy, organ preservation, and survival in patients with advanced laryngeal carcinoma. METHODS: A total of 332 patients with stage III (188 patients) or stage IV (144 patients) squamous cell carcinoma of the larynx were entered in the prospective trial conducted by the Department of Veteran Affairs Laryngeal Cancer Study Group. Of this patient population, 20 pretreatment biopsy specimens were available from the chemotherapy arm for immunohistochemical analysis of Factor VIII expression. Two blinded investigators determined microvessel density in each patient by manual inspection of 10 high-power (400 x) fields (HPF). RESULTS: The patients who had a partial response (>50% decrease in tumor volume) or complete response to chemotherapy had a mean value of 20.90 (+/- 8.09 standard deviation [SD]) blood vessels per HPF. Those who did not respond to chemotherapy and thus required a total laryngectomy had a mean value of 32.99 (+/- 10.10 SD) vessels per HPF. The difference of the means was statistically significant using a two-tailed t test (P < .0085). Kaplan-Meier survival curve analysis also revealed that patients with vessel counts above the mean tended to have poorer survival than those below the mean regardless of treatment selection. The most-vascular tumors, those greater than 1 SD above the mean, had a statistically significant difference in survival and laryngeal preservation (P = .0345). CONCLUSIONS: These results indicate that tumor angiogenesis, as measured by number of vessels per HPF, was associated with decreased responsiveness to chemotherapy and radiation for larynx preservation. The most-vascular tumors also were associated with poorer survival than those with lesser degrees of angiogenesis.

    Title Expression of Bcl-2 Family Proteins in Advanced Laryngeal Squamous Cell Carcinoma: Correlation with Response to Chemotherapy and Organ Preservation.
    Date August 2002
    Journal The Laryngoscope
    Excerpt

    OBJECTIVES/HYPOTHESIS: Induction chemotherapy and definitive radiation therapy in advanced laryngeal cancer has been shown to achieve survival rates that are similar to total laryngectomy and postoperative radiation therapy. In patients with advanced laryngeal cancer, quality of life can be significantly enhanced by treatment regimens that preserve the larynx. However, which patients will respond best to organ preservation protocols remains unknown. The Bcl-2 family proteins are involved in control of apoptosis and, potentially, tumor response to chemotherapy. STUDY DESIGN: Retrospective analysis of immunohistochemical tumor characteristics and clinical outcome. METHODS: To determine whether Bcl-2 family proteins were predictive of successful organ preservation, immunohistochemical analysis of tissue specimens from 47 patients with advanced laryngeal cancer from the U.S. Department of Veterans Affairs Cooperative Study Program (VA CSP-268) were evaluated for the expression of Bcl-2, Bcl-X(L), and Bax protein expression. Tumor response was classified as either complete or partial/nonresponse after induction chemotherapy. Protein expression was correlated with tumor response, organ preservation, and overall patient survival. RESULTS: The Bcl-2 protein was expressed at high levels in only 15% of specimens, but five of seven tumors with high Bcl-2 showed complete response (P = .10). The majority of tumors expressed high levels of Bcl-X(L) (74%). Reduced expression of Bcl-X(L) was associated with a complete response (P = .143) and with larynx preservation (P = .06). Most patients (81%) had increased levels of Bax expression. Reduced expression of Bax was associated with a complete response rate (P = .074), but there was no correlation between Bax expression and larynx preservation. CONCLUSIONS: The findings indicate that laryngeal cancer cells typically produce high levels of only one of the apoptosis protective proteins, Bcl-2 or Bcl-X(L). Prospective studies of larger numbers of patients are under way to determine whether Bcl-X(L) expression will be a useful marker predicting larynx preservation.

    Title Immunostaining for Cytokeratin 20 Improves Detection of Micrometastatic Merkel Cell Carcinoma in Sentinel Lymph Nodes.
    Date June 2002
    Journal Journal of the American Academy of Dermatology
    Excerpt

    BACKGROUND: Sentinel lymph node biopsy (SLNBx) can identify Merkel cell carcinoma (MCC) micrometastasis. OBJECTIVE: We attempted to examine the effectiveness of immunostaining and identify antibodies most appropriate for evaluation of SLNBxs for MCC. METHODS: Histopathologic material from 10 patients with MCC who had SLNBx was reviewed. RESULTS: Twenty-three SLNBxs from 10 patients appeared tumor-free in routine hematoxylin-eosin (H&E)-stained sections. However, tumor cells were detected in immunostained sections from 5 (22%) of 23 SLNBxs in 4 (40%) of 10 patients. Immunostains with pancytokeratin (panCK), cytokeratin-20 (CK-20), neurofilament protein, and chromogranin A were used for all primary and SLNBx specimens. All 5 (100%) micrometastatic foci stained strongly for CK-20 and panCK. Background normal lymph node tissue also stained for panCK but not for CK-20. CONCLUSION: Examination of H&E sections alone is insufficient for excluding micrometastatic MCC in sentinel lymph nodes. We observed the greatest sensitivity and specificity with anti-CK-20 antibody in identifying micrometastatic MCC in sentinel lymph nodes.

    Title Objective Assessment of Swallowing Dysfunction and Aspiration After Radiation Concurrent with Chemotherapy for Head-and-neck Cancer.
    Date May 2002
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: To objectively assess swallowing function after an intensive chemoradiation regimen for locally advanced head-and-neck cancer and to assess the clinical implications of swallowing dysfunction. PATIENTS AND METHODS: Twenty-nine patients with nonresectable Stage IV head-and-neck cancer participated in a Phase I study of radiation, 70 Gy/7 weeks, concurrent with weekly gemcitabine. Because of a high rate of mucosal toxicity, reduced drug doses were delivered to subsequent patient groups: 300, 150, 50, and 10 mg/m(2)/week. Twenty-six of these patients underwent prospective evaluation of swallowing function with videofluoroscopy and esophagogram. Studies were performed pretherapy, early post-therapy (1-3 months), and late post-therapy (6-12 months). RESULTS: Complete tests were performed pretherapy in 22 patients, early post-therapy in 20, and late post-therapy in 13. Twenty-five patients had at least one post-therapy study. Post-therapy dysfunction was characterized by reduced inversion of the epiglottis, delayed swallow initiation and uncoordinated timing of the propulsion of the bolus, opening of the cricopharyngeal muscle, and closure of the larynx, all of which promoted aspiration during and after the swallow. In addition, reduced base-of-tongue retraction with reduced contact to the posterior pharyngeal wall and incomplete cricopharyngeal relaxation resulted in pooling in the pyriform sinuses and vallecula of residue, which was frequently aspirated after the swallow. Post-therapy aspirations were typically "silent," eliciting no cough reflex, or the cough was delayed and noneffective in expelling the residue. Aspiration was observed in 3 patients (14%) in the pretherapy studies, in 13 (65%) in the early post-therapy studies, and in 8 (62%) in the late post-therapy studies (aspiration rates post-therapy vs. pretherapy: p = 0.0002). Six patients had pneumonia requiring hospitalization 1-14 months after therapy (median: 2.5 months), being the likely cause of death in 2 patients. Five cases of pneumonia occurred among 17 patients who had demonstrated aspiration in the post-therapy studies, compared with no cases of pneumonia among 8 patients who had not demonstrated aspiration (p = 0.1). Of the 4 patients who had not undergone any post-therapy study, 1 developed pneumonia. Mucositis scores, prolonged tube feeding, presence of tracheostomy tube, and gemcitabine doses were not found to be related to aspiration or pneumonia risk. CONCLUSIONS: After intensive chemoradiotherapy, significant objective swallowing dysfunction is prevalent. It promotes aspiration, which may not elicit a cough reflex and may be associated with pneumonia. Aspiration pneumonia may be an underdocumented complication of chemoradiotherapy for head-and-neck cancer. Future studies should examine whether routine post-therapy videofluoroscopy and training aspirating patients in safe swallowing strategies can reduce this risk.

    Title Development and Validation of the Neck Dissection Impairment Index: a Quality of Life Measure.
    Date January 2002
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVES: To validate a health-related quality-of-life (QOL) instrument for patients following neck dissection and to identify the factors that affect QOL following neck dissection. DESIGN: Cross-sectional validation study. SETTING: The outpatient clinic of a tertiary care cancer center. PATIENTS: Convenience sample of 54 patients previously treated for head and neck cancer who underwent a selective neck dissection or modified radical neck dissection (64 total neck dissections). Patients had a minimum postoperative convalescence of 11 months. Thirty-two underwent accessory nerve-sparing modified radical neck dissection, and 32 underwent selective neck dissection. MAIN OUTCOME MEASURE: A 10-item, self-report instrument, the Neck Dissection Impairment Index (NDII), was developed and validated. Reliability was evaluated with test-retest correlation and internal consistency using the Cronbach alpha coefficient. Convergent validity was assessed using the 36-Item Short-Form Health Survey (SF-36) and the Constant Shoulder Scale, a shoulder function test. Multiple variable regression was used to determine variables that most affected QOL following neck dissection RESULTS: The 10-item NDII test-retest correlation was 0.91 (P<.001) with an internal consistency Cronbach alpha coefficient of.95. The NDII correlated with the Constant Shoulder Scale (r = 0.85, P<.001) and with the SF-36 physical functioning (r = 0.50, P<.001) and role-physical functioning (r = 0.60, P<.001) domains. Using multiple variable regression, the variables that contributed most to QOL score were patient's age and weight, radiation treatment, and neck dissection type. CONCLUSIONS: The NDII is a valid, reliable instrument for assessing neck dissection impairment. Patient's age, weight, radiation treatment, and neck dissection type were important factors that affect QOL following neck dissection.

    Title Pseudoaneurysm of the Proximal Facial Artery Presenting As Oropharyngeal Hemorrhage.
    Date October 2001
    Journal Head & Neck
    Excerpt

    BACKGROUND: Penetrating trauma to the neck traversing zones II and III may cause considerable damage to soft tissues and neurovascular structures. Delayed sequelae of vascular injuries, such as pseudoaneurysm (PA), may present weeks to months after the initial injury. METHODS: We report an unusual case of a traumatic PA of the proximal facial artery that ruptured into the oropharynx. RESULTS: A 30-year-old man presented with oropharyngeal hemorrhage one month after a gunshot wound to the neck. Angiography revealed a PA of the proximal facial artery, which was treated with embolization. The arterial injury leading to the pseudoaneurysm had not been detected by arteriography at the time. CONCLUSIONS: PAs are rare complications of penetrating neck trauma. To our knowledge, this is only the second report of PA involving the proximal facial artery, and the first of a facial PA rupture into the pharynx.

    Title Free Tissue Reconstruction of the Hypopharynx After Organ Preservation Therapy: Analysis of Wound Complications.
    Date October 2001
    Journal The Laryngoscope
    Excerpt

    PURPOSE: Previous series have demonstrated a 77% rate of major wound complications in salvage surgery of the larynx following organ preservation protocols. The purpose of this study is to determine the incidence of wound complications in these patients when microvascular free tissue transfers are used for reconstruction of the hypopharynx. DESIGN: Retrospective case series. SETTING: Academic tertiary care center. PATIENTS AND METHOD: We reviewed the medical records of 42 patients with stage III and IV laryngeal squamous cell carcinoma treated with an organ-sparing protocol consisting of induction chemotherapy followed by definitive radiation therapy. Ten of these patients who required surgical salvage were reconstructed using radial forearm free tissue or lateral arm transfer and constitute the study group. MAIN OUTCOME MEASURES: Wound complications. RESULTS: Wound complications occurred in 2 patients (20%) undergoing free flap reconstruction of the hypopharynx after organ preservation protocols, which was significantly lower (P =.003) than previous reports using other forms of closure and/or reconstruction. One patient in this study group had a small pharyngocutaneous fistula that resolved with conservative therapy after 1 week. The other patient had a larger pharyngocutaneous fistula that resolved over 3 weeks. The mean interval from completion of the chemoradiation regimen to surgery was 21.3 months (range, 2-60 mo). The average free tissue flap size was 94.3 cm(2) (range, 45-165 cm(2)). Average harvest and ischemia times were 59 minutes (range, 41-87 min) and 187.7 minutes (range, 120-240 min), respectively. All flaps survived, and one patient had a minor donor site wound dehiscence. The average hospital stay was 7.8 days. There were no mortalities in this series. CONCLUSIONS: Our results suggest that free tissue transfer reconstruction of the hypopharynx is the preferred method of reconstruction following combined chemotherapy and radiation therapy protocols. Surgical complications are significantly reduced and hospital stays are minimized.

    Title Sentinel Node Localization in Oral Cavity and Oropharynx Squamous Cell Cancer.
    Date September 2001
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To evaluate the feasibility and predictive ability of the sentinel node localization technique for patients with squamous cell carcinoma of the oral cavity or oropharynx and clinically negative necks. DESIGN: Prospective, efficacy study comparing the histopathologic status of the sentinel node with that of the remaining neck dissection specimen. SETTING: Tertiary referral center. PATIENTS: Patients with T1 or T2 disease and clinically negative necks were eligible for the study. Nine previously untreated patients with oral cavity or oropharyngeal squamous cell carcinoma were enrolled in the study. INTERVENTIONS: Unfiltered technetium Tc 99m sulfur colloid injections of the primary tumor and lymphoscintigraphy were performed on the day before surgery. Intraoperatively, the sentinel node(s) was localized with a gamma probe and removed after tumor resection and before neck dissection. MAIN OUTCOME MEASURES: The primary outcome was the negative predictive value of the histopathologic status of the sentinel node for predicting cervical metastases. RESULTS: Sentinel nodes were identified in 9 previously untreated patients. In 5 patients, there were no positive nodes. In 4 patients, the sentinel nodes were the only histopathologically positive nodes. In previously untreated patients, the sentinel node technique had a negative predictive value of 100% for cervical metastasis. CONCLUSIONS: Our preliminary investigation shows that sentinel node localization is technically feasible in head and neck surgery and is predictive of cervical metastasis. The sentinel node technique has the potential to decrease the number of neck dissections performed in clinically negative necks, thus reducing the associated morbidity for patients in this group.

    Title Sympathetic Paraganglioma As an Unusual Cause of Horner's Syndrome.
    Date August 2001
    Journal Head & Neck
    Excerpt

    BACKGROUND: Paragangliomas are rare tumors arising from paraganglionic tissue of neural crest origin. They are present in any location where autonomic ganglia are found. The most common location in the head and neck is the carotid body, followed by the jugular bulb and vagus nerve. METHODS: A 30-year-old woman with a slowly growing left neck mass, aniscoria, and left eyelid ptosis was found to have a vascular tumor consistent with a paraganglioma arising near the left carotid bifurcation. After preoperative embolization, the patient underwent resection of the tumor. RESULTS: The tumor was found to be arising from the left sympathetic trunk and did not involve any other surrounding structures. Histopathologic analysis revealed the typical findings of a paraganglioma. CONCLUSIONS: Sympathetic paragangliomas are exceedingly rare tumors in the head and neck and should be considered in the differential diagnosis when clinical and radiographic evidence suggest a paraganglioma. The presentation is typically a slow-growing neck mass with the presence of an ipsilateral Horner's syndrome.

    Title Conformal Re-irradiation of Recurrent and New Primary Head-and-neck Cancer.
    Date June 2001
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: To review the outcome of head-and-neck cancer patients re-irradiated using conformal radiation. PATIENTS AND METHODS: From 1983 to 1999, 60 patients with recurrent or new primary head-and-neck cancer received re-irradiation at the University of Michigan. Twenty patients were excluded due to the planned cumulative radiation dose being less than 100 Gy (18) and absence of prior radiation details (2), leaving 40 patients. Thirty-five patients were re-irradiated for unresectable disease, while 4 patients received adjuvant re-irradiation for high-risk disease. Thirty-eight patients had recurrences from previously treated cancer (19 regional, 14 local, 5 regional and local), and 2 patients had new primary tumors. The median time from the first course of radiation to re-irradiation was 21 months. Thirty-one patients (78%) were re-irradiated with curative intent, whereas 9 were treated with palliative intent. Re-irradiation was delivered using conformal techniques in the majority of patients and with concurrent chemotherapy in 14 patients. The median re-irradiation dose was 60 Gy. The median cumulative dose received was 121 Gy. Five patients (13%) did not complete their prescribed course of re-irradiation. RESULTS: The median survival following completion of re-irradiation was 12.5 months. The 1- and 2-year actuarial survival rates were 51.1% and 32.6%, respectively. On multivariate analysis, palliative intent of treatment, tumor bulk, and tumor site other than nasopharynx or larynx were associated with worse survival. The patients treated for unresectable disease did no worse than those treated adjuvantly. The median times to relapse-free survival, local-regional recurrence (LRR)-free survival, and ultimate LRR-free survival (allowing for surgical salvage) were 3.9 months, 7.8 months, and 8.7 months, respectively. Seven patients (18%) are presently alive with no evidence of disease, with a median follow-up of 49.9 months (range 3.3-78.9). Severe radiation-induced complications were seen in 7 patients (18%). Two other patients developed orocutaneous fistulas in the presence of tumor recurrence. Moderate fibrosis and trismus were common. CONCLUSION: Despite the use of conformal techniques, the prognosis of patients treated with re-irradiation is poor, and complications are not infrequent. A subset of patients is salvageable, and high-dose re-irradiation should be considered in selected patients.

    Title Radiation Concurrent with Gemcitabine for Locally Advanced Head and Neck Cancer: a Phase I Trial and Intracellular Drug Incorporation Study.
    Date March 2001
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level. PATIENTS AND METHODS: Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured. RESULTS: Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2). CONCLUSION: A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.

    Title Voice-related Quality of Life (v-rqol) Following Type I Thyroplasty for Unilateral Vocal Fold Paralysis.
    Date February 2001
    Journal Journal of Voice : Official Journal of the Voice Foundation
    Excerpt

    Unilateral vocal fold paralysis is a common clinical problem which frequently causes severe dysphonia. Various treatment options exist for this condition, with the type I thyroplasty being one of the more commonly performed surgical procedures for vocal rehabilitation. The Voice-Related Quality of Life (V-RQOL) Measure is a validated outcomes instrument for voice disorders. This study measured the V-RQOL of patients with unilateral vocal fold paralysis who had undergone a type I thyroplasty and compared these scores to those of patients with untreated and uncompensated unilateral vocal fold paralysis and to normals. Treated patients had significantly higher domain and overall V-RQOL scores than untreated patients, but also scored lower than normals. These differences were true across gender and age. Patients who were more distant from surgery had lower V-RQOL scores than those who had more recently been treated. It is concluded that type I thyroplasty leads to a significantly higher V-RQOL for patients with unilateral vocal fold paralysis. This study also demonstrates further the utility of patient-oriented measures of treatment outcome.

    Title Neoadjuvant Therapy for Organ Preservation in Head and Neck Cancer.
    Date January 2001
    Journal The Laryngoscope
    Excerpt

    OBJECTIVES/HYPOTHESIS: We designed two sequential trials of induction chemotherapy followed by definitive radiation in patients with potentially resectable head and neck cancer to determine whether organ preservation is feasible without apparent compromise of survival Study Design Both trials were Phase II studies. METHODS: Two clinical trials were conducted sequentially at the University of Michigan. Fifty-two patients enrolled in the first study and were treated with a planned three cycles of carboplatin and 5-fluorouracil. Patients who achieved at least 50% reduction in the size of the primary tumor received definitive radiation therapy, to a dose of 6600 to 7380 cGy. Patients with minimal response or progression had immediate salvage surgery. Thirty-seven patients enrolled in the second trial, in which the chemotherapy consisted of carboplatin, 5-fluororuracil, and leukovorin. Responders were treated with accelerated radiation therapy, to a total dose of 7120 cGy delivered in 41 fractions over 5.5 weeks. RESULTS: Toxicity and response were similar in both trials; therefore, the results are reported first separately and then combined for all 89 patients. Tumor sites included: oropharynx, 55 patients; hypopharynx, 34 patients. Eighty-three percent of patients tolerated all three cycles of chemotherapy and toxicity was mild. Response to chemotherapy was: 48% complete response at the primary tumor site, and 34% partial response at the primary tumor site. Initial organ preservation at individual tumor sites was: oropharynx, 58%; hypopharynx, 59%. Median survival was 28 months, and survival at 3 and 5 years was 40% and 24%, respectively. CONCLUSIONS: These two regimens were well tolerated, and survival did not appear to be compromised by organ preservation treatment compared with historical controls. This approach warrants further investigation, particularly in those patients for whom surgery could be functionally debilitating.

    Title Human Papillomavirus Infection in "young" Versus "old" Patients with Squamous Cell Carcinoma of the Head and Neck.
    Date November 2000
    Journal Head & Neck
    Excerpt

    BACKGROUND: Human papillomavirus (HPV) represents a potential risk factor for squamous cell cancer of the head and neck (SCCHN). We evaluated the prevalence of HPV DNA in patients with SCCHN diagnosed at the University of Michigan from 1994-1996. METHODS: Patients were stratified by age at diagnosis as "young" (<50 years; median, 39) or "old" (>50 years; median, 66). Fourteen "young" and 14 "old" were matched for tumor site, and 4 additional "old" patients were included. Specimens were analyzed by polymerase chain reaction for HPV DNA using 2 sets of consensus primers. HPV sequences were confirmed by Southern blot hybridization and typed with type-specific probes. RESULTS: Overall, 15 of 32 (46.9%) samples contained HPV sequences. HPV 16 was detected in 9 of 15 (60%), HPV-18 in 1 of 15 (6.6%), and 5 of 15 (33.3%) remained untyped by multiple methods. When stratified, 7 of 14 (50%) "young" were HPV-positive compared with 8 of 18 (44.4%) "old" (p =.76). Survival in patients with HPV-positive SCCHN was significantly longer than that for HPV-negative patients. CONCLUSIONS: The incidence of HPV in "young" versus "old" is not significantly different, suggesting similar roles for both groups. Patients with HPV-positive tumors may have a survival advantage relative to patients with HPV-negative tumors.

    Title Fibromatosis of the Head and Neck: a Challenging Lesion.
    Date October 2000
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    Fibromatosis is a histologically benign fibrous neoplasm that arises from the musculoaponeurotic tissues of the body. It can have significant morbidity when it occurs in the head and neck region because of the proximity of vital structures. This review article considers the etiology, demographics, pathology, natural history, and various treatment modalities for this lesion. Therapeutic guidelines are provided.

    Title Pain, Quality of Life, and Spinal Accessory Nerve Status After Neck Dissection.
    Date April 2000
    Journal The Laryngoscope
    Excerpt

    OBJECTIVE: To assess quality of life (QOL) in patients with head and neck cancer who underwent neck dissection and to compare QOL scores for patients in whom the spinal accessory nerve (CN XI) was resected or preserved. SETTING AND DESIGN AND OUTCOMES MEASURES: Three hundred ninety-seven patients who had undergone treatment for head and neck cancer completed the University of Michigan Head and Neck Quality of Life (HNQOL) instrument, the Medical Outcomes Study SF-12 General Health Survey, and questions on "pain despite pain medications" and headaches. RESULTS: Of the 397 patients, 222 had no neck dissection, 46 had neck dissections resecting CN XI, and 129 had dissection sparing CN XI. Of the latter group, 68 patients had dissections sparing level V and 61 dissections included level V. Age, sex, primary site distribution, and T stage were not different between the groups. Patients who had neck dissections sparing CN XI had better scores on the HNQOL pain domain (P = .002), had less shoulder or neck pain (P = .003), and took pain medications less frequently (P = .0004) compared with patients who had neck dissections sacrificing CN XI. When CN XI was preserved, patients who had no level V dissection had better pain domain scores (P = .03) and eating domain scores (P = .007) on the HNQOL, had less shoulder or neck pain (P = .006), and had less physical problems (P = .03) than patients who had level V dissected. On multivariate analysis, pain-related QOL scores after neck dissection were significantly better (P < .01) if patients had dissections with preservation of CN XI and if level V was not dissected. CONCLUSION: Neck dissections sparing CN XI are associated with better pain scores on the HNQOL, less shoulder and neck pain, and less need for medications. When CN XI is spared, not dissecting level V of the neck is associated with better HNQOL pain scores, less shoulder or neck pain, and fewer physical problems.

    Title Conformal and Intensity Modulated Irradiation of Head and Neck Cancer: the Potential for Improved Target Irradiation, Salivary Gland Function, and Quality of Life.
    Date February 2000
    Journal Acta Oto-rhino-laryngologica Belgica
    Excerpt

    PURPOSE: To develop techniques which facilitate sparing of the major salivary glands while adequately treating the targets in patients requiring comprehensive bilateral neck irradiation (RT). PATIENTS AND METHODS: Conformal and static, multisegmental intensity modulated (IMRT) techniques have been developed. The salivary flow rates before and periodically after RT have been measured selectively from each major salivary gland and the residual flows correlated with glands' dose volume histograms. Subjective xerostomia questionnaires have been developed and validated. The pattern of local-regional recurrences has been examined using CT scans at the time of recurrence, transferring the recurrence volumes to the planning CT scans and regenerating the dose distributions at the recurrence sites. RESULTS: Target coverage and dose homogeneity in IMRT treatment plans were found to be significantly better than standard RT plans. Significant parotid gland sparing was achieved. The relationships among dose, irradiated volume and saliva flow rates from the parotid glands were characterized by dose and volume thresholds. A mean dose of 26 Gy was found to be the threshold for stimulated saliva. Subjective xerostomia was significantly reduced in patients irradiated with parotid sparing techniques, compared to patients with similar tumors treated with standard RT. The large majority of recurrences occurred inside high-risk targets. CONCLUSIONS: Tangible gains in salivary gland sparing and target coverage are being achieved and an improvement in some measures of quality of life is suggested by our findings. A mean parotid gland dose of < or = 26 Gy should be a planning objective if significant parotid function preservation is desired. The pattern of recurrence suggests that careful escalation of the dose to targets judged to be at highest risk may improve tumor control.

    Title Predictive Markers for Response to Chemotherapy, Organ Preservation, and Survival in Patients with Advanced Laryngeal Carcinoma.
    Date November 1999
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    OBJECTIVE: A systematic retrospective study of the largest randomized trial of induction chemotherapy and radiation for advanced laryngeal cancer was undertaken to determine whether specific tumor or biologic factors were predictive of chemotherapy response, organ preservation, or survival. METHODS: The variables analyzed included clinical and histologic factors, immunohistochemical expression of proliferating cell nuclear antigen and p53, and adjusted DNA index measurements. Variables were evaluated for correlation with outcomes of tumor response, organ preservation, and survival. RESULTS: Multivariate analysis revealed that the best predictor of complete response to induction chemotherapy was low T class. The full multivariate model for predicting larynx preservation in patients treated with induction chemotherapy plus radiation shows that T class, p53 overexpression, and elevated proliferating cell nuclear antigen index were independent predictors of successful organ preservation. CONCLUSIONS: These predictive markers should be included in future clinical trials of advanced laryngeal cancer to determine their usefulness prospectively.

    Title Management of Tonsil Cancer.
    Date November 1999
    Journal Head & Neck
    Title Predictive Factors in Head and Neck Cancer.
    Date October 1999
    Journal Hematology/oncology Clinics of North America
    Excerpt

    As new knowledge of the molecular mechanisms of tumor development and progression is gained, studies are required to determine whether specific molecular genetic changes might be useful indicators in selecting patients for specific therapies. Alternatively, molecular or genetic changes may identify the patients at greatest risk for progression and relapse so that they can be treated with adjuvant therapy. p53 has an important function in the regulation of the cell cycle, DNA repair, and programmed cell death pathways. The Bcl-2 protein family has gained recent attention for its role in permitting or blocking apoptosis. Interaction between p53, Bcl-2, and other products of tumor suppressor genes or oncogenes are probably critical in tumor progression and response to treatment.

    Title Health Impact of Head and Neck Cancer.
    Date June 1999
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    A multidimensional Head and Neck Quality of Life (HNQOL) instrument and a general health status measure were administered to 397 patients with head and neck cancer. Scores for the 4 domains of the HNQOL (communication, eating, pain, and emotional well-being) were calculated. Patient demographics, comorbidities, clinical characteristics, treatment data, disability status, and a global "overall bother" score were assessed. When compared with the US population aged 55 to 64 years, the group had significantly worse scores in the 8 health domains of the SF-36. Patients' overall bother scores from the head and neck cancer treatment correlated best with the HNQOL emotion domain (r = 0.71) and the HNQOL pain domain (r = 0.63), and least with the patients' perception of their response to treatment (r = 0.39). Pain, eating, emotion, physical component summary score, age, and an interaction term between eating and emotion were significant predictors for overall bother. Of the 217 patients who were working before the diagnosis of cancer, 74 (34. 1%) reported that they had become disabled. Patients who had more than 1 type of treatment were 5.9 times more likely to report themselves as disabled (odds ratio [OR] = 5.94, P < 0.01), even after adjusting for age, emotion score, and physical component summary score, which were other factors that predicted disability.

    Title Expression of Major Histocompatibility Complex Antigens in Squamous Cell Carcinomas of the Head and Neck: Effects of Interferon Gene Transfer.
    Date May 1999
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    The effect of retroviral-mediated interferon-gamma (IFN-gamma) gene transfer on major histocompatibility complex (MHC) class I and II antigen expression was investigated in 13 head and neck squamous carcinoma cell lines. Six cell lines exhibited increased MHC class I expression, and 10 exhibited increased MHC class II expression after IFN-gamma gene transfer. Differences in MHC antigen expression between parental and transduced cell lines were significant (P = 0. 002) only for cell lines that upregulated MHC class II expression. After incubation in medium containing 100 U/mL recombinant IFN-gamma, or in medium from IFN-gamma retrovirus-transduced NIH 3T3 cells, 12 cell lines significantly upregulated MHC class I expression, and 9 significantly upregulated MHC class II expression. Only cell lines that exhibited increased MHC class II expression after retroviral transduction also upregulated class II expression with exogenous IFN-gamma treatment. Thus some head and neck squamous carcinoma cell lines can upregulate MHC class I and II expression after exogenous application of either IFN-gamma or IFN-gamma retroviral transduction. These are promising findings for head and neck cancer immunotherapy and gene therapy.

    Title High-risk Human Papillomavirus Types and Squamous Cell Carcinoma in Patients with Respiratory Papillomas.
    Date May 1999
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    Respiratory papillomas (RPs) are benign, virally induced tumors of the larynx and respiratory epithelium that may obstruct the airway and tend to recur frequently. RPs are thought to be the result of infection with the human papillomaviruses (HPVs) types 6 and 11. We surveyed archival RP specimens to determine whether there were correlations of HPV type with patient characteristics or clinical course. Paraffin-embedded papilloma specimens of 45 different patients were analyzed. We assessed HPV types using the polymerase chain reaction with E6 consensus primers, hybrid capture assays (high or low risk), and dot blot hybridization of generic E6 PCR products with E6 type-specific oligonucleotide probes. The presence and type of HPV were correlated with patient data from a retrospective chart review. We found that RPs may have either low- or high-risk HPV types and some contain multiple HPV types. Respiratory infection with high-risk HPV apparently introduces a long-term risk of squamous cell carcinoma development, even in the absence of conventional cofactors. Low-risk HPV infection may also act in association with these cofactors to promote carcinogenesis. Our data also show a racial imbalance in RP that may indicate a difference in genetic resistance and/or susceptibility to HPV infection and the development of RP.

    Title Expanded Tumor-reactive Cd4+ T-cell Responses to Human Cancers Induced by Secondary Anti-cd3/anti-cd28 Activation.
    Date April 1999
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    Generation of tumor-reactive T cells in large numbers ex vivo is a requisite step in the adoptive immunotherapy of patients. We examined the immune responses of T cells derived from tumor vaccine-primed lymph nodes activated with anti-CD3 alone and with an anti-CD3/anti-CD28 combination. Nylon wool-purified CD3+ cells were isolated from vaccine-primed lymph nodes obtained from melanoma, renal cell, and head and neck cancer patients. In the absence of antigen-presenting cells, activation with anti-CD3/anti-CD28 greatly enhanced subsequent T-cell expansion in interleukin 2 (>100-fold), compared to anti-CD3 alone. CD4+ T cells were preferentially stimulated. In four of eight patients, we found evidence of CD4+ cellular responses to autologous tumors by cytokine release assays. Positively selected CD4+ cells activated with anti-CD3/anti-CD28 released greater amounts of cytokine (IFN-gamma and granulocyte macrophage colony-stimulating factor) in response to autologous tumors compared to cells activated by anti-CD3 alone. The CD4+ reactivity was MHC class II restricted and appeared to be associated with the expression of class II molecules on the vaccinating tumor cells. The CD4+ T-cell responses to class II-restricted tumor-associated antigens in patients with renal cell cancers represent unique findings.

    Title Spindle Epithelial Tumor with Thymus-like Differentiation: a Case Report and Review of the Literature.
    Date April 1999
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Title Squamous Cell Carcinoma of the Buccal Mucosa.
    Date March 1999
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    The purpose of this study was to establish treatment criteria for patients with early-stage squamous cell carcinoma of the buccal mucosa. Thirty-one patients were analyzed in a retrospective fashion. Distribution of patients according to tumor stage was relatively even. Within 5 years recurrent disease developed in nearly 80% of evaluable patients. There was a 100% overall incidence of local disease recurrence for patients with stage I and II tumors treated with wide local excision alone and followed up for more than 2 years. On the basis of these data, we conclude that wide local excision for early-stage buccal carcinoma is associated with a high local failure rate. Possible causes for failure and alternative treatment approaches are discussed.

    Title The Hpv 6 E6/e7 Transforming Genes Are Expressed in Inverted Papilloma.
    Date April 1998
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    A role for human papilloma virus (HPV) infection in the pathogenesis of head and neck neoplasms has gained support in recent years. Expression of two early-region HPV genes, E6 and E7, is widely accepted as essential for viral-induced carcinomas of the genital tract. These oncoproteins interact with the products of the cellular tumor suppressor genes, p53 and retinoblastoma, and inactivate them. Examining E6/E7 transforming gene expression is an important step toward elucidating the pathogenesis of HPV in head and neck neoplasms. We introduce nasal inverted papilloma (IP) as a novel system for evaluating viral genomic expression and transforming gene regulation of tumorigenesis by virtue of its association to HPV infection and potential for malignant progression. We describe here a reverse transcriptase-polymerase chain reaction approach for the detection of HPV E6/E7-specific transcripts in RNA extracted from IR. A primer pair flanking previously mapped HPV 6 E6/E7 splice donor/acceptor sites was used to direct amplification of cDNA. Reverse transcriptase-polymerase chain reaction experiments generated products representing the 1.2 Kb E1E4 splice transcript and a smaller unclassified fragment in IP from two patients. These results provide evidence for HPV 6 E6/E7 expression in IP with the potential to encode transforming proteins.

    Title Expression of Human Papillomavirus 6 in Inverted Papilloma Arising in a Renal Transplant Recipient.
    Date January 1998
    Journal The Laryngoscope
    Excerpt

    A 36-year-old renal transplant recipient taking cyclosporin A presented with bilateral nasal polypoid lesions involving the nasal septum and lateral nasal walls. Pathologic findings from surgical excision demonstrated inverted papilloma (IP) with focal atypia and mild dysplasia. DNA extracted from the tissue was tested with the polymerase chain reaction (PCR) using human papillomavirus (HPV) E6 and L1 consensus primers. This revealed amplification of the expected size fragment consistent with the presence of HPV DNA. Hybridization of PCR products with HPV type-specific oligonucleotide probes revealed a strong signal with only HPV 6. This result was confirmed by PCR amplification with HPV 6 type-specific primers. RNA extracted from the tissue was subjected to reverse transcription PCR (RT-PCR) with a primer pair specific for viral E6/E7 transcripts. The HPV early proteins, E6 and E7, are the transforming proteins implicated as critical for tumorigenesis. RT-PCR experiments generated products representing the E1/E4 spliced transcript originating from the E6/E6 promoter and a smaller unclassified fragment. These results provide evidence for HPV 6 E6/E7 expression in IP, lending credence to the concept that HPV may play a role in the origin of this neoplasm. Histologically normal nasal tissue from the same patient contained HPV DNA and similar transcripts to those described in the IP specimen.

    Title Clinical Outcome of Continuous Facial Nerve Monitoring During Primary Parotidectomy.
    Date November 1997
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVES: To assess whether continuous facial nerve monitoring during parotidectomy is associated with a lower incidence of facial nerve paresis or paralysis compared with parotidectomy without monitoring and to assess the cost of such monitoring. DESIGN: A retrospective analysis of outcomes for patients who underwent parotidectomy with or without continuous facial nerve monitoring. SETTING: University medical center. PATIENTS: Fifty-six patients undergoing parotidectomy in whom continuous electromyographic monitoring was used and 61 patients in whom it was not used. MAIN OUTCOME MEASURES: (1) The incidence of early and persistent facial nerve paresis or paralysis and (2) the cost associated with facial nerve monitoring. RESULTS: Early, unintentional facial weakness was significantly lower in the group monitored by electromyograpy (43.6%) than in the unmonitored group (62.3%) (P=.04). In the subgroup of patients without comorbid conditions or surgeries, early weakness in the monitored group (33.3%) remained statistically lower than the rate of early weakness in the unmonitored group (57.5%) (P=.03). There was no statistical difference in the final facial nerve function or incidence of permanent nerve injury between the groups or subgroups. After multivariate analysis, nonmonitored status (odds ratio [OR], 3.22), advancing age (OR, 1.47 per 10 years), and longer operative times (OR, 1.3 per hour) were the only significant independent predictive variables significantly associated with early postoperative facial weakness. The incremental cost of facial nerve monitoring was $379. CONCLUSIONS: The results suggest that continuous electromyographic monitoring of facial muscle during primary parotidectomy reduces the incidence of short-term postoperative facial paresis. Advantages and disadvantages of this technique need to be considered together with the additional costs in deciding whether routine use of continuous monitoring is a useful, cost-effective adjunct to parotid surgery.

    Title Head and Neck Cancer-specific Quality of Life: Instrument Validation.
    Date November 1997
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    BACKGROUND: The disfigurement and dysfunction associated with head and neck cancer affect emotional well-being and some of the most basic functions of life. Most cancer-specific quality-of-life assessments give a single composite score for head and neck cancer-related quality of life. OBJECTIVE: To develop and evaluate an improved multidimensional instrument to assess head and neck cancer-related functional status and well-being. METHODS: The item selection process included literature review, interviews with health care workers, and patient surveys. A survey with 37 disease-specific questions and the SF-12 survey were administered to 253 patients in 3 large medical centers. Factor analysis was performed to identify disease-specific domains. Domain scores were calculated as the standardized score of the component items. These domains were assessed for construct validity based on clinical hypotheses and test-retest reliability. RESULTS: Four relevant domains were identified: Eating (6 items), Communication (4 items), Pain (4 items), and Emotion (6 items). Each had an internal consistency (Cronbach alpha value) of greater than 0.80. Construct validity was demonstrated by moderate correlations with the SF-12 Physical and Mental component scores (r=0.43-0.60). Test-retest reliability for each domain demonstrated strong reliability between the 2 time points. Correlations were strong for each individual question, ranging from 0.53 to 0.93. Construct validity testing demonstrated that the direction of differences for each domain were as hypothesized. CONCLUSION: The Head and Neck Quality of Life questionnaire is a promising multidimensional tool with which to assess head and neck cancer-specific quality of life.

    Title Retropharyngeal Abscess: Pitfalls of Plain Films and Computed Tomography.
    Date September 1997
    Journal American Journal of Otolaryngology
    Title Flap Monitoring.
    Date August 1997
    Journal Facial Plastic Surgery : Fps
    Title P53 Mutation As a Prognostic Marker in Advanced Laryngeal Carcinoma. Department of Veterans Affairs Laryngeal Cancer Cooperative Study Group.
    Date July 1997
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To determine the relationship of p53 mutations in advanced laryngeal carcinomas to p53 immunohistochemistry, organ preservation, and patient survival. DESIGN: Paraffin-embedded tumor specimens were obtained from patients enrolled in the Department of Veterans Affairs Laryngeal Cancer Cooperative Study, a multi-institutional randomized clinical trial comparing induction chemotherapy (cisplatin and fluorouracil) plus radiation therapy surgery plus postoperative radiation therapy. Tumor specimens were analyzed for p53 mutations in exons 5 through 8 by using single-strand conformational polymorphism (SSCP) analysis followed by DNA sequencing of all variants. Five-year follow-up data were available for all patients studied. SUBJECTS: Forty-four patients enrolled in the Department of Veterans Affairs Laryngeal Cancer Cooperative Study from whom paraffin-embedded tumor specimens were readily available. RESULTS: p53 immunostaining did not correlate with p53 SSCP and DNA sequencing results. More than half (62% [16/26]) of the tumors that overexpressed p53 immunohistochemically did not have a detectable p53 gene mutation. Similarly, 39% (7/18) of tumors that did not overexpress p53 did have a p53 gene mutation. p53 mutations were present in 39% of tumors tested. Mutations within exon 5 made up 41% of p53 gene mutations in laryngeal carcinomas. Transitions were the most common type of mutation in this study (92% of mutations). CONCLUSIONS: The presence of a p53 mutation as detected by SSCP is associated with decreased patient survival. Further study is required to confirm this relationship and to determine whether specific p53 mutations predict organ preservation.

    Title Frequent Loss of Heterozygosity on Chromosome Arm 18q in Squamous Cell Carcinomas. Identification of 2 Regions of Loss--18q11.1-q12.3 and 18q21.1-q23.
    Date July 1997
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVES: To determine the frequency and regions of loss on chromosome arm 18q in uncultured head and neck squamous cell carcinomas. DESIGN: Polymerase chain reaction amplification of DNA extracted from 18 tumor specimens (1 patient had 2 tumors) and blood samples from 17 patients with head and neck squamous cell carcinoma was performed using primers flanking 16 microsatellite repeat polymorphisms spanning most of chromosome 18q. DNA was extracted only from specimens with greater than 70% tumor nuclei. SETTING: Research university. PATIENTS: Seventeen individuals with newly diagnosed head and neck cancer. MAIN OUTCOME MEASURE: Loss of heterozygosity (LOH). RESULTS: There was LOH at more than 1 locus in 52% (9/ 17) of the tumors; 3 tumors had LOH at all informative markers. Four had loss at only 1 locus, raising the total with loss to 12 (75%) of 16. Loss of 18q11.1-q12.3 in 4 tumors without distal loss defines a proximal region of loss. Loss of heterozygosity affecting 18q21.1 in 1 tumor, without proximal loss and LOH for 18q21.1, 18q22, or 18q23 in 9 (52%) of 17 tumors defines a distal region of loss. CONCLUSIONS: Loss of heterozygosity on chromosome arm 18q is not an artifact of in vitro culture. The finding of 18q LOH in 50% to 70% tumors makes 18q an important region for study. Regions 18q11.1-q12.3 and 18q21.1-q23 are common regions of loss, indicating that there may be more than one 18q tumor suppressor gene involved in the genesis and progression of head and neck squamous cell carcinomas.

    Title Prognostic Importance of Surgical Margins in Advanced Laryngeal Squamous Carcinoma.
    Date December 1996
    Journal Head & Neck
    Excerpt

    BACKGROUND: The prognostic significance of the status of surgical margins remains unclear in patients with cancer of the larynx. METHODS: To further evaluate this issue, a cohort of 159 surgically treated patients with advanced (stage III, IV) squamous carcinoma of the larynx who were part of a prospective multi-institutional clinical trial (VA Laryngeal Cancer Study Group) were studied. RESULTS: All patients underwent total laryngectomy (n = 144) or supraglottic laryngectomy (n = 15) followed by radiotherapy. Surgical margins were assessed intraoperatively and reported on final pathology as either clear (n = 134), tumor within 5-10 mm of the surgical margin (n = 6), less than 5 mm from the surgical margin (n = 8), or involved (n = 11). Postoperative complications, especially fistula rates, were significantly associated with margin status (p = .04 and p = .004, respectively). No significant differences were detected in patterns of recurrence (p = .584) or time to recurrence (p = .712) according to margin status. Patients with close or involved margins received significantly higher doses of radiation (p = .0017), as prescribed in the protocol. Patient survival percentages were 50% for clear margins, 57% for close margins, and 27% for involved margins (p = .286). When grouped by margins > 5 mm or < 5 mm, patients with wider margins tended to have prolonged disease-free survival (p = .1413) and overall survival (p = .1879). CONCLUSIONS: Despite the small number of patients with histologically proven close margins (16%) in this trial, the data suggest that high-dose postoperative radiation does not eliminate the benefit of obtaining widely clear surgical margins. Better methods of assessing and obtaining wide surgical margins may translate into added survival benefit and lower complication rates.

    Title Parotid Gland Sparing in Patients Undergoing Bilateral Head and Neck Irradiation: Techniques and Early Results.
    Date November 1996
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: To minimize xerostomia in patients receiving bilateral head and neck irradiation (RT) by using conformal RT planning to spare a significant volume of one parotid gland from radiation. METHODS AND MATERIALS: The study involved 15 patients with head and neck tumors in whom bilateral neck radiation was indicated. The major salivary glands and the targets (tumor, surgical bed, metastases to lymph nodes, and the locations of lymph nodes at risk for metastases) were outlined on axial computed tomography images. Beam's-eye view (BEV) displays were used to construct conformal beams that delivered the prescribed doses to the targets while sparing from direct radiation most of one parotid gland. The gland that was planned to be spared resided in the neck side that was judged in each patient to be at a lesser risk of metastatic disease. Major salivary gland flow rates and the responses to a subjective xerostomia questionnaire were assessed before, during, and after radiation. RESULTS: Radiation planning for patients with central oropharyngeal tumors required the generation of multiple axial nonopposed beams. The resulting isodoses encompassed the targets, including the retropharyngeal nodes and the jugular nodes up to the base of skull bilaterally, while limiting the dose to the oral cavity, spinal cord, and one parotid gland. For patients with lateralized tumors, the ipsilateral neck side was treated up to the base of the skull; in the contralateral neck side, the treatment included the subdigastric nodes but excluded the jugular nodes at the base of the skull and most of the parotid gland. This was accomplished by a moderate gantry angle that was chosen using the BEV displays. Three months following the completion of radiation, the spared parotid glands retained on average 50% of their unstimulated and stimulated flows. In contrast, no saliva flow was measured from the unspared glands in any of the patients. Subjective xerostomia was absent, mild, or not different from that reported before radiation in 10 of 15 patients (67%). CONCLUSION: Partial parotid gland sparing is feasible by using three-dimensional planning in patients undergoing bilateral head and neck radiation. Approximately 50% of the saliva flow from the spared glands may be retained, and most patients thus treated have no or mild xerostomia in the early period after the completion of radiation. Whether tumor control and late complications are comparable to standard radiation will be assessed as more experience is gained.

    Title Chemotherapy Followed by Accelerated Fractionated Radiation for Larynx Preservation in Patients with Advanced Laryngeal Cancer.
    Date September 1996
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: Larynx preservation in advanced, resectable laryngeal cancer may be achieved using induction chemotherapy (CT) followed in responding patients by definitive radiation (RT). To address potential accelerated repopulation of clonogenic tumor cells during the prolonged total treatment time, we studied the feasibility of accelerated fractionated RT after CT. METHODS: Patients with advanced laryngeal cancer received two cycles of cisplatin 100 mg/m2 and fluorouracil (5-Fu) 1,000 mg/m2/d for 5 days. Responding patients received a third cycle after which those who had complete response or tumor down-staging to T1 proceeded with accelerated RT: 70.4 Gy delivered over 5.5 weeks. Patients who achieved a lesser response to CT underwent total laryngectomy and postoperative RT. RESULTS: Thirty-three patients were accrued. Three died during the course of CT and two declined definitive treatment after CT. Twenty-one patients had a major response to CT, 20 of whom received accelerated RT. Median weight loss during RT was 11%. Late severe morbidity was observed in five patients (25%). All four patients who underwent salvage laryngectomy after accelerated RT experienced major postoperative complications. The locoregional failure rate was 25%. The larynx was preserved in 48% of the total study population and in 80% of the patients irradiated according to the study protocol. CONCLUSION: Accelerated RT after CT as delivered in this study may increase both acute and long-term morbidity rates compared with studies using standard RT after CT. It did not seem to improve local/regional tumor control or survival despite stringent patient selection criteria.

    Title Recurrence of Head and Neck Cancer After Surgery or Irradiation: Prospective Comparison of 2-deoxy-2-[f-18]fluoro-d-glucose Pet and Mr Imaging Diagnoses.
    Date July 1996
    Journal Radiology
    Excerpt

    PURPOSE: To evaluate the diagnostic accuracy of positron emission tomography (PET) with administration of 2-deoxy-2-[fluorine-18]fluoro-D-glucose (FDG) relative to that of magnetic resonance (MR) imaging and/or computed tomography (CT) in recurrent head and neck cancers. MATERIALS AND METHODS: Twelve adult patients (mean age, 63 years) with previously treated head and neck cancers and clinical suspicion of recurrence underwent FDG PET and MR imaging and/or CT. All images were blindly and independently interpreted without histopathologic findings (obtained within 1 week of imaging). The level of confidence in image interpretation was graded by using a five-point rating system (0 = definitely no recurrence to 4 = definite recurrence). RESULTS: Recurrence was confirmed in eight patients. With a rating of 4 as a positive finding, FDG PET yielded a sensitivity and specificity of 88% (seven of eight) and 100% (four of four), respectively; MR imaging and/or CT, 25% (two of eight) and 75% (three of four), respectively. Receiver-operating characteristic analysis showed significantly better diagnostic accuracy with FDG PET than with MR imaging and/or CT (area under curve = 0.96 vs 0.55, P < .03). CONCLUSION: These data indicate that PET metabolic imaging, as compared with anatomic methods, has improved diagnostic accuracy for recurrent head and neck cancer.

    Title Hemangiopericytoma of the Oral Cavity.
    Date July 1996
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Title Human Papillomavirus Types Important in Progression of Inverted Papilloma.
    Date December 1995
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    Recent evidence suggests that human papillomavirus may play a role in the pathogenesis of inverted papilloma, a benign but locally aggressive neoplasm with a high recurrence rate and an association with squamous cell carcinoma. Histologic features of inverted papilloma have not been useful in discriminating lesions at high risk for malignant transformation. We studied archival pathology specimens from 39 patients with inverted papilloma treated at the University of Michigan between 1980 and 1994 using polymerase chain reaction techniques and human papillomavirus L1 and E6 consensus primers. Previously we reported that 63% of these specimens tested positive for human papillomavirus sequences and that presence of human papillomavirus predicted recurrence of inverted papilloma. We used type-specific primer pairs and polymerase chain reaction techniques as well as hybridization with type-specific oligonucleotide probes to determine human papillomavirus type. A significant correlation was observed between the severity of the lesion (dysplasia or carcinoma) and high risk human papillomavirus type (p < 0.01). All 12 benign inverted papilloma specimens that contained human papillomavirus tested positive for human papillomavirus 6 or 11. Of seven inverted papilloma specimens that exhibited dysplasia, five were human papillomavirus positive, three contained human papillomavirus 6, one contained human papillomavirus 11, and one contained human papillomavirus 18. In each of the three specimens that contained inverted papilloma in association with squamous cell carcinoma, the inverted papilloma portion of the specimen tested positive for a single human papillomavirus type: human papillomavirus 6, 11, or 16.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Overexpression of P53 Predicts Organ Preservation Using Induction Chemotherapy and Radiation in Patients with Advanced Laryngeal Cancer. Department of Veterans Affairs Laryngeal Cancer Study Group.
    Date November 1995
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    A critical research frontier in head and neck oncology involves defining the use of induction chemotherapy regimens to allow organ preservation and to avoid functionally debilitating surgical resections. Completed clinical trials in laryngeal cancer indicate that such an approach is feasible, but progress thus far has been limited by our inability to predict which patients are likely to respond to chemotherapy and preserve their larynx. Mutation of the p53 tumor-suppressor gene is the most common genetic alteration identified thus far in human cancers, and it may be important in regulation of cell proliferation and chemosensitivity. To determine whether p53 overexpression predicts chemotherapy response, organ preservation, and survival in patients with advanced laryngeal cancer, we analyzed immunohistologic expression of p53 in tissue sections from 178 patients with advanced laryngeal cancer who were entered in the Department of Veterans Affairs Laryngeal Cancer Cooperative Study, a multiinstitutional clinical trial comparing induction chemotherapy (cis-platinum and 5-fluorouracil) plus radiation therapy (94 patients) to surgery plus postoperative radiation therapy (84 patients). Larynx preservation was significantly higher in the group of patients whose tumors overexpressed p53 (74% vs. 52.5%; p = 0.03). The presence of p53 overexpression did not predict survival in either the surgery or the chemotherapy groups (p = 0.82 and p = 0.53).

    Title Presence of Human Papillomavirus Predicts Recurrence of Inverted Papilloma.
    Date August 1995
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    Recent evidence suggests that human papillomavirus may play a role in the pathogenesis of inverted papilloma, a benign but locally aggressive neoplasm with a high recurrence rate and an association with squamous cell carcinoma. Histologic features of inverted papilloma have not been useful in discriminating lesions at high risk for recurrence. We studied archival pathology specimens from 32 patients with inverted papilloma treated at the University of Michigan between 1980 and 1994 with polymerase chain reaction techniques and human papillomavirus E6 and L1 consensus primers. Twenty (63%) specimens tested positive for human papillomavirus. The clinical status of the remaining 25 patients was reviewed after seven patients with recent diagnosis or who were lost to follow-up were excluded. A significant association was identified between the presence of human papillomavirus DNA in inverted papilloma and recurrence after surgical excision. Thirteen of 15 patients whose tumors tested positive for HPV recurred, whereas none of the 10 patients whose tumors were human papillomavirus negative recurred (p < 0.00002). This strongly suggests that the presence of human papillomavirus predicts recurrence of inverted papilloma.

    Title Hemilaryngectomy for Glottic Carcinoma After Radiation Therapy Failure.
    Date October 1994
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To determine the efficacy and safety of vertical hemilaryngectomy (VHL) for the treatment of early glottic carcinoma recurrent after radiation therapy (RT). DESIGN: Retrospective study. SETTING: Major referral center. PATIENTS: Forty patients were identified who underwent VHL for T1 or T2 glottic carcinoma between July 1975 and March 1991, and all were included in this study. Twenty-two patients had received full-course RT before VHL, and 18 patients underwent primary VHL. MAIN OUTCOME MEASURES: The local control rates were determined for T1 and T2 tumors in each group, along with actuarial survival rates and complications. RESULTS: Local control of tumor for VHL after RT failure was 85% for T1 tumors, 78% for T2 tumors, and 82% overall. Three of four of the local failures in this group occurred in patients who had contraindications to VHL. Total laryngectomy for treatment of local failures in this group increased the local control rate to 93% for T1 tumors, 89% for T2 tumors, and 91% overall. Local control rates for the primary VHL group were 90% for T1 tumors, 75% for T2 tumors, and 83% overall. Total laryngectomy for treatment of local recurrences increased local control to 87% for T2 tumors and 89% overall. Five-year actuarial survival was 85% for each group. Delayed tracheal decannulation occurred more frequently in the patients who had undergone RT. CONCLUSIONS: Our results support the oncologic safety and effectiveness of VHL for the surgical treatment of recurrent early glottic carcinomas after RT, with minimal increased morbidity.

    Title Analysis of Recurrence, Complications, and Functional Results with Free Jejunal Flaps.
    Date August 1994
    Journal Head & Neck
    Excerpt

    The medical records of 20 patients undergoing revascularized jejunal flap reconstruction of hypopharyngeal defects were retrospectively reviewed to analyze the incidence of distal marginal recurrence, complication rates, and success of early functional restoration. This report is one of few in the literature to address distal marginal recurrence in patients undergoing jejunal free flap reconstruction of hypopharyngeal defects. In 15 evaluable patients, two (13%) developed distal marginal recurrences. Both patients had tumor involving the hypopharynx at the junction of the cervical esophagus. The major complication rate was five of 20 patients (25%) and included three flap failures, one death, and one intra-abdominal hemorrhage. The minor complication rate was 35%. The median hospital stay was 15.5 days and the median time to successful swallowing was 14.5 days. The functional success rate for swallowing was 58%. Because of the aggressive nature of this disease, we feel partial esophagectomy with jejunal flap reconstruction is warranted to achieve early functional restoration in a select group of patients when a 2-cm distal margin can be obtained above the cervical esophagus with frozen-section control, and the distal esophagus is normal.

    Title Airway Obstruction Secondary to Central Line Intravenous Fluid Extravasation.
    Date May 1994
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    The differential diagnosis of neck masses is well known to the otolaryngologist-head and neck surgeon. To our knowledge, we present the first reported case of airway obstruction secondary to the extravasation of intravenous fluid from an internal jugular central venous line. This novel entity, with its rapidly progressive course and morbid implications, should be considered in the differential diagnosis of a neck mass in the patient with a central venous line. We discuss the management of this problem in the context of the complications of central venous lines as it relates to the otolaryngologist.

    Title Pericardial Extramedullary Haemopoiesis in Chronic Myelomonocytic Leukaemia.
    Date May 1994
    Journal Journal of Clinical Pathology
    Excerpt

    Chronic myelomonocytic leukaemia (CMML) is a myelodysplastic syndrome with a diverse clinical spectrum. A case of a 60 year old man with CMML who developed cardiac tamponade is reported. Cytological examination of the pericardial effusion fluid showed extramedullary haemopoiesis. Serous effusions are well recognised in association with this disease, but this seems to be the first reported case of extramedullary haemopoiesis resulting in a pericardial effusion in a patient with CMML.

    Title Tension Pneumocephalus After Endoscopic Sinus Surgery.
    Date April 1994
    Journal The Annals of Otology, Rhinology, and Laryngology
    Title The Platysma Myocutaneous Flap. Indications and Caveats.
    Date February 1994
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    The platysma myocutaneous flap has enjoyed limited popularity despite its versatility, dependability, and ease of harvesting. In this article, we describe 12 consecutive patients who underwent platysma flap reconstruction of various oral cavity and oropharyngeal defects. Complications included loss of one skin paddle, one pharyngocutaneous fistula, and one intraoral wound dehiscence. In all patients, bare bone was covered or appropriate spacing between the tongue and other structures was maintained to avoid ankyloglossia. We discuss specific indications and caveats.

    Title Use of Colony Stimulating Factors for the Treatment of Drug-induced Agranulocytosis.
    Date September 1993
    Journal British Journal of Haematology
    Title Esophagogastroduodenoscopy by Family Physicians Phase Ii: a National Multisite Study of 2,500 Procedures.
    Date July 1993
    Journal The Family Practice Research Journal
    Excerpt

    We have prospectively studied 1,783 upper gastrointestinal tract endoscopy procedures as performed by family physicians from thirteen separate office practices. Phase I of the study previously reported on 717 procedures in which patient management was enhanced, diagnostic yields were high, and biopsies were performed where appropriate. In Phase II, the data totaled 2,500 procedures representing 51.1 years of cumulative practice experience by the entire group. All cases were gathered prospectively and biopsies were confirmed by a pathologist's independent tissue analysis. In this series, family physicians were asked to record all complications, and to specify the exact manner in which performance of the procedure enhanced patient management. There have been biopsies in 1,230 (69% biopsy rate) Phase II cases with biopsy reports available in 1,194 (97% reporting rate) cases. There is pathological confirmation of the family physicians' visual diagnosis in 1,104 of 1,194 (93%) available biopsy reports for a 92% accuracy rate. There have been no complications, and the complication rate for the total series (1/2, 500) is now 0.0004.

    Title Alveolar Rhabdomyosarcoma Infiltrating Bone Marrow at Presentation: the Value to Diagnosis of Bone Marrow Trephine Biopsy Specimens.
    Date November 1992
    Journal Journal of Clinical Pathology
    Excerpt

    AIMS: To describe the histological appearances of bone marrow infiltrated with rhabdomyosarcoma at presentation and to determine their value in establishing the diagnosis. METHODS: Patients presenting over seven years in the northern health region of England with rhabdomyosarcoma were studied. Bone marrow aspirates and trephine biopsy specimens taken at presentation were examined. RESULTS: Seven of 32 patients with rhabdomyosarcoma had bone marrow infiltration, resulting in marrow failure in all cases, at diagnosis. The diagnosis was established in these seven by the typical cytological appearances and immunophenotype of the infiltrating cells (all seven patients) and cytogenetic abnormalities (three patients). Histological examination of the bone marrow showed a pseudoalveolar pattern with fibrous septal bands, enlarged vascular channels, and lack of cohesion of the tumour cells within the subdivided aggregates in all seven. In four cases multinucleate giant cells, often with peripherally sited nuclei, were found. CONCLUSIONS: These histological features of infiltrated marrow are so characteristic that the diagnosis of alveolar rhabdomyosarcoma can be made, or at least suspected, in many cases even without recourse to technically difficult and expensive further investigations. Bone marrow biopsy should be a routine part of the investigation of patients with bone marrow failure and will be of particular value in the diagnosis of those with disseminated alveolar rhabdomyosarcoma.

    Title Monitoring of Revascularized Jejunal Autografts.
    Date November 1992
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    Free jejunal autografts have been widely used to reconstruct circumferential pharyngeal defects in a single stage. Close postoperative monitoring of the perfusion of the free jejunal autograft is extremely important in achieving a successful outcome. Presented herein is our method of postoperative monitoring of jejunal autografts in which a segment of jejunum pedicled on its connecting mesentery is exteriorized. This method of monitoring was performed in 17 cases, and there were no cases of late graft failure. Of three patients who had undergone this operation before the use of this monitoring technique, one had an unrecognized late graft failure. We present our experience with this simple and reliable method to monitor free jejunal autografts.

    Title Olfactory Neuroblastoma Associated with Kallman's Syndrome.
    Date May 1992
    Journal The Journal of Otolaryngology
    Excerpt

    Kallman's syndrome is an unusual clinical entity that includes anosmia and hypogonadotropic hypogonadism. We present a patient in whom an olfactory neuroblastoma was discovered during evaluation of his Kallman's syndrome. While other craniofacial abnormalities have been associated with this condition, to our knowledge this is the first report of its association with olfactory neuroblastoma.

    Title Comparison of the Multiple Dose Pharmacokinetics of Two Formulations of Itraconazole During Remission Induction for Acute Myeloblastic Leukaemia.
    Date February 1992
    Journal The Journal of Antimicrobial Chemotherapy
    Excerpt

    This double-blind cross-over study compares the serum pharmacokinetics of a polyethylene glycol formulation of itraconazole (ITRA-PEG; 4 x 50 mg once daily) with a new pelleted formulation (ITRA-PEL; 2 x 100 mg once daily) during remission induction for acute myeloblastic leukaemia. Each formulation was administered for 28 days with a seven day washout period. Five of eight patients (median age 52 years, range 18-65) entering completed both arms of the study. At day 7 for ITRA-PEL (n = 8) the mean +/- one standard deviation and median maximum concentrations (Cmax) were 307 +/- 155 ng/mL and 275 ng/mL respectively and for ITRA-PEG (n = 6) 272 +/- 212 ng/mL and 193 ng/mL. At day 14 for ITRA-PEL (n = 8) the mean +/- S.D. and median Cmax were 412 +/- 227 ng/mL and 375 ng/mL respectively and for ITRA-PEG (n = 5), 315 +/- 177 ng/mL and 327 ng/mL. The Cmax mean and median values were therefore greater with ITRA-PEL but the differences between the two formulations were not statistically significant. Adequate therapeutic levels of itraconazole can be achieved in this clinical setting. However, the wide variation within and between patients suggests that an ITRA-PEL dosage of 400 mg/day may ensure earlier and more consistent therapeutic levels. Measurement of serum levels may be indicated in suspected failure of prophylaxis or treatment.

    Title 11p Deletions and Breakpoints in Squamous Cell Carcinoma: Association with Altered Reactivity with the Um-e7 Antibody.
    Date January 1992
    Journal Genes, Chromosomes & Cancer
    Excerpt

    The UM-E7 monoclonal antibody raised against the UM-SCC-I human squamous cell carcinoma (SCC) cell line identifies a cell surface antigen that is strongly expressed in normal tissues. The locus (MICI) controlling the expression of E7 and related cell surface antigens has been mapped to chromosome band 11p13. This band has been identified as a region of cancer-associated aberrations and as the probable locus of a tumor suppressor gene. Although E7 antigen expression is strong in normal keratinocytes, it varies among squamous carcinoma cell lines. Some SCC lines (12/26) exhibit weak expression of the E7 antigen, whereas other SCC cell lines (14/26) and 21 cell lines from other tumor types express the antigen strongly. On the basis of these observations and of mapping data, we postulated that low E7 antigen expression in a subset of SCC cell lines might be associated with chromosomal rearrangement or deletion involving the E7 locus on 11p. Fully evaluable karyotypes were prepared from 19 SCC cell lines, including 11 with weak and eight with strong E7 expression. Eight of the 11 lines with weak E7 expression had 11p abnormalities. Four of these contained 11p deletions, and four others had a breakpoint in 11p. In contrast, none of the cell lines in the group with strong E7 expression had an 11p deletion, although one had a rearrangement with an 11p breakpoint. In the four tumors with visible 11p deletions, the smallest region of overlap corresponded to the 11p13-p14 region. The mean log10 50% endpoint E7 titer in the group with 11p deletions or breakpoints was nearly two orders of magnitude lower than that of the lines with no 11p abnormality (1.95 +/- 0.53) (P less than 0.02). Our results indicate that the UM-E7 antibody identifies tumors with 11p13-p14 deletions and other 11p rearrangements and that the 11p region is a site of nonrandom chromosome rearrangement in a subset of human squamous cancers. The strong association of loss of antigen expression with visible 11p deletion or rearrangement in some tumors suggests that other tumors with this phenotype may contain submicroscopic lesions of 11p13-p14.

    Title Human Papillomavirus Dna Sequences in Cell Lines Derived from Head and Neck Squamous Cell Carcinomas.
    Date June 1991
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    There is increasing evidence that human papillomaviruses (HPV) have a casual role in some neoplasms in human beings. As examples, DNA of HPV types 16, 18, and 31 are frequently present in genital cancers in humans. Recently, oncogenic HPV types have also been identified in neoplasms of the head and neck, including verrucous carcinoma of the larynx, squamous cell carcinomas of the oral cavity and larynx, and inverted papillomas of the nose. These findings and our resource of an extensive panel of head and neck squamous cell carcinoma (HNSCC) cell lines led us to begin to investigate how frequently HPV DNA was present in these tumor cell lines. For initial analysis, twenty-two HNSCC cell lines derived from 20 patients' tumors were selected as representative of our tumor cell line panel with respect to diversity of primary site, tumor stage, patient age, sex, and clinical course. For Southern analysis, cell line DNA was tested for hybridization with DNA probes for HPV types 6, 11, 16, 18, and 31. Polymerase chain reaction (PCR) analysis was also performed on five tumor cell lines using types 6, 11, 16, 18, and 52 as probes. Southern blot analysis revealed HPV-specific signals in two of the 22 HNSCC cell lines tested. One of these, UM-SCC-23, was HPV 31 positive, which to our knowledge is the first identification of HPV 31 in HNSCC. UM-SCC-63, the other HPV-positive tumor identified by Southern analysis, hybridized with both type 18 and 31. Of the five tumor cell lines tested with PCR, two were HPV positive.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Control of Haemostasis.
    Date August 1990
    Journal British Journal of Hospital Medicine
    Title Esophagogastroduodenoscopy by Family Physicians: a National Multisite Study of 717 Procedures.
    Date June 1990
    Journal The Journal of the American Board of Family Practice / American Board of Family Practice
    Excerpt

    This is the first multisite report of esophagogastroduodenoscopies (EGDs) performed by family physicians. The first 717 EGDs performed by family physicians from 8 separate office practices provide a practical and safe rationale for selected cognitive and psychomotor aspects of continuing medical education after residency training. Although primarily in private practice, these physicians were affiliated with 6 academic institutions. This group of family physicians received training in short courses. The average amount of hands-on training before independent EGD was 8 supervised cases. Cumulatively, these data represent 227 months (18.9 years) of office practice. All cases were collected sequentially from the beginning of each physician's experience, and 454 cases were collected prospectively. Physicians reported excellent patient tolerance. Diagnostic yields were high, and biopsies were performed where appropriate. Pathologists reviewed biopsy specimens from 213 sites. The family physician endoscopic diagnosis agreed with the tissue diagnosis in 188 cases (88 percent). Physicians believed that EGD enhanced management or changed the diagnosis in more than 89 percent of cases. One bleeding complication requiring overnight hospitalization was noted. This complication rate 0.0014 (1/717) compares favorably with published subspecialty complication rates 0.0013 (1.3/1000). These data confirm the ability of some family physicians to perform EGD and suggest that continuation is safe. Biopsy analysis indicates diagnostic accuracy is high. Further study on the cognitive aspects and the defragmentation of care is needed.

    Title Squamous Carcinoma of the Head and Neck in Organ Transplant Recipients: Possible Role of Oncogenic Viruses.
    Date March 1990
    Journal The Laryngoscope
    Excerpt

    A consistently increased incidence of malignancies in renal transplant recipients has been attributed to the effect of chronic immunosuppression required to prevent transplant rejection. Tumors arising in such patients offer a unique opportunity to study the interactions of the immune system and tumor development. A series of three cases of head and neck squamous cell carcinoma arising in patients after renal, cardiac, or bone marrow transplantation are reported. Patient ages at tumor diagnosis were 18, 29, and 53 years, respectively. Time from transplant to diagnosis of tumor ranged from 7 months to 12 years. Only the youngest patient lacked a history of exposure to the traditional pre-disposing factors of tobacco and alcohol use. Histopathologic examination in all three tumors showed features of koilocytosis with hyperkeratosis and parakeratosis suggestive of papillomavirus infection. Squamous carcinoma cells from one of these patients have been successfully established in cell culture. Immune system impairments secondary to the use of antirejection drugs could allow the expression of oncogenic viruses. A recent report of human papillomavirus (HPV) DNA in a primary and metastatic perianal squamous cell carcinoma from a renal transplant recipient, as well as the reported presence of HPV in benign and malignant neoplasms of the upper aerodigestive tract suggests that HPV infection could play a role in the development of squamous carcinomas in transplant recipients. Further studies of HPV infection in cultured cell lines derived from head and neck tumors occurring in immunosuppressed patients are needed to define this relationship.

    Title Characterization of Human Laryngeal Primary and Metastatic Squamous Cell Carcinoma Cell Lines Um-scc-17a and Um-scc-17b.
    Date November 1989
    Journal Cancer Research
    Excerpt

    The squamous cell carcinoma (SCC) cell lines UM-SCC-17A and -17B were derived, respectively, from the primary laryngeal cancer and a metastatic neck tumor of a patient who failed to respond to radiation therapy but achieved long-term remission after surgery. The karyotypes of both cell lines and a subline of 17A were pseudodiploid and stable in multiple in vitro passages. Several karyotypic abnormalities were common to all three cell lines and therefore represent mutations present in the tumor before the divergence of the metastatic and subline populations whereas those rearrangements observed only in one cell are more likely to be secondary. The shared mutations include: duplication of the short and proximal long arm of chromosome 2, isochromosome 3q, duplication 7, inversion 8, duplication of the distal long arm of 18, and monosomy 21 or ring 21. Each line had different rearrangements involving chromosome 7 that resulted in three copies of most of the short arm being present in both cell lines, except for high passages of 17B, in which one structurally normal 7 was replaced by a dicentric isochromosome, dic(7)(q11.22), resulting in four copies of 7p. The dic(7) may represent an in vitro mutation. An isochromosome 13q was noted in both the stemline and subline of UM-SCC-17A but not in UM-SCC-17B. A del(11p) and an iso(21q) were present only in the 17A subline. The cell lines expressed the membrane antigen phenotype characteristic of squamous cancers although the UM-SCC-17A subline differed with respect to three markers. Of these, the A9 and blood group antigen changes are thought to be associated with progression. The subline, which carried the del(11)(p13-p15.1), also failed to express the E7 antigen mapped to the band 11p13. It is possible that the two apparently normal 11s in this subline carry a point mutation or microscopically undetected deletion involving the E7 antigen locus.

    Title Isoantigenicity of Rabbit Sperm, Testis, and Their Extracts As Demonstrated by Western Blot Enzyme Immunobinding Procedure.
    Date October 1985
    Journal Archives of Andrology
    Excerpt

    The isoantigenicity of rabbit germ cells and their extracts was studied by using a Western blot enzyme immunobinding procedure after systemic and local intrauterine immunization. In the deoxycholate (DOC) sperm extract, the antisperm isoantiserum (ASA) recognized proteins of 100, 96, 92, 82, 53, 47, 43, and 29 kD, and the antitestis isoantiserum (ATA) recognized proteins of 100, 96, 92, 82, 43, and 29 kD. In the lithium diiodosalicylate (LIS) sperm extract, ASA reacted with four antigen bands of 92, 30, 14, and 6 kD, and ATA reacted with proteins of 94, 92, 91, 23, 17, 7, and 6 kD. In the reduced sodium dodecyl sulfate (SDS) sperm extract, ASA recognized proteins of 95, 76, 51, 41, 33, 30, 28, 26, and 22 kD; ATA showed a reaction only with proteins of 100, 98, and 95 kD, and anti-LIS/sperm isoantiserum (ALA) recognized three proteins of 98, 81, and 65 kD. The IgA of the immune uterine fluid (IUF) from the LIS/sperm-immunized rabbits recognized a 14-kD antigen in the DOC conceptus extract, a 51-kD antigen in the DOC testis extract, and 53-, 49-, 31-, and 28-kD proteins in the reduced SDS-sperm pellet extract. The IgA of the IUF from the NP-40/pellet-immunized rabbits showed two proteins of about 100 kD, plus ones of 56, 36, 31, 29, 19, 17, and 14 kD in the DOC conceptus extract; proteins of 92, 70, 51, 29, and 14 kD in the DOC testis extract; and of 61, 57, 53, 49, 35, 31, and 28 kD in the reduced SDS-sperm pellet extract.

    Title Intrapartum Foetal Monitoring.
    Date April 1983
    Journal Canadian Anaesthetists' Society Journal
    Title Uterine Torsion During Pregnancy.
    Date November 1977
    Journal Canadian Medical Association Journal
    Title Active Management of Severe Pre-eclampsia.
    Date January 1974
    Journal Canadian Medical Association Journal
    Title Anti-oxidant Treatment Enhances Anti-tumor Cytotoxicity of (-)-gossypol.
    Date
    Journal Cancer Biology & Therapy
    Excerpt

    We showed that tumor cells with wild-type p53 and high levels of Bcl-x(L) are cisplatin resistant but are induced to undergo apoptosis by (-)-gossypol, making this a promising agent for overcoming cisplatin resistance. However, some cells in a population with this phenotype are not killed and continue to survive. Conversely, tumor cells with low Bcl-x(L) expression and either wild type or mutant p53 are relatively cisplatin sensitive and do not exhibit such high levels of apoptosis. However, these do undergo progressive loss of viability after (-)-gossypol that may not be tumor specific. We sought to elucidate the basis for these observations using cDNA microarray analysis of (-)-gossypol treated cisplatin sensitive and resistant cells. Genes in the reactive oxygen species (ROS) pathway were highly upregulated in response to (-)-gossypol. The upregulation was of much greater magnitude in cisplatin sensitive than resistant cells. Staining with an oxidation reporter dye confirmed differential induction of ROS in tumor cells with low Bcl-x(L). As (-)-gossypol is known to undergo oxidative metabolism in vivo, ROS generation may be responsible for both off-target cytotoxicity and inactivation of the drug. In agreement with this hypothesis, oxidation of (-)-gossypol by pre-treatment with hydrogen peroxide eliminated its activity. Combined treatment with the antioxidant N-acetyl-cysteine (NAC) to block ROS increased (-)-gossypol-induced cytotoxicity to tumor but not normal cells. Furthermore, NAC increased the induction of apoptosis as measured by the sub-G(1) population, in both cisplatin sensitive and resistant cells. We postulate that concurrent treatment with antioxidant to block ROS prevents oxidative inactivation of (-)-gossypol and limits off-target toxicity allowing more potent (-)-gossypol-induced anti-tumor activity.

    Title Do Micromorphometric Features of Metastatic Deposits Within Sentinel Nodes Predict Nonsentinel Lymph Node Involvement in Melanoma?
    Date
    Journal Annals of Surgical Oncology
    Excerpt

    INTRODUCTION: Multiple attempts have been made to identify melanoma patients with a positive sentinel lymph node (SLN) who are unlikely to harbor residual disease in the nonsentinel lymph nodes (NSLN). We examined whether the size and location of the metastases within the SLN may help further stratify the risk of additional positive NSLN. METHODS: A review of our Institutional Review Board (IRB)-approved melanoma database was undertaken to identify all SLN positive patients with SLN micromorphometric features. Univariate logistic regression techniques were used to assess potential significant associations. Decision tree analysis was used to identify which features best predicted patients at low risk for harboring additional disease. RESULTS: The likelihood of finding additional disease on completion lymph node dissection was significantly associated with primary location on the head and neck or lower extremity (P = 0.01), Breslow thickness >4 mm (P = 0.001), the presence of angiolymphatic invasion (P < 0.0001), satellitosis (P = 0.004), extranodal extension (P = 0.0002), three or more positive SLN (P = 0.02) and tumor burden within the SLN >1% surface area (P = 0.004). Sex, age, mitotic rate, ulceration, Clark level, histologic subtype, regression, and number of SLN removed had no association with finding a positive NSLN. Location of the metastases (capsular, subcapsular or parenchymal) showed no correlation with a positive NSLN. Decision tree analysis incorporating size of the metastatic burden within the SLN along with Breslow thickness can identify melanoma patients with a positive SLN who have a very low risk of harboring additional disease with the NSLN. CONCLUSION: Size of the metastatic burden within the SLN, measured as a percentage of the surface area, helps stratify the risk of harboring residual disease in the nonsentinel lymph nodes (NSLN), and may allow for selective completion lymphadenectomy.

    Title Skin Cancer of the Head and Neck with Perineural Invasion: Defining the Clinical Target Volumes Based on the Pattern of Failure.
    Date
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: To analyze patterns of failure in patients with head-and-neck cutaneous squamous cell carcinoma (HNCSCC) and clinical/radiologic evidence of perineural invasion (CPNI), in order to define neural clinical target volume (CTV) for treatment planning. METHODS AND MATERIALS: Patients treated with three-dimensional (3D) conformal or intensity-modulated radiotherapy (IMRT) for HNCSCC with CPNI were included in the study. A retrospective review of the clinical charts, radiotherapy (RT) plans and radiologic studies has been conducted. RESULTS: Eleven consecutive patients with HNCSCCs with CPNI were treated from 2000 through 2007. Most patients underwent multiple surgical procedures and RT courses. The most prevalent failure pattern was along cranial nerves (CNs), and multiple CNs were ultimately involved in the majority of cases. In all cases the involved CNs at recurrence were the main nerves innervating the primary tumor sites, as well as their major communicating nerves. We have found several distinct patterns of disease spread along specific CNs depending on the skin regions harboring the primary tumors, including multiple branches of CN V and VII. These patterns and the pertinent anatomy are detailed in the this article. CONCLUSIONS: Predictable disease spread patterns along cranial nerves supplying the primary tumor sites were found in this study. Awareness of these patterns, as well as knowledge of the relevant cranial nerve anatomy, should be the basis for CTV definition and delineation for RT treatment planning.

    Title High Sept9_v1 Expression Is Associated with Poor Clinical Outcomes in Head and Neck Squamous Cell Carcinoma.
    Date
    Journal Translational Oncology
    Excerpt

    The purpose of this work was to determine SEPT9_v1 expression levels in head and neck squamous cell carcinoma (HNSCC) and to analyze whether SEPT9_v1 expression is relevant to clinical outcomes. Recently, the SEPT9 isoform SEPT9_v1 has been implicated in oncogenesis, and methylation of the SEPT9 promoter region was reported in HNSCC. These findings led us to hypothesize that SEPT9_v1 could be differently expressed in HNSCC. To determine whether SEPT9_v1 is expressed in HNSCC, tissue microarray immunohistochemical analysis was performed using a SEPT9_v1-specific antibody. Tissue microarrays stained with a polyclonal SEPT9_v1-specific antibody was used to determine protein expression levels in HNSCC tissue samples, some with known clinical outcomes. This analysis showed that SEPT9_v1 is in fact highly expressed in HNSCC compared with normal epithelium, and high expression levels directly correlated with poor clinical outcomes. Specifically, a high SEPT9_v1 expression was associated with decreased disease-specific survival (P = .012), time to indication of surgery at primary site (P = .008), response to induction chemotherapy (P = .0002), and response to chemotherapy (P = .02), as well as advanced tumor stage (P = .012) and N stage (P = .0014). The expression of SEPT9_v1 was also strongly correlated with smoking status (P = .00094). SEPT9_v1 is highly expressed in HNSCC, and a high expression of SEPT9_v1 is associated with poor clinical outcomes. These data indicate that SEPT9_v1 warrants additional investigation as a potential biomarker for HNSCC.

    Title Proposal for a Rational Classification of Neck Dissections.
    Date
    Journal Head & Neck
    Title Metastatic Potential of Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma.
    Date
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    to design in vitro and in vivo models of metastasis to study the behavior of cancer stem cells (CSCs) in head and neck squamous cell carcinoma (HNSCC).

    Title Correlation of Cellular Immunity with Human Papillomavirus 16 Status and Outcome in Patients with Advanced Oropharyngeal Cancer.
    Date
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    to determine whether the favorable outcome associated with human papillomavirus (HPV) 16-positive oropharyngeal cancer is related to a patient's adaptive immunity.

    Title The Role of Full-thickness Scalp Resection for Management of Primary Scalp Melanoma.
    Date
    Journal Annals of Plastic Surgery
    Excerpt

    BACKGROUND:: Scalp melanoma is aggressive and has a proclivity for regional metastasis. We hypothesize that subperiosteal scalp melanoma resection reduces in-transit/satellite recurrence, when compared with subgaleal resection. METHODS:: We identified patients with intermediate to deep, primary scalp melanoma referred to head/neck surgery over an 8-year period. Patients were compared based on scalp resection depth, including subperiosteal (resection to the level of calvarium) and subgaleal (resection including skin, subcutaneous tissue, and galea). The dependent variables were in-transit/satellite recurrence and time to in-transit/satellite recurrence. RESULTS:: Among 48 identified patients, the in-transit/satellite recurrence rate was 16.7%. Subgaleal resection patients had higher in-transit/satellite recurrence rates than subperiosteal resection patients (24.0% vs. 8.7%, P = 0.155). Among node-negative patients, subgaleal resection had significantly higher in-transit/satellite metastasis rates when compared with subperiosteal resection (26.3% vs. 0%, P = 0.047). CONCLUSION:: For node-negative, primary scalp melanoma, subperiosteal resection significantly decreases in-transit/satellite recurrence when compared with subgaleal resection. Given our small sample size, further studies are necessary to confirm these results.

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