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Otolaryngologist (ear, nose, throat)
39 years of experience

Credentials

Education ?

Medical School Score Rankings
University of Michigan Medical School (1973)
  •  
Top 25%

Awards & Distinctions ?

Awards  
One of America's Leading Experts on:
(Mouth Cancer) Mouth Neoplasms
Head and Neck Cancer (Head and Neck Neoplasm)
Laryngectomy
Oral Cavity and the Oropharynx Cancer (Oropharyngeal Neoplasm)
Squamous Cell Carcinoma
Throat Cancer (Laryngeal Neoplasm)
Associations
American College of Surgeons
American Rhinologic Society
American Board of Otolaryngology
American Academy of Otolaryngology: Head and Neck Surgery
American Board of Facial Plastic and Reconstructive Surgery
American Society of Clinical Oncology

Affiliations ?

Dr. Wolf is affiliated with 3 hospitals.

Hospital Affiliations

Score

Rankings

  • University of Michigan Hospitals & Health Centers
    Otolaryngology
    1500 E Medical Center Dr, Ann Arbor, MI 48109
    •  
    Top 25%
  • Saint Joseph Mercy Hospital
    Otolaryngology
    505 E Huron St, Ann Arbor, MI 48104
    •  
    Top 50%
  • University of Michigan Health System
  • Publications & Research

    Dr. Wolf has contributed to 176 publications.
    Title National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Head and Neck Cancers.
    Date November 2011
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    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 Human Papillomavirus Status in Head and Neck Cancer: the Ethics of Disclosure.
    Date October 2010
    Journal Cancer
    Excerpt

    Human papillomavirus (HPV) is an emerging causative factor for squamous carcinoma of the oropharynx and perhaps other head and neck cancers. There is a great deal of uncertainty regarding the clinical significance and implications of HPV status in this patient population. As a result, there is no established protocol for informing patients of the potential link between viral infection and their cancer. This paper discusses some of the ethical issues involved with informing head and neck cancer patients of their HPV status, recognizing the dilemma posed by unresolved clinical questions and the need to respect the autonomy of patients by disclosing relevant information.

    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 Phase Ii Evaluation of Sorafenib in Advanced and Metastatic Squamous Cell Carcinoma of the Head and Neck: Southwest Oncology Group Study S0420.
    Date July 2010
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    We conducted a phase II trial to evaluate the efficacy and safety of single-agent sorafenib in chemotherapy-naïve patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN). The primary end point was response probability (ie, confirmed complete and partial response [PR]).

    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 Routine Computed Tomography Scanning for Tumor Staging in Advanced Laryngeal Cancer: Implications for Treatment Selection.
    Date May 2010
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    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 Reexamining the Treatment of Advanced Laryngeal Cancer: the Va Laryngeal Cancer Study Revisited.
    Date April 2010
    Journal Head & Neck
    Title Docetaxel, Cisplatin, and Fluorouracil Induction Chemotherapy Followed by Accelerated Fractionation/concomitant Boost Radiation and Concurrent Cisplatin in Patients with Advanced Squamous Cell Head and Neck Cancer: A Southwest Oncology Group Phase Ii Trial (s0216).
    Date March 2010
    Journal Head & Neck
    Excerpt

    In an effort to optimize nonoperative therapy in patients with locoregionally advanced head and neck squamous cell cancer, the Southwest Oncology Group conducted a phase II trial combining 3-drug taxane-containing induction chemotherapy with accelerated fractionation/concomitant boost radiation and concomitant single-agent cisplatin.

    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 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 Tradition, Teamwork, and Tailored Treatment: Surgical Oncology in the Genomic Era.
    Date May 2009
    Journal Archives of Otolaryngology--head & Neck Surgery
    Title Pretreatment Health Behaviors Predict Survival Among Patients with Head and Neck Squamous Cell Carcinoma.
    Date May 2009
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    Our prior work has shown that the health behaviors of head and neck cancer patients are interrelated and are associated with quality of life; however, other than smoking, the relationship between health behaviors and survival is unclear.

    Title Sensitization of Squamous Cell Carcinoma to Cisplatin Induced Killing by Natural Agents.
    Date May 2009
    Journal Cancer Letters
    Excerpt

    Cisplatin resistance is a major problem in the successful treatment of squamous cell carcinoma (SCC). In the present study we showed, for the first time, that the constitutive activation of NF-kappaB partly contributes to cisplatin resistance and that the inactivation of NF-kappaB by natural agents [G2535 (isoflavone mixture containing genistein and diadzein), 3,3'-diindolylmethane (Bioresponse BR-DIM referred to as B-DIM)] could overcome this resistance, resulting in the inhibition of cell growth and induction of apoptosis, which might be an useful strategy for achieving better treatment outcome in patients diagnosed with cisplatin-resistant tumors of SCC.

    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 Interleukin-6 Predicts Recurrence and Survival Among Head and Neck Cancer Patients.
    Date September 2008
    Journal Cancer
    Excerpt

    BACKGROUND: Increased pretreatment serum interleukin (IL)-6 levels among patients with head and neck squamous cell carcinoma (HNSCC) have been shown to correlate with poor prognosis, but sample sizes in prior studies have been small and thus unable to control for other known prognostic variables. METHODS: A longitudinal, prospective cohort study determined the correlation between pretreatment serum IL-6 levels, and tumor recurrence and all-cause survival in a large population (N = 444) of previously untreated HNSCC patients. Control variables included age, sex, smoking, cancer site and stage, and comorbidities. Kaplan-Meier plots and univariate and multivariate Cox proportional hazards models were used to study the association between IL-6 levels, control variables, and time to recurrence and survival. RESULTS: The median serum IL-6 level was 13 pg/mL (range, 0-453). The 2-year recurrence rate was 35.2% (standard error, 2.67%). The 2-year death rate was 26.5% (standard error, 2.26%). Multivariate analyses showed that serum IL-6 levels independently predicted recurrence at significant levels [hazard ratio (HR) = 1.32; 95% confidence interval (CI), 1.11 to 1.58; P = .002] as did cancer site (oral/sinus). Serum IL-6 level was also a significant independent predictor of poor survival (HR = 1.22; 95% CI, 1.02 to 1.46; P = .03), as were older age, smoking, cancer site (oral/sinus), higher cancer stage, and comorbidities. CONCLUSIONS: Pretreatment serum IL-6 could be a valuable biomarker for predicting recurrence and overall survival among HNSCC patients. Using IL-6 as a biomarker for recurrence and survival may allow for earlier identification and treatment of disease relapse.

    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 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 Consensus Statement on the Classification and Terminology of Neck Dissection.
    Date June 2008
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To update the guidelines for neck dissection terminology, as previously recommended by the American Head and Neck Society. PARTICIPANTS: Committee for Neck Dissection Classification, American Head and Neck Society; representation from the Committee for Head and Neck Surgery and Oncology, American Academy of Otolaryngology-Head and Neck Surgery (T.A.D.). EVIDENCE: Review of current literature on neck dissection classification. CONSENSUS PROCESS: Semiannual face-to-face meetings of the Committee for Neck Dissection Terminology and e-mail correspondence. CONCLUSIONS: Standardization of terminology for neck dissection is important for communication among clinicians and researchers. New recommendations have been made regarding the following: boundaries between levels I and II and between levels III/IV and VI; terminology of the superior mediastinal nodes; and the method of submitting surgical specimens for pathologic analysis.

    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 Health Behaviors of Head and Neck Cancer Patients the First Year After Diagnosis.
    Date March 2008
    Journal Head & Neck
    Excerpt

    BACKGROUND: This prospective, cohort study is the first to describe 5 health behaviors of head and neck cancer patients the first year after diagnosis. METHODS: Patients (N = 283) were recruited in otolaryngology clinic waiting rooms and asked to complete written surveys. A medical record audit was also conducted. Descriptive statistics and multivariate analyses were conducted to determine which variables were associated with the 5 health behaviors. RESULTS: Half of the patients smoked and 25% were problem drinkers. Over half of the smokers and drinkers quit 1 year post-diagnosis. Smoking and problem drinking were highly associated and both were associated with lower body mass index (BMI) (p < .01). Moreover, physical activity and sleep were associated with each other (p < .01). Low SLEEP (Medical Outcomes Study Sleep Scale) scores were common and highly associated with depression (p < .01). CONCLUSION: The health behaviors of head and neck cancer patients are interrelated, and assessing and treating these behaviors together may be beneficial.

    Title Recent Changes in the Treatment of Patients with Advanced Laryngeal Cancer.
    Date March 2008
    Journal Head & Neck
    Excerpt

    Since the original data from the Department of Veterans Affairs Laryngeal Cancer Study Group demonstrated that nonsurgical therapy could achieve survival rates comparable to total laryngectomy in selected cases, there has been a progressive increase in employment of nonsurgical therapy for the management of advanced laryngeal cancer. Both neoadjuvant chemotherapy followed by conventionally fractionated or hyperfractioned radiotherapy for chemotherapy responders, or simultaneously administered chemoradiation has resulted in a significant number of patients who achieved cure while preserving their larynges. Nevertheless, combined chemotherapy and external beam radiation is associated with a variety of acute and chronic sequelae that can have a debilitating impact on function and quality of life. Although no therapeutic option is without risk, the decision regarding the modality of therapy for a patient with advanced laryngeal cancer should prompt a careful review of the current surgical techniques available for treatment. Data on quality of life and aging, as well as advances in minimally invasive surgical techniques, are available today that were not available at the time of the Veterans study. Selection of optimal therapy is often complex and raises the question whether the pendulum may have swung too far in the direction of nonsurgical therapy for advanced laryngeal cancer. This article reviews the current options available for a patient with advanced laryngeal cancer and discusses the impact of therapy.

    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 Integrating Surgery into Treatment Paradigms for Organ Preservation: Tailoring Treatment to Biology Improves Outcomes.
    Date November 2007
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: Neoadjuvant chemotherapy was introduced into treatment paradigms for curable head and neck cancer in the early 1970s in an effort to reduce the magnitude of mutilating surgery and to provide a rationale for adjuvant systemic chemotherapy in patients who responded to initial chemotherapy. The large number of trials that followed failed to demonstrate improved survival when neoadjuvant chemotherapy was added to conventional surgery or radiation. Importantly, a consistent observation in these neoadjuvant trials was the significant association of clinical tumor response to neoadjuvant therapy and favorable prognosis. RESULTS: The findings led to development of a new treatment paradigm that was based on the hypothesis that the biology of an individual cancer is more predictive of response to specific therapy and overall outcome than is anatomic tumor site or extent, and on the corollary that matching treatment modality to biology will improve overall survival rates. CONCLUSIONS: This report identifies key findings that are important in the design and analysis of organ preservation trials and biologic markers predictive of response and outcomes. Ongoing studies incorporating biomarkers such as p53, Bcl-xL, HPV, EGFR, COX-2, and tumor promoter gene methylation are underway and will identify new targets for molecular manipulation, response monitoring, and tumor imaging that could allow real-time changes in how we integrate the various components of multi-modal therapy.

    Title An Unusual Thyroglossal Duct Cyst Infection with Coccidioidomycosis.
    Date July 2007
    Journal The Journal of Otolaryngology
    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 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 Identification of a Subpopulation of Cells with Cancer Stem Cell Properties in Head and Neck Squamous Cell Carcinoma.
    Date February 2007
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Like many epithelial tumors, head and neck squamous cell carcinoma (HNSCC) contains a heterogeneous population of cancer cells. We developed an immunodeficient mouse model to test the tumorigenic potential of different populations of cancer cells derived from primary, unmanipulated human HNSCC samples. We show that a minority population of CD44(+) cancer cells, which typically comprise <10% of the cells in a HNSCC tumor, but not the CD44(-) cancer cells, gave rise to new tumors in vivo. Immunohistochemistry revealed that the CD44(+) cancer cells have a primitive cellular morphology and costain with the basal cell marker Cytokeratin 5/14, whereas the CD44(-) cancer cells resemble differentiated squamous epithelium and express the differentiation marker Involucrin. The tumors that arose from purified CD44(+) cells reproduced the original tumor heterogeneity and could be serially passaged, thus demonstrating the two defining properties of stem cells: ability to self-renew and to differentiate. Furthermore, the tumorigenic CD44(+) cells differentially express the BMI1 gene, at both the RNA and protein levels. By immunohistochemical analysis, the CD44(+) cells in the tumor express high levels of nuclear BMI1, and are arrayed in characteristic tumor microdomains. BMI1 has been demonstrated to play a role in self-renewal in other stem cell types and to be involved in tumorigenesis. Taken together, these data demonstrate that cells within the CD44(+) population of human HNSCC possess the unique properties of cancer stem cells in functional assays for cancer stem cell self-renewal and differentiation and form unique histological microdomains that may aid in cancer diagnosis.

    Title Research Education and Training in Otolaryngology: Meeting Summary and Research Opportunities.
    Date October 2006
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Title American Society of Clinical Oncology Clinical Practice Guideline for the Use of Larynx-preservation Strategies in the Treatment of Laryngeal Cancer.
    Date August 2006
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: To develop a clinical practice guideline for treatment of laryngeal cancer with the intent of preserving the larynx (either the organ itself or its function). This guideline is intended for use by oncologists in the care of patients outside of clinical trials. METHODS: A multidisciplinary Expert Panel determined the clinical management questions to be addressed and reviewed the literature available through November 2005, with emphasis given to randomized controlled trials of site-specific disease. Survival, rate of larynx preservation, and toxicities were the principal outcomes assessed. The guideline underwent internal review and approval by the Panel, as well as external review by additional experts, members of the American Society of Clinical Oncology (ASCO) Health Services Committee, and the ASCO Board of Directors. RESULTS: Evidence supports the use of larynx-preservation approaches for appropriately selected patients without a compromise in survival; however, no larynx-preservation approach offers a survival advantage compared with total laryngectomy and adjuvant therapy with rehabilitation as indicated. RECOMMENDATIONS: All patients with T1 or T2 laryngeal cancer, with rare exception, should be treated initially with intent to preserve the larynx. For most patients with T3 or T4 disease without tumor invasion through cartilage into soft tissues, a larynx-preservation approach is an appropriate, standard treatment option, and concurrent chemoradiotherapy therapy is the most widely applicable approach. To ensure an optimum outcome, special expertise and a multidisciplinary team are necessary, and the team should fully discuss with the patient the advantages and disadvantages of larynx-preservation options compared with treatments that include total laryngectomy.

    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 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 Head and Neck Cancers.
    Date September 2005
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    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 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 Evaluation of Head and Neck Squamous Cell Carcinoma After Treatment.
    Date January 2004
    Journal Ajnr. American Journal of Neuroradiology
    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 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 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 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 Research Training in Otolaryngology: an Impending Crisis?
    Date December 2002
    Journal Archives of Otolaryngology--head & Neck Surgery
    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 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 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 Neck Dissection Classification Update: Revisions Proposed by the American Head and Neck Society and the American Academy of Otolaryngology-head and Neck Surgery.
    Date July 2002
    Journal Archives of Otolaryngology--head & Neck Surgery
    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 Options for Preserving the Larynx in Patients with Advanced Laryngeal and Hypopharyngeal Cancer.
    Date March 2002
    Journal Ear, Nose, & Throat Journal
    Excerpt

    The introduction of newer surgical and combined-modality approaches to organ preservation in patients with advanced laryngeal or hypopharyngeal cancer is the most exciting clinical frontier in head and neck cancer treatment today. The use of these techniques at other sites, the exploration of improved methods for patient selection and tumor assessment, and the development of newer combination regimens will need to be rigorously studied in future clinical trials. In all these efforts, the major focus must remain on improving survival. This article reviews the latest developments in organ-preservation strategies and techniques for patients with advanced laryngeal or hypopharyngeal cancer.

    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 Conservation Laryngeal Surgery for Malignant Tumors of the Larynx and Pyriform Sinus.
    Date December 2001
    Journal Hematology/oncology Clinics of North America
    Excerpt

    Conservation surgery for cancers of the larynx and pyriform sinus is an expansive and complicated subject. A great deal of technical expertise and clinical judgement are required for appropriate surgical and oncologic outcomes. In the appropriate setting, surgery continues to play an important role in voice preservation for patients with laryngeal and hypopharyngeal carcinoma. Perhaps most importantly, options for organ preservation surgery have expanded, and the number of patients requiring total laryngectomy as primary surgical management has decreased. The medical surgical decision making is complex and requires precise delineation of tumor extent, careful patient evaluation, and thorough interdisciplinary discussion to select an optimal course of treatment for the individual patient.

    Title Commentary: Phase Iii Trial to Preserve the Larynx: Induction Chemotherapy and Radiotherapy Versus Concurrent Chemotherapy and Radiotherapy Versus Radiotherapy--intergroup Trial R91-11.
    Date October 2001
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    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 Clinical Experience with Hla-b7 Plasmid Dna/lipid Complex in Advanced Squamous Cell Carcinoma of the Head and Neck.
    Date August 2001
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To investigate the safety and efficacy of alloantigen plasmid DNA therapy in patients with advanced head and neck squamous cell carcinoma using Allovectin-7 (Vical Inc, San Diego, Calif), a DNA/lipid complex designed to express the class I major histocompatibility complex antigen HLA-B7. DESIGN: Multi-institutional prospective trial. SETTING: Academic medical setting. PATIENTS: A total of 69 patients were enrolled in 3 sequential clinical trials: a single-center phase 1 trial and 2 multicenter phase 2 trials. Eligibility criteria included unresectable squamous cell carcinoma that failed conventional therapy, Karnofsky performance status score of 70 or greater, and no concurrent anticancer or immunosuppressive therapies. INTERVENTION: Patients received 2 biweekly intratumoral injections of 10 microg (phase 1 and first phase 2 trials) or 100 microg (second phase 2 trial) of Allovectin-7 followed by 4 weeks of observation. Patients with stable or responding disease after the observation period were given a second treatment cycle identical to the first. MAIN OUTCOME MEASURES: Patients were assessed for toxic effects, and tumor size was measured after cycles 1 (at 6 weeks) and 2 (at 16 weeks). RESULTS: Allovectin-7 treatment was well tolerated, with no grade 3 or 4 drug-related toxic effects. Of 69 patients treated, 23 (33%) had stable disease or a partial response after the first cycle of treatment and proceeded to the second cycle. After the second cycle, 6 patients had stable disease, 4 had a partial response, and 1 had a complete response. Responses persisted for 21 to 106 weeks. CONCLUSIONS: Intratumoral plasmid DNA immunotherapy for head and neck cancer with Allovectin-7 is safe, and further investigations are planned in patients with less advanced disease, where it could potentially improve patient survival and reduce the need for radical high-morbidity treatments.

    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 Nccn Practice Guidelines for Head and Neck Cancers.
    Date March 2001
    Journal Oncology (williston Park, N.y.)
    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 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 Workshop Report: Organ Preservation Strategies in Advanced Head and Neck Cancer--current Status and Future Directions.
    Date December 1999
    Journal Head & Neck
    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 Head and Neck Cancer: Detection of Recurrence with Three-dimensional Principal Components Analysis at Dynamic Fdg Pet.
    Date July 1999
    Journal Radiology
    Excerpt

    Fully automated principal components analysis (PCA) was applied to dynamic 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomographic (PET) images obtained in 15 patients with previously treated head and neck cancer. PCA with time-activity curves incorporated kinetic information about FDG uptake, which improved tissue characterization on FDG PET images. The combination of standardized uptake value and PCA image sets likely will improve the reliability of tumor detection in head and neck cancers.

    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 Incidence and Management of Tension Pneumocephalus After Anterior Craniofacial Resection: Case Reports 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 Long-term Quality of Life After Treatment of Laryngeal Cancer. The Veterans Affairs Laryngeal Cancer Study Group.
    Date September 1998
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To assess long-term quality of life in surviving patients with advanced laryngeal cancer. DESIGN: A follow-up long-term quality-of-life survey of patients randomized to the Veterans Affairs Laryngeal Cancer Study No. 268 on induction chemotherapy and radiation (CT + RT) vs surgery and RT. SETTING AND PATIENTS: Forty-six (71%) of the 65 surviving patients with prior stage III or IV laryngeal cancer who could be contacted completed the survey: 25 from the surgery and RT group and 21 from the CT + RT group. Baseline demographic and clinical characteristics among survey respondents were similar, except that those in the CT + RT group were significantly older (mean, 61.2 years) than those in the surgery and RT group (mean, 55.7 years; P<.05). INTERVENTIONS AND MAIN OUTCOME MEASURES: Patients completed the University of Michigan Head and Neck Quality of Life (HNQOL) instrument, the Medical Outcomes Studies Short-Form 36 (SF-36) general health survey, the Beck Depression Inventory as well as smoking and alcohol consumption surveys. RESULTS: Patients randomized to the CT + RT group had significantly better (P<.05) quality-of-life scores on the SF-36 mental health domain (76.0) than the surgery and RT group (63.0), and also had better HNQOL pain scores (81.3 vs 64.3). Compared with patients who underwent laryngectomy, patients with intact larynges (CT + RT with larynx) had significantly less bodily pain (88.5 vs 56.5), better scores on the SF-36 mental health (79.8 vs 64.7), and better HNQOL emotion (89.7 vs 79.4) scores. More patients in the surgery and RT group (28%) were depressed than in the CT + RT group (15%). CONCLUSION: Better quality-of-life scores in the CT + RT groups appear to be related to more freedom from pain, better emotional well-being, and lower levels of depression than to preservation of speech function.

    Title Functional Outcomes Following Treatment for Advanced Laryngeal Cancer. Part I--voice Preservation in Advanced Laryngeal Cancer. Part Ii--laryngectomy Rehabilitation: the State of the Art in the Va System. Research Speech-language Pathologists. Department of Veterans Affairs Laryngeal Cancer Study Group.
    Date June 1998
    Journal The Annals of Otology, Rhinology & Laryngology. Supplement
    Excerpt

    This two-part investigation assessed functional outcomes related to communication (including amount of speech therapy), swallowing and eating, and employment status for patients who received one of the two treatment modalities for advanced laryngeal cancer (stage III or IV laryngeal squamous cell carcinoma) in Veterans Administration Cooperative Study #268. One hundred sixty-six patients were randomized to primary surgery (laryngectomy) and radiotherapy (RT), and 166 to induction chemotherapy (CT) and RT. The first investigation dealt with examining and comparing functional outcomes for patients in the two treatment arms of the main study. Results showed clearly that patients with advanced laryngeal cancer are better off from the standpoint of speech communication if they can be treated for this disease without removal of the larynx. In contrast, there were few significant differences between patient groups for other non-speech-related measures. The second investigation focused on communication-related outcomes associated with the rehabilitation of total laryngectomy patients. Results revealed that only relatively small percentages of total laryngectomy patients (6%) developed usable esophageal speech or remained nonvocal (8%), and that a majority of patients ended up as users of artificial electrolarynx (55%) or tracheoesophageal (31%) speech. The results from both investigations are discussed with respect to factors that can influence the rehabilitation process and long-term outcome status of patients who are treated for advanced laryngeal cancer with these two strategies.

    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 Planned Early Neck Dissection Before Radiation for Persistent Neck Nodes After Induction Chemotherapy.
    Date September 1997
    Journal The Laryngoscope
    Excerpt

    Optimal management of advanced neck metastases as part of an organ preservation treatment approach for head and neck squamous carcinoma (HNSC) is unclear. Since 1989, our management paradigm for patients on organ preservation was modified to incorporate planned early neck dissection before radiation therapy for patients who did not achieve a complete response (CR) of neck nodes after induction chemotherapy (IC). The purpose of this study was to determine if planned early neck dissection is a safe and effective approach in the management of advanced nodal disease as part of organ preservation. Fifty-eight consecutive patients with advanced HNSC who were entered in organ preservation trials using induction chemotherapy and radiation with surgical salvage were studied. Median follow-up was 26 months. Of the 58 patients, 71% were stage IV. Patients were grouped by nodal response to chemotherapy and N class, and were analyzed with respect to patterns of recurrence, complications, and survival. Overall, the rate of CR of neck nodes was 49%. Fifty-one percent had less than a complete response of neck nodes after IC and required planned early neck dissection. There were no significant differences in patterns of recurrence, complications, interval time to start of radiation, recurrence, or survival rates between the CR and less than CR groups. These data suggest that planned early neck dissection for patients with less than CR in the neck after IC is not detrimental with respect to neck relapse or overall survival. We believe that planned early neck dissection can be safely incorporated into future organ preservation treatment protocols for patients with advanced head and neck carcinoma.

    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 Expression of N-cadherin by Human Squamous Carcinoma Cells Induces a Scattered Fibroblastic Phenotype with Disrupted Cell-cell Adhesion.
    Date January 1997
    Journal The Journal of Cell Biology
    Excerpt

    E-cadherin is a transmembrane glycoprotein that mediates calcium-dependent, homotypic cell-cell adhesion and plays an important role in maintaining the normal phenotype of epithelial cells. Disruption of E-cadherin activity in epithelial cells correlates with formation of metastatic tumors. Decreased adhesive function may be implemented in a number of ways including: (a) decreased expression of E-cadherin; (b) mutations in the gene encoding E-cadherin; or (c) mutations in the genes that encode the catenins, proteins that link the cadherins to the cytoskeleton and are essential for cadherin mediated cell-cell adhesion. In this study, we explored the possibility that inappropriate expression of a nonepithelial cadherin by an epithelial cell might also result in disruption of cell-cell adhesion. We showed that a squamous cell carcinoma-derived cell line expressed N-cadherin and displayed a scattered fibroblastic phenotype along with decreased expression of E- and P-cadherin. Transfection of this cell line with antisense N-cadherin resulted in reversion to a normal-appearing squamous epithelial cell with increased E- and P-cadherin expression. In addition, transfection of a normal-appearing squamous epithelial cell line with N-cadherin resulted in downregulation of both E- and P-cadherin and a scattered fibroblastic phenotype. In all cases, the levels of expression of N-cadherin and E-cadherin were inversely related to one another. In addition, we showed that some squamous cell carcinomas expressed N-cadherin in situ and those tumors expressing N-cadherin were invasive. These studies led us to propose a novel mechanism for tumorigenesis in squamous epithelial cells; i.e., inadvertent expression of a nonepithelial cadherin.

    Title Extranodal Non-hodgkin's Lymphoma of the Head and Neck: Presentation in the Facial Bones.
    Date December 1996
    Journal American Journal of Otolaryngology
    Excerpt

    1. The most common site of ENL is the head and neck, with Waldeyer's ring and specifically, the tonsil, standing as the most frequent area of involvement. Most patients have intermediate or high-grade histologies. 2. Patients present with identical signs and symptoms as squamous cell carcinoma of the head and neck, underscoring the importance of a thorough otolaryngological examination. 3. Biopsy samples should be submitted as fresh and permanent samples specifically labeled for lymphoma evaluation. 4. A thorough and timely staging work-up should be conducted once a positive biopsy diagnosis is obtained. 5. Treatment consists of radiation and/or chemotherapy. Prognosis depends on histology, stage, and site of lesion. Newer treatment strategies may lead to improved survival for patients with head and neck NHL.

    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 Unknown Primary of the Head and Neck.
    Date October 1996
    Journal The Journal of Laryngology and Otology
    Excerpt

    The occurrence of metastases to the cervical lymph nodes from an unknown primary tumour is seen in approximately three to six per cent of patients with cervical adenopathy and the primary tumour commonly remains elusive. Single modality treatment is occasionally advocated but combined treatment seems to obtain the best results. A retrospective analysis of patients' charts with unknown primary of the head and neck in the University of Michigan Medical Center was undertaken for the years 1978-1992. Forty-eight records met study criteria and were reviewed. Our series' size and heterogeneity prevents drawing conclusions regarding treatment effectiveness. The majority (67.5 per cent) of our patients were treated by surgery followed by irradiation. Our overall survival rates compare favourably with the general statistics although it should be noted that longer follow-up in our first group of patients may alter our results. Extracapsular spread did not adversely affect survival in our small series of five cases. We discovered six primary sites within one year and three additional cases within four years. The primary site was included in the radiation fields in all instances of squamous cell tumours that were eventually found. It has been suggested than eventual manifestation of the primary site adversely affects prognosis, which is in agreement with our results.

    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 Regional Metastases in Patients with Advanced Laryngeal Cancer. Department of Veterans Affairs Laryngeal Cancer Study Group.
    Date July 1996
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVES: To determine patterns of regional metastases in patients with advanced squamous cell carcinoma of the larynx and the effect of these patterns on regional and distant tumor recurrence and disease-free and overall survival. METHODS: One hundred fifty-nine patients treated with conventional surgery and radiation in the Veterans Affairs Cooperative Study were studied. Ninety-three of the patients underwent modified or classic radical neck dissection. Median follow-up was 5 years. Patient data collected included age, gender, alcohol consumption, tobacco use, and performance status. Tumor variables evaluated included TNM classification, tumor site, surface area, presence of ulceration and invasion, and histologic growth pattern. Histologically positive regional lymph nodes were examined for level, number, site, and extracapsular spread. Outcome variables included time and location of recurrence, distant metastases, and survival. RESULTS: Regional metastases were more common in supraglottic than glottic or subglottic tumors (P < .001) and in tumors with larger surface dimensions (P = .004). Cervical metastases were associated with decreased disease-free interval (P < .001) and survival (P = .001) and increased distant metastases (P < .001). Presence of 3 or more positive nodes predicted distant recurrence (P < .001) and decreased survival (P < .001, multivariate analysis). An analysis of lymph node involvement (levels I-V) indicated that level 1 and 5 involvement was a significant prognostic factor. Age, sex, race, and tobacco or alcohol use were not associated with number or extent of regional metastases. CONCLUSIONS: These findings confirm the prognostic importance of number and level of lymph nodes in advanced laryngeal cancer. The association of distant metastases with number and level of regional nodes indicates a use for these variables in considering adjuvant chemotherapy.

    Title Elevated Arginine Vasopressin Levels in Squamous Cell Cancer of the Head and Neck.
    Date June 1996
    Journal The Laryngoscope
    Excerpt

    The reported effectiveness of single tumor markers (TMs) associated with squamous cell cancer of the head and neck ranges from 15% to 71%, with most studies reporting sensitivity no higher than 50%. An increased incidence of the syndrome of inappropriate secretion of antidiuretic hormone or arginine vasopressin (SIADH) in patients with head and neck cancer has been reported. Serum arginine vasopressin (AVP) was studied as a possible TM in these patients. Sixty-three patients with squamous cell carcinoma of the head and neck determined as potentially curable were prospectively evaluated before treatment and compared to 17 patients with apparent cure of head and neck squamous cell cancer who served as controls. Serum AVP levels were obtained and determined by radioimmunoassay in the preoperative period and 1 week postoperatively in 15 patients. Thirty-four patients were staged as T4, 26 as T3, and 3 as T2. Twenty-one (33%) of the 63 patients had no neck involvement. Twenty-four (38%) of 63 patients had elevated serum AVP levels corrected for serum osmolarity. Of the 15 patients evaluated before and after surgery, 8 (53%) had elevated serum AVP levels preoperatively. Of these 8 patients, 3 had reduction in AVP levels and 5 had complete normalization after 1 week. The result obtained for serum AVP do not exceed results of other TMs reported. AVP may also not be as specific as other TMs for cancer of the head and neck. Our group with AVP sampled postoperatively is too small for us to draw conclusions, but reduction of its levels after treatment in all patients may be significant. These preliminary results indicate that further evaluation of AVP during the posttreatment course in a larger number of cases, and perhaps with other TMs as well, is warranted.

    Title Fdg Pet Imaging of Paragangliomas of the Neck: Comparison with Mibg Spet.
    Date March 1996
    Journal European Journal of Nuclear Medicine
    Excerpt

    Two patients with cervical paragangliomas underwent positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG). There was marked tumor uptake and retention of FDG. Adjacent salivary gland accumulation of FDG was minimal, though quite prominent with meta-iodobenzylguanidine. FDG PET offers another potentially useful approach to functional imaging of these uncommon tumors, independent of the presence of specific amine uptake mechanisms or cell surface receptors required by other scintigraphic techniques.

    Title Increase in Suprabasilar Integrin Adhesion Molecule Expression in Human Epidermal Neoplasms Accompanies Increased Proliferation Occurring with Immortalization and Tumor Progression.
    Date December 1995
    Journal Cancer Research
    Excerpt

    In a previous prospective study of 80 patients with squamous cell carcinoma of the upper aerodigestive tract, a progressive increase in expression of the integrin cell adhesion molecule alpha 6 beta 4 in suprabasilar cell layers of the tumor parenchyma was associated with an increase in early recurrence after therapy. In this study, we determined the relationship of the altered expression pattern of the integrin to changes occurring during benign, invasive, or metastatic stages of tumor development. Suprabasilar expression of integrin alpha 6 beta 4 appeared with neoplastic transformation in benign squamous papillomas, but homogeneous expression occurred more frequently in the parenchyma of primary and metastatic squamous cell carcinomas. The variation in the extent of suprabasilar integrin expression among the tumors corresponded to the variation in the population undergoing proliferation as determined by two independent markers of proliferation. Integrin expression was quantified in primary, HPV 16 DNA-immortalized, and v-ki-ras oncogene-transformed keratinocytes, and the pattern of expression was compared with cell cycle progression. Primary keratinocyte lines showed a bimodal distribution of integrin expression, with one population showing decreased integrin expression, cell size, and a block of cell cycle progression consistent with differentiation, whereas another population exhibited high integrin expression and full progression through the cell cycle, consistent with proliferation. HPV-immortalized and v-ki-ras-transformed cell lines undergoing continuous proliferation exhibited uniformly strong integrin expression, which was similar in intensity to that observed in the proliferating population of normal keratinocytes. Similar increases in expression of two additional integrins, alpha 2 beta 1 and alpha 3 beta 1, occurred along with integrin alpha 6 beta 4 in tissue specimens and cell lines derived from neoplasms. Thus, epidermal neoplasms display an increase in a population of cells exhibiting constitutive expression of a repertoire of integrins, which is similar to that found transiently in the acute phase of epidermal wound healing, a physiological response in which hyperproliferation, retention of multiple layers of proliferating cells, and migration occur. The association of a progressive increase in suprabasilar expression of these integrins with early tumor recurrence and advanced neoplasia suggests that constitutive expression and function of the same repertoire of integrins may be advantageous, rather than sufficient, for tumor progression.

    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 Induction Chemotherapy for Organ Preservation in Advanced Laryngeal Cancer: is There a Role?
    Date October 1995
    Journal Head & Neck
    Title Organ Preservation in Advanced Head and Neck Cancer.
    Date July 1995
    Journal Cancer Treatment and Research
    Title Eosinophilic Infiltration in Advanced Laryngeal Squamous Cell Carcinoma. Veterans Administration Laryngeal Cooperative Study Group.
    Date May 1995
    Journal The Laryngoscope
    Excerpt

    Tumor-associated tissue eosinophilia (TATE) has been related to prognosis in epithelial cancers, including cancers at several head and neck sites. This study prospectively examined 248 patients with stage III and IV laryngeal squamous cell carcinoma to determine prevalence and potential prognostic significance of TATE. Pretreatment tumor specimens were histopathologically evaluated. Presence and degree of TATE were analyzed with regard to other tumor characteristics, patient characteristics, and outcome criteria. Median follow-up was 48 months. Eosinophilia was found in 22.5% of specimens and was not related to tumor site, stage, patient age or sex, or treatment modality. Overall and disease-free survival rates and response to induction chemotherapy did not differ significantly with respect to TATE. This study represents the first long-term, prospective evaluation of TATE and its prognostic significance in a single head and neck site. Contrary to the findings of earlier preliminary reports, our results suggest that TATE is not a clinical useful prognostic parameter in advanced laryngeal squamous cell carcinoma.

    Title Perilesional Interleukin-2 in the Vx-2 Carcinoma in Rabbits: a Preliminary Investigation.
    Date March 1995
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    Immune system amplification by perilesional injection of interleukin-2 is a promising adjuvant approach for treating squamous cell carcinoma of the head and neck. A pilot study was designed to develop an animal model bearing squamous cell carcinoma in which to test the efficacy of perilesional interleukin-2. Rabbits were inoculated intramuscularly with the papilloma virus-induced squamous carcinoma VX-2 cell line. Tumor regression and host lymphatic response after perilesional interleukin-2 were measured. Variable responses were found. Growth of tumor cells implanted from cell culture was rapid in most animals. Tumor growth was prevented in animals receiving 10,000 units of interleukin-2 per injection initiated 9 days after tumor inoculation. This inhibition approached statistical significance when compared with growth of saline controls. Histologic responses consisted primarily of plasma cell and eosinophil infiltration. The intensity of the inflammatory response did not correlate with interleukin-2 dose. A trend toward enhanced tumor growth was seen with lower doses of interleukin-2 and when interleukin-2 therapy was initiated simultaneously with tumor inoculation. These findings suggest that high-dose recombinant interleukin-2 can prevent tumor growth if initiated after tumor inoculation. Whether this effect was caused by direct tumor cytotoxicity or mediated by the immune system is unclear. These preliminary results underscore the importance of understanding the effects of dose and schedule in the design of immunotherapy models before clinical use.

    Title Surgery After Organ Preservation Therapy. Analysis of Wound Complications.
    Date March 1995
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To determine the incidence and risk factors for the development of major wound complications in patients with squamous cell cancer of the head and neck that require surgical salvage after an initial treatment regimen of induction chemotherapy and definitive radiation therapy for organ preservation. DESIGN: Retrospective survey. SETTING: Academic tertiary care referral center. PATIENTS AND INTERVENTION: The medical records of 96 patients treated with induction chemotherapy followed by definitive radiation therapy were reviewed; 18 of these patients requiring a surgical salvage procedure after completing chemotherapy and radiation therapy and these constituted the study group. MAIN OUTCOME MEASURES: Major wound complications. RESULTS: Major wound complications occurred in 11 (61%) of the 18 patients. Surgical salvage within 1 year of initial treatment had a 77% incidence of major wound complications vs a 20% incidence if performed 1 year after initial treatment. The mean time to resolution of fistulae and flap necrosis was 7.7 months. Two deaths were attributed to major wound complications: one patient had a carotid blowout; one had postoperative pneumonia. CONCLUSIONS: Salvage surgical procedures performed after induction chemotherapy and definitive radiation therapy have a high rate of major wound complications. This should be considered when assessing organ preservation treatment strategies.

    Title Pathologic Quiz Case 2. Burn Scar Carcinoma (bsc).
    Date October 1994
    Journal Archives of Otolaryngology--head & Neck Surgery
    Title Tumor Response, Toxicity, and Survival After Neoadjuvant Organ-preserving Chemotherapy for Advanced Laryngeal Carcinoma. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group.
    Date August 1994
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: In 1984, the Department of Veterans Affairs Cooperative Studies Program began a trial in which patients with resectable squamous cell carcinoma of the larynx were randomized to receive standard surgery followed by radiation therapy or to receive neoadjuvant therapy with cisplatin and fluorouracil (5-FU) followed by radiation therapy for those achieving a greater than 50% tumor response to chemotherapy. This analysis reviews the tumor responses, toxicity, compliance, and long-term survival for those patients randomized to the chemotherapy arm. PATIENTS AND METHODS: One hundred sixty-six patients were randomized to the chemotherapy arm. Standard tumor response data, chemotherapy toxicity, and survival have been examined using standard statistical methods. RESULTS: The high response rates and acceptable toxicity to cisplatin and 5-FU of previously untreated patients were confirmed. Long-term disease-free survival was more likely to occur in patients who achieved a complete response to chemotherapy, particularly in those who had a confirmed histologic response to chemotherapy. Pretreatment histologic growth patterns were highly predictive of responses to chemotherapy. CONCLUSION: Neoadjuvant chemotherapy was well tolerated and did not negatively affect the definitive treatment that followed. The survival of nonresponding patients who underwent prompt salvage surgery was also not impaired. The role of organ preservation should be explored in other head and neck sites.

    Title Recurrent Cytogenetic Abnormalities in Squamous Cell Carcinomas of the Head and Neck Region.
    Date July 1994
    Journal Genes, Chromosomes & Cancer
    Excerpt

    We characterized the breakpoints, gains, and losses of chromosome material in squamous cell carcinomas of the head and neck region from 29 patients. Cell lines were karyotyped in 1/3 of cases, direct preparations or early in vitro harvests in 1/3, and both in 1/3 of cases. GTG-banding was employed in all cases, as were C-banding and RBG- and AgNOR-staining in most. Some tumors were near-diploid and others near-tetraploid, but many had mixed populations, with diploid, tetraploid, and octoploid subclones representing essentially the same karyotypic pattern. The most frequent changes were deletions. Losses affecting 3p13-p24, 5q12-q23, 8p22-p23, 9p21-p24, and 18q22-q23 ranged in frequency from 40% to 60% of tumors. Loss of the short arm of the inactive X occurred in 70% of tumors from female patients, and loss or rearrangement of the Y occurred in 74% of tumors from male patients. Loss of 18q appeared to be associated with short survival, as did the presence of multiple deletions. There was gain (2-5 extra copies) of 3q21-qter, 5p, 7p, 8q, and 11q13-q23 in 28-38% of tumors. Three tumors had an hsr involving 11q13-q21. Gain of material at 11q13 is postulated to be associated with amplification of the PRADI/CCND gene at that locus. A translocation between proximal 1p and either an acrocentric short arm or proximal 8p or 9p was observed in squamous cell carcinomas of the head and neck region but not in female genital tract tumors. No other abnormalities appeared to be site specific, suggesting a pattern of genetic evolution in squamous cell carcinoma that is independent of anatomic site.

    Title Management of an Osteogenic Sarcoma of the Maxilla.
    Date June 1994
    Journal The Annals of Otology, Rhinology, and Laryngology
    Title Dna Content and Regional Metastases in Patients with Advanced Laryngeal Squamous Carcinoma. Department of Veterans Affairs Laryngeal Study Group.
    Date May 1994
    Journal The Laryngoscope
    Excerpt

    Abnormal DNA content of cancer cells in a primary tumor is thought to reflect the altered proliferative capacity of that cancer and overall patient prognosis. Recently, increased DNA content has been associated with early tumor recurrence in patients with advanced laryngeal cancer. To determine if DNA content correlates with a tumor's metastatic behavior, 94 previously untreated patients with stage III (n = 54) or stage IV (n = 40) squamous carcinoma of the larynx were prospectively studied. The adjusted DNA index (aDI) of the primary tumor was measured by computerized cytomorphometry, and correlations with regional metastases, number of positive nodes, extracapsular spread, and pattern of relapse were determined. Median follow-up was 35 months. Of 94 patients, 73 underwent neck dissection. Positive nodes were found in 51 patients (70%) and three or more positive nodes were found in 31 patients (42%). High aDI (> .024) was significantly associated with the presence and number of histologically positive nodes (P = .016). Among patients with high aDI, 19 (50%) of 38 had three or more nodes positive compared to 12 (21%) of 56 of those with low aDI. Median aDI levels in patients with three or more nodes were significantly higher than in patients with 1 or 2 nodes (P = .003). Time to recurrence was shorter in patients with high aDI (P = .0078). These findings provide further evidence that increased DNA content is associated with more aggressive laryngeal cancers having high rates of multiple lymph node metastases and worse overall prognosis.

    Title Intensive Induction Chemotherapy and Radiation for Organ Preservation in Patients with Advanced Resectable Head and Neck Carcinoma.
    Date May 1994
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: We designed a protocol to evaluate the possibility of organ preservation in patients with advanced, resectable carcinoma of the head and neck. The regimen consisted of intensive chemotherapy followed by radiation therapy alone for patients with good response to treatment. The end points of the study were response rate, organ preservation, toxicity, and survival. PATIENTS AND METHODS: Forty-two eligible patients with carcinoma of the oral cavity, oropharynx, hypopharynx, larynx, and paranasal sinuses were enrolled. Induction chemotherapy consisted of three cycles of mitoguazone, fluorouracil (5-FU), and high-dose continuous infusion cisplatin. Patients who had a complete response to chemotherapy, or whose tumor was downstaged to T1N1, were treated with definitive radiation therapy, to a total dose of 66 to 73.8 Gy. Patients with residual disease greater than T1N1 underwent surgery and postoperative radiation. RESULTS: The overall response rate to chemotherapy was 84%, with a 43% complete response rate, and a 68% complete response rate at the primary tumor site. Sixty-nine percent of patients (29 of 42) were initially spared surgery to the primary tumor site, and four of these patients (14%) required neck dissection only, after radiation therapy. These tumor sites included oral cavity, oropharynx, hypopharynx, larynx, and sinuses. Eventually, five of these patients (17%) required salvage surgery and eight patients (28%) had unresectable or metastatic relapses. With a median follow-up duration of 38.5 months, 36% of all patients have had preservation of the primary tumor site and remain disease-free. The median survival duration is 26.8 months. Toxicity was substantial, with a 70% incidence of grade 3 to 4 granulocytopenia and two septic deaths. CONCLUSION: Organ preservation without apparent compromise of survival was achieved in patients with selected nonlaryngeal sites of head and neck carcinoma. Larger site-specific trials with less toxic regimens conducted in randomized fashion are required to extend these data.

    Title Induction Chemotherapy for Organ Preservation in Advanced Squamous Cell Carcinoma of the Oral Cavity and Oropharynx.
    Date May 1994
    Journal Recent Results in Cancer Research. Fortschritte Der Krebsforschung. Progrès Dans Les Recherches Sur Le Cancer
    Title Results of Primary and Adjuvant Ct-based 3-dimensional Radiotherapy for Malignant Tumors of the Paranasal Sinuses.
    Date April 1994
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: This study reports our clinical experience supporting the normal tissue-sparing capability of 3-dimensional (3-D) treatment planning when applied to advanced neoplasms of the paranasal sinuses. METHODS AND MATERIALS: Between 1986 and 1992, computed tomography (CT)-based 3-D radiotherapy was used to treat 39 patients with advanced stage malignant tumors of the paranasal sinuses as all or part of initial treatment. Fifteen unresectable patients were treated with primary radiotherapy to a median prescribed total dose of 68.4 Gy. Twenty-four patients were treated with postoperative adjuvant radiotherapy for close margins (< 5 mm), microscopic or gross residual disease. The median prescribed total doses were 55.8 Gy, 59.4 Gy and 67.8 Gy, respectively. Globe-sparing fields were used in the primary treatment plans of 37 patients (95%). The median follow-up is 4.5 years (range, 19-86 months). RESULTS: For the unresectable patients who were treated with radiotherapy alone, the local control rate at 3 years is 32%. The actuarial overall survivals at 3 and 4 years are 32%. For the patients who received postoperative adjuvant radiotherapy, none of the five patients irradiated for close surgical margins recurred locally. Three of the 14 with microscopic residual (21%) recurred locally at 26, 63, and 74 months from the start of irradiation. Four of the five with gross residual (80%) recurred locally with a median time to recurrence of 2 years. The local control rates at 3 and 5 years for the adjuvant group are 75% and 65%, respectively. The actuarial overall survival at 3 and 5 years are 65% and 60%, respectively. None of the first sites of local disease progression were judged to have occurred outside the high-dose region. There was one case of mild osteoradionecrosis successfully treated with conservative treatment, one case of limited optic neuropathy and one case of possible radiation-induced cataract. There was no blindness related to irradiation. CONCLUSION: This study indicates that computed tomography-based 3-D radiotherapy can preserve critical structures unaffected by tumor invasion and achieve the generally expected local control rates when it is used as all or part of initial treatment for extensive malignant tumors of the paranasal sinus. The presence of gross disease was a major adverse prognostic factor in this study. Additional therapeutic maneuvers are essential to improve the local control and survival rate in patients with advanced paranasal sinus carcinomas.

    Title Dyspnea in a Patient Years After Severe Poliomyelitis. The Role of Cardiopulmonary Exercise Testing.
    Date April 1994
    Journal Chest
    Excerpt

    Dyspnea after polio can occur for a variety of reasons, including neuromuscular disease and upper airway abnormalities resulting from prolonged intubation, including tracheal stenosis, tracheomalacia, and vocal cord paralysis. Routine studies such as spirometry and maximum voluntary ventilation (MVV) measurements can give similar results in these conditions. We present a 50-year-old woman who as a child developed poliomyelitis that required tracheostomy and negative pressure ventilation. Thirty-nine years later, she developed breathlessness with normal spirometry but decreased MVV. The flow volume loop showed flattening of the inspiratory and expiratory limbs, consistent with a fixed upper airway obstruction or neuromuscular weakness. Exercise testing with measurement of exercise flow volume loops and respiratory pressures was performed. The patient was ventilatory limited with increasing end-expiratory lung volume through exercise. Flow volume loops confirmed flow limitation. Respiratory pressures did not change after maximal exercise. Further evaluation confirmed left vocal cord paralysis and tracheomalacia. This patient demonstrates that the causes of dyspnea after poliomyelitis can be multifactorial, and that routine evaluation may fail to elucidate the limiting factor. In this case, exercise testing provided valuable insight into the limiting factor for this patient and provided useful data for counseling and for further management.

    Title Tension Pneumocephalus After Endoscopic Sinus Surgery.
    Date April 1994
    Journal The Annals of Otology, Rhinology, and Laryngology
    Title Clinical Correlates of Circulating Immune Complexes and Antibody Reactivity in Squamous Cell Carcinoma of the Head and Neck. The Department of Veterans Affairs Laryngeal Cancer Study Group.
    Date December 1993
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: To evaluate the correlation between the presence and titer of host-derived antibody reactivity, circulating immune complexes, and clinical course and prognosis in patients with squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: Serum samples, obtained from untreated patients with squamous cell carcinoma of the larynx entered onto a multiinstitutional trial, were evaluated for the presence of elevated circulating immune complexes (221 patients) and host-derived antibody directed against two SCCHN cell lines (107 patients). RESULTS: Patients had significantly elevated levels of circulating immune complexes as measured by C1q binding compared with normal controls. Patients with higher levels of circulating immune complexes were less likely to respond to chemotherapy. No correlations were noted between immune complex levels and stage of disease, nodal status, site of disease, recurrence, or survival. Evaluation of native antibody titers for their relationship to clinical correlates showed no statistically significant associations. In sera subjected to immune complex dissociation, patients with moderately or poorly differentiated tumors had significantly higher antibody titers when compared with patients with well-differentiated tumors. Because marked variation in the increase of antibody titers following immune complex dissociation was noted, the ratio of immune complex-dissociated to native antibody titer was examined. Patients with a high ratio had a lower proportion of complete and partial responses to chemotherapy. CONCLUSION: Our results support the conclusion that the formation of tumor-associated immune complexes in patients with SCCHN is associated with a decreased response to chemotherapy.

    Title Preservation of Parotid Function After External Beam Irradiation in Head and Neck Cancer Patients: a Feasibility Study Using 3-dimensional Treatment Planning.
    Date December 1993
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: Radiation-induced xerostomia is a frequent complication and major cause of morbidity in head and neck cancer patients. The severity of xerostomia is related to radiation dose and the amount of parotid tissue included in the irradiated volume. To reduce this side-effect and preserve salivary function, we have evaluated the use of 3-dimensional (3-D) treatment planning to spare the contralateral parotid gland in twelve patients undergoing radiation therapy for head and neck cancers. METHODS AND MATERIALS: In each case, beam's eye view displays were used to design beam and blocking arrangements that excluded the contralateral parotid. Ten patients were treated with 2 nonopposing oblique fields in the axial and non-axial plane while two patients required a non-axial, non-coplanar 3-field arrangement. These 3-D treatment plans were also compared with conventional 2-dimensional (2-D) plans. The 2-dimensional plans were designed independently of the 3-D treatment planning information using the orthogonal radiographs and hard copies of the computed tomography scans. RESULTS: An average of 1.8% (range, 0-7%) of the target volume was underdosed with the 95% isodose level for the 3-D plans compared with 18.8% (range, 2.0-36.6%) for the 2-D plans. This was due to improved identification of the target volumes and better design of blocked fields with beam's eye view treatment planning. Furthermore, the mean dose to the opposite parotid was 3.9 Gy for the 3-D plans vs 28.9 Gy for the conventional plans. With a minimum follow-up of 4 months, only 2 of 12 patients have complained of a dry mouth. CONCLUSION: These encouraging results suggest that this approach is feasible in many cases. 3-D treatment planning may allow the use of parotid sparing techniques in patients who otherwise would not have been considered candidates using conventional radiotherapy techniques.

    Title Recent Advances in Head and Neck Cancer--larynx Preservation and Cancer Chemoprevention: the Seventeenth Annual Richard and Hinda Rosenthal Foundation Award Lecture.
    Date November 1993
    Journal Cancer Research
    Title Blood Group Antigens and Integrins As Biomarkers in Head and Neck Cancer: is Aberrant Tyrosine Phosphorylation the Cause of Altered Alpha 6 Beta 4 Integrin Expression?
    Date November 1993
    Journal Journal of Cellular Biochemistry. Supplement
    Excerpt

    Head and neck cancer is a capricious disease that varies greatly in its clinical behavior. The development of biomarkers that can distinguish between biologically aggressive and indolent tumors has been a long term goal of our laboratories. Predictive markers applicable to biopsy specimens should facilitate clinical management through early identification of patients at greatest risk for early relapse or metastatic spread. Two prominent cell surface markers that we identified by raising monoclonal antibodies to squamous cell carcinomas are blood group antigens and the A9 antigen/alpha 6 beta 4 integrin. Both of these markers are abnormally displayed in squamous cancers of the head and neck and serve as indicators of early relapse. Loss of blood group antigen expression is a stronger single indicator than is overexpression of the alpha 6 beta 4 integrin. However, use of both markers together is a stronger predictive indicator than is either alone. We know little about the function of the blood group antigens in squamous cells except that the mature antigens are associated with differentiation. Similarly, the function of the alpha 6 beta 4 integrin is also not fully understood. Integrin alpha 6 beta 4 is thought to serve as an extracellular matrix receptor, but its ligand has not been confirmed. In resting epithelium, the alpha 6 beta 4 integrin is polarized to the basal aspect of the basal cell as a component of the hemidesmosome, the anchoring structures of the epithelia. This basal polarization is lost in migrating normal squamous cells and squamous carcinomas. Tyrosine phosphorylation of the beta 4 subunit is absent or greatly reduced in malignant cells and this may be a critical signal for subcellular localization of alpha 6 beta 4 and cell anchoring. On the basis of our current experimental results, we postulate that tyrosine phosphorylation of the beta 4 subunit is a reversible signal that regulates cell migration in normal and malignant cells, and may therefore be an important initial event in the metastatic cascade.

    Title Ionized Serum Calcium Levels Following Combined Treatment for Cancer of the Head and Neck.
    Date September 1993
    Journal The Laryngoscope
    Excerpt

    Thyroid function may be reduced after treatment of cancer of the head and neck, and hypothyroidism is much more common after combination therapy. Whether hypoparathyroidism and subsequent hypocalcemia also occur after such treatment is unknown. Few related studies have been published in which changes in total serum calcium have been studied after cancer treatment with radioactive iodine or external radiation. Twenty-two disease-free head and neck cancer patients were studied, 1 to 3 years after multimodal treatment, to determine if changes in serum ionized calcium levels or thyroid function were present. Our results suggest that parathyroid function, as represented by ionized calcium levels remains normal after multimodality (surgery, radiation and/or chemotherapy) combined treatment.

    Title Dna Content and Tumor Response to Induction Chemotherapy in Patients with Advanced Laryngeal Squamous Cell Carcinoma.
    Date July 1993
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    Recent results indicate that the adjusted DNA Index (aDI), a measure of nuclear DNA content, is a significant prognostic factor for patients with advanced laryngeal cancer treated with surgery and radiation therapy. Because DNA aneuploidy is an indirect measure of the proliferative activity of a cell population, a study was conducted to examine differences in tumor response to induction chemotherapy based on aDI values. Pretreatment tumor specimens were obtained from 50 patients with stage III and IV laryngeal squamous cell carcinoma who underwent induction chemotherapy (cisplatin/5-FU). With the use of computerized cytomorphometry, DNA content and nuclear area were measured and associations with tumor site, stage, chemotherapy response, tumor recurrence, and survival were examined. An elevated aDI was more frequent in patients with a chemotherapeutic response (p = 0.08), and mean aDI was higher among the complete responders. There were no complete responders among patients with a low aDI value (< 0.024). Neither aDI nor nuclear area correlated significantly with organ preservation or patient survival. Our results indicate that a complete response is more likely for patients with tumors with an elevated aDI and that pretreatment aDI may be useful in selecting high-risk patients who might benefit from chemotherapy.

    Title Olfactory Neuroblastoma: the Results of Modern Treatment Approaches at the University of Michigan.
    Date June 1993
    Journal Head & Neck
    Excerpt

    A retrospective study was undertaken to review patterns of treatment and survival for patients with olfactory neuroblastomas at the University of Michigan since the introduction of craniofacial resection in the late 1970s. Recent results were compared to previous reports. Disease-free and overall survival for patients with Kadish stage B tumors were unchanged from prior years. Improvement in both disease-free intervals and overall survival was evident for patients with stage C tumors. Interestingly, in two patients with "unresectable" local disease, complete responses to induction chemotherapy followed by radiotherapy were noted.

    Title Intensive Recombinant Interleukin-2 and Alpha-interferon Therapy in Patients with Advanced Head and Neck Squamous Carcinoma.
    Date April 1993
    Journal Cancer
    Excerpt

    BACKGROUND. Cellular immune deficiency is a consistent finding in patients with advanced head and neck cancer. Interleukin-2 and alpha-interferon are modulators of the immune system. METHODS. Eleven patients with recurrent head and neck cancer were treated in a Phase II study of recombinant human interleukin-2 (rIL-2) and alpha-2a-interferon (Roferon-A, Hoffmann-La Roche, Inc., Nutley, NJ). Each course consisted of rIL-2, 3 x 10(6) U/m2/day, as a continuous intravenous infusion over 24 hours for 4 days, and recombinant alpha-2a-interferon, 5 x 10(6) U/m2/day intramuscularly or subcutaneously daily for 4 days. This treatment was repeated weekly for 4 weeks, and then a second cycle was given after a 2-week break. RESULTS. Two patients (18%) achieved a partial response. Toxic effects were substantial. Three of 11 patients experienced Grade 3 hypotension, 3 patients had Grade 3 oliguria, and Grade 3 fatigue was one of the most common reasons for withdrawal from the study. There were no deaths or need for intensive care monitoring. CONCLUSIONS. In view of the 18% response rate, additional investigation of biologic therapy in advanced head and neck cancer is warranted.

    Title Tumor Antigen Phenotype, Biologic Staging, and Prognosis in Head and Neck Squamous Carcinoma.
    Date November 1992
    Journal Journal of the National Cancer Institute. Monographs
    Excerpt

    Prior studies of alterations in tumor expression of normal blood group antigens and A9/alpha 6 beta 4 integrin, an extracellular matrix receptor, have suggested that these immunohistologic markers reflect the biologic aggressiveness of head and neck squamous carcinomas. To confirm these preliminary observations, prospective long-term follow-up of 82 previously untreated head and neck squamous carcinoma patients was performed. All patients were treated with conventional therapy. Median follow-up was 57 months. Tumor immunohistology for ABH blood group and A9/alpha 6 beta 4 integrin expression was performed and correlated with measures of host cellular immunity, disease-free survival, and overall survival. Loss of blood group expression and high A9/alpha 6 beta 4 integrin expression were each directly related to an increased frequency of early tumor recurrence. The combination of both variables was significantly associated with both disease-free (P = .029) and overall survival (P = .05). Increased expression of A9/alpha 6 beta 4 was associated with impaired T-lymphocyte function (P = .005), and loss of blood group expression was associated with decreased peripheral blood levels of CD8+ T-lymphocytes (P = .013). The findings suggest that these phenotypic characteristics of antigen expression in head and neck squamous carcinomas are important markers of biologically aggressive cancers and impaired host immune response. The clinical use of these biologic staging parameters in the initial assessment of patients should allow selection of more aggressive primary treatment strategies for individual patients.

    Title Regulation of Expression and Phosphorylation of A9/alpha 6 Beta 4 Integrin in Normal and Neoplastic Keratinocytes.
    Date November 1992
    Journal Journal of the National Cancer Institute. Monographs
    Excerpt

    The A9 antigen is a basement membrane antigen of normal squamous epithelial cells that is strongly expressed in many squamous carcinomas. High expression of this antigen is associated with early relapse in squamous cell carcinomas of the head and neck. We now know that the A9 antigen is structurally, immunologically, and functionally similar to the alpha 6 beta 4 integrin that has been shown to be linked to metastatic behavior in murine tumor models. The alpha 6 and beta 4 genes have been cloned and sequenced, and a model has been constructed from the deduced amino acid composition. In this study we present a hypothetical model and use it to design experiments to assess the factors that influence the expression of the A9/alpha 6 beta 4 integrin in normal and malignant keratinocytes. High calcium induces down regulation of A9/alpha 6 beta 4 antigen in normal but not malignant keratinocytes within 24 hours. Although calcium can down-regulate beta 4 message in tumor cells in the absence of epidermal growth factor (EGF), transcription of beta 4 increased in the tumor cells under the conditions we used for assessing antigen expression (calcium plus EGF). Retinoic acid also stimulated transcription of beta 4 in tumor cells, but this was partially inhibited by the presence of high calcium. Phosphorylation of the beta 4 chain was stimulated by epidermal growth factor and calcium in normal keratinocytes, but in the malignant cells phosphorylation was constant regardless of the culture conditions. Our results indicate that high expression of the alpha 6 beta 4 integrin is associated with conditions that favor migration and undifferentiated proliferation of normal keratinocytes and that malignant keratinocytes differ from normal keratinocytes by constitutive phosphorylation of beta 4 and by failure to downregulate beta 4 transcription in response to calcium in the presence of EGF.

    Title Effectiveness of Salvage Neck Dissection for Advanced Regional Metastases when Induction Chemotherapy and Radiation Are Used for Organ Preservation.
    Date September 1992
    Journal The Laryngoscope
    Excerpt

    The recently completed VA Cooperative Study (CSP #268) of induction chemotherapy (cisplatin/5-FU) and definitive radiation (6600 to 7600 cGy) for organ preservation in advanced (stage III or IV) laryngeal cancer demonstrated that, although larynx preservation could be achieved in 64% of randomized preservation could be achieved in 64% of randomized patients, overall survival rates were not improved over conventional treatment (surgery/postoperative radiation). Of 166 patients randomized to induction chemotherapy, 46 had N2 or N3 disease and were analyzed to determine the effectiveness of the organ preservation treatment strategy on control of neck disease and survival. The clinical response of neck metastases to induction chemotherapy was significantly associated with subsequent salvage neck dissection (P = .008). The overall death rate was increased (P = .014) and survival time decreased in patients with less than a complete response in the neck after chemotherapy (P = .15). This was related primarily to failure to control the disease in the neck. The overall survival of patients achieving a complete response in the neck was improved over the randomized group of N2 or N3 patients treated with primary surgery. The findings suggest that response of neck nodes should be assessed independently of primary tumor response in trials of organ preservation strategies using induction chemotherapy, and that failure to achieve a clinical complete response in the neck warrants planned early salvage neck dissection in order to achieve improved overall survival.

    Title Cervical Metastatic Glioblastoma Multiforme.
    Date August 1992
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    Glioblastoma multiforme is an anaplastic neoplasm of glial origin. In spite of the aggressive histologic features and poor prognosis, metastasis outside the cranial vault is distinctly unusual. A patient with glioblastoma multiforme metastatic to the neck is presented. We also review the topic of metastatic intracranial tumors.

    Title Dna Content and Histologic Growth Pattern Correlate with Prognosis in Patients with Advanced Squamous Cell Carcinoma of the Larynx. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group.
    Date July 1992
    Journal Cancer
    Excerpt

    BACKGROUND. Alterations in DNA content, nuclear morphologic characteristics, and histologic grading have been associated with prognosis in several types of solid malignant neoplasms. METHODS. To determine the potential usefulness of these factors in predicting tumor behavior in patients with laryngeal squamous cell carcinoma, tumor specimens from 88 previously untreated patients with Stage III or IV cancers were studied. The DNA content and nuclear area (NA) were measured for individual nuclei of each tumor with the use of Azure A-stained frozen sections. An adjusted DNA index (aDI) for each patient was calculated from the slope of the linear regression analysis of nuclear DNA index on NA. Hematoxylin and eosinstained sections were examined and graded systematically for histologic growth pattern. All patients were enrolled in a prospective clinical trial and had laryngectomy and postoperative radiation therapy. RESULTS. The disease-free survival length was longer and the relapse rates were lower in patients with a low aDI (P less than 0.005) and with tumors exhibiting low-grade growth patterns (P less than 0.001). CONCLUSIONS. These parameters were independent of staging variables and were better predictors of tumor relapse than traditional clinical staging classifications.

    Title Signet-ring Cell Adenocarcinoma Metastatic to the Maxillary Sinus.
    Date July 1992
    Journal Oral Surgery, Oral Medicine, and Oral Pathology
    Excerpt

    Signet-ring cell variant is a rare type of adenocarcinoma that has been reported in the paranasal sinuses and in other areas, most commonly the gastrointestinal tract. We describe a patient with signet-ring cell adenocarcinoma of the maxillary sinus who had dental and facial pain. Further evaluation revealed that the lesion was metastatic from an esophageal primary lesion. The unusual nature of this cell type and the importance of careful evaluation to exclude the possibility of these lesions representing metastatic lesions is discussed.

    Title Predictive Value of Objective Esophageal Insufflation Testing for Acquisition of Tracheoesophageal Speech.
    Date July 1992
    Journal The Laryngoscope
    Excerpt

    This prospective study was undertaken to assess the predictive value of esophageal insufflation on the acquisition of tracheoesophageal (TE) speech. Fourteen total laryngectomy patients were evaluated prior to tracheoesophageal puncture (TEP) using objective esophageal pressure measurements. These patients then were followed prospectively for 6 to 13 months. Speech was assessed at the time of prosthesis fitting, at 1 month, at less than 6 months, and at greater than 6 months post-TEP. No patient underwent pharyngeal myotomy. Pre-TEP esophageal insufflation pressure was associated (P = .065) with successful TE speech at the time of prosthesis fitting, but was not associated with successful TE speech acquisition after 6 months. This study's results suggest that patients with poor pre-TEP esophageal insufflation test results will usually obtain successful TE speech given adequate time and training, even without pharyngeal myotomy.

    Title Intracellular Calcium Changes Associated with in Vitro Lymphokine-activated Killer and Natural Killer Cell Cytotoxicity.
    Date January 1992
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    Interleukin 2-activated peripheral blood lymphocytes (lymphokine-activated killer [LAK] cells) have been shown to lyse tumor cells in a nonspecific fashion. Although the mechanisms involved in this cell-mediated lysis are unknown, previous work has shown that T-lymphocyte-mediated cytolysis is associated with massive fluctuations in the intracellular calcium concentration within target cells. Studies were undertaken to determine whether intracellular calcium concentration changes were associated with LAK-mediated cytotoxicity and to determine the effects of calcium channel blockade on in vitro cell-mediated cytotoxicity. Natural killer (NK) and LAK cell cytotoxicity in vitro were measured against head and neck squamous cell carcinoma (UMSCC-11a and UMSCC-38) and Daudi cell lines. Assays were performed in parallel with flow cytometry to measure changes in intracellular calcium concentration within the target cells. Compared with NK cells, LAK cells showed enhanced cytotoxicity against the UMSCC-11a and Daudi lines but not the UMSCC-38 cell line. Both NK and LAK cell cytotoxicity against all the target cell lines directly paralleled significant increases in calcium concentration in the target cells. The addition of verapamil hydrochloride inhibited the rise in intracellular calcium concentration in the sensitive target cells and significantly inhibited both NK and LAK cell cytotoxicity in all the cell lines. The NK cell activity was more sensitive than LAK cell activity to verapamil inhibition. These data suggest that changes in the target cell calcium concentration are early and important events in both NK and LAK cell cytotoxicity in vitro.

    Title Palatal Inclusion Cyst: an Unusual Complication of Uvulopalatopharyngoplasty.
    Date December 1991
    Journal Ear, Nose, & Throat Journal
    Excerpt

    Inclusion cyst formation after uvulopalatopharyngoplasty has not been previously reported. We describe a case of postoperative inclusion cyst in a 62-year-old man who presented with recurrent obstructive sleep apnea symptoms. Simple transoral excision of the cyst was curative. Careful eversion of the mucosal edges at the time of the original palatal surgery may have prevented this problem from occurring.

    Title Organ Preservation in Multimodality Therapy of Head and Neck Cancer.
    Date October 1991
    Journal Hematology/oncology Clinics of North America
    Excerpt

    Several conclusions can be drawn from the studies that have been done to evaluate induction chemotherapy and organ preservation. These principles can serve as the foundation for the design of future trials for organ preservation. 1. The addition of chemotherapy to surgery/radiation for advanced head and neck cancer has not improved overall patient survival. 2. Surgery and radiation therapy can safely and effectively be given after chemotherapy to patients who have had induction chemotherapy. 3. Neoadjuvant chemotherapy followed by definitive radiation therapy can achieve laryngeal preservation in a high percentage of patients, without compromise of survival. 4. In order to change the standard of care, organ preservation trials must be conducted in a randomized, prospective fashion. 5. Organ preservation trials must be conducted for specific sites and stages of head and neck cancer. 6. All patients with nonlaryngeal head and neck cancer who are treated with induction chemotherapy for organ preservation should be treated within a protocol setting.

    Title In Vitro Radiation Resistance Among Cell Lines Established from Patients with Squamous Cell Carcinoma of the Head and Neck.
    Date June 1991
    Journal Cancer
    Excerpt

    Twenty-five squamous cell carcinoma (SCC) cell lines from 20 patients with head and neck cancer were assessed for radiosensitivity in vitro using a 96-well plate assay. Four non-SCC lines were also tested. Radiation sensitivity of individual cell lines was compared using the area under the survival curve (AUC) as a measure of the mean inactivation dose. Tumor lines were tested with either a cobalt-60 (60Co) gamma-irradiator having a dose rate of 100 cGy/minute or with a 4-meV photon beam having a dose rate of 200 cGy/minute. The mean AUC of the 25 SCC cell lines was 188 +/- 7 (SEM) cGy (range, 100 to 250 cGy) whereas the four non-SCC lines had a mean AUC of 225 +/- 9 cGy. The SCC cell lines with mean inactivation dose values greater than 188 cGy were classified as relatively radioresistant whereas those with values less than 188 cGy were considered relatively radiosensitive. In seven cases SCC cell lines were derived from patients who had already received radiation therapy. In four of these cases the tumor cell lines were radioresistant (AUC, 210 to 250) but in the other three cases the tumor lines were radiosensitive (AUC, 160 to 180). Thus, failure of a tumor to respond to radiation did not always select for radioresistant cells. The mean of the AUC for cell lines from previously irradiated patients (197 +/- 11 cGy) did not differ significantly from that of the cell lines from patients who received no prior radiation therapy (182 +/- 9 cGy). However, among radiation-resistant lines those from the four previously irradiated patients were significantly more resistant (mean AUC = 235 +/- 9) than seven other radioresistant lines from nonirradiated patients (mean AUC, 208 +/- 4) (P = 0.0194). In four cases more than one cell line was derived from different tumor specimens in the same patient. In each of these cases the lines from the same patients were similar to one another in their degree of radioresistance. Based on these observations the authors conclude that the degree of in vitro radiation resistance is an inherent property of some squamous cell tumors.

    Title Altered Antigen Expression Predicts Outcome in Squamous Cell Carcinoma of the Head and Neck.
    Date October 1990
    Journal Journal of the National Cancer Institute
    Excerpt

    Monoclonal antibody UM-A9 identifies an antigen found on the basal surface of epithelial cells and expressed on all of the squamous cell carcinomas (SCC) that we have tested. In a previous study, we showed that cell lines from metastatic or recurrent SCC exhibit stronger expression of the A9 cell membrane antigen than cell lines from the primary tumor of the same donors, suggesting that this marker is associated with tumor progression. Loss of expression in tumor tissue of normal A, B, and H (ABH) blood group antigens has also been linked to clinical behavior in some epithelial cancers. To determine the prognostic significance of these antigen markers, we prospectively evaluated tissue specimens for expression of these markers in a group of 82 consecutive, previously untreated patients with SCC of the head and neck. Three patterns corresponding to strong (pattern 1), intermediate (pattern 2), or weak (pattern 3) A9 antigen expression were observed. Fifty-eight percent of the patients whose tumors had pattern 1 A9 antigen expression and 78% of the patients with loss of blood group antigen had early relapse, compared with only 34% of those with A9 antigen pattern 2 or 3 (P = .042) and 37% of those whose tumors expressed the mature ABH blood group antigen (P = .012). The combination of A9 pattern and ABH blood group antigen expression in tumor tissue was the variable most strongly associated with duration of disease-free survival, even after adjustment for the traditional prognostic factors of tumor site, stage, and TNM classification. Loss of blood group was the most significant single variable associated with early recurrence, but among patients whose tumors retained ABH blood group antigen expression, the A9 pattern distinguished good and poor prognostic groups. To our knowledge, our study is the first to demonstrate that differences in blood group antigen expression are significantly correlated with disease-free survival in SCC of the head and neck. We have initiated a study (a) to determine the relationship of the A9 antigen and the blood group antigens with clinical response of the tumors and (b) to determine whether these markers should be used as prognostic indicators.

    Title Circulating Immune Complexes in Patients with Nasopharyngeal Carcinoma.
    Date April 1990
    Journal The Laryngoscope
    Excerpt

    Studies of the serum of patients with nasopharyngeal carcinoma (NPC) demonstrate increased levels of immunoglobulins (Igs), Epstein-Barr virus (EBV) antibodies, and specific immunosuppressive acute-phase proteins (haptoglobin, alpha 1-acid glycoprotein). Recent correlations of the levels of acute-phase and immune-reactive proteins with tumor extent, immune reactivity, and circulating immune complex (CIC) levels in patients with head and neck squamous carcinoma prompted an investigation of the relationship of CICs to those protein factors characteristically altered in the serum of patients with NPC. In 70 untreated NPC patients and 21 normal participants, levels of CIC, Igs, immune-reactive proteins, and EBV antibody titers were measured and correlations with tumor extent and clinical stage determined. In patients with advanced tumors (stages III and IV), levels of CIC, immunoglobulin A (IgA), immunoglobulin M (IgM), and acute-phase proteins (haptoglobin, alpha 1-acid glycoprotein, alpha 1-antitrypsin) were significantly increased compared to stage I, stage II patients, or normals. In patients with elevated CIC levels, levels of IgA and IgM were significantly increased compared to normals or patients with normal CIC levels. Uniquely, serum IgA levels correlated directly with CIC levels among patients but not controls. EBV antibody titers were increased in the NPC patients and were not significantly related to tumor extent or CIC levels. The immunosuppressive properties of CICs might account, in part, for the immune suppression previously reported in patients with NPC. Thus, the increased levels of CICs demonstrated in these patients provide a rationale for evaluating the effects of removing CICs, since such therapeutic manipulations have been associated with tumor regressions in patients with other tumor types.

    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 Tamoxifen Therapy in Patients with Recurrent Laryngeal Squamous Carcinoma.
    Date January 1990
    Journal The Laryngoscope
    Excerpt

    Twelve patients with recurrent, advanced laryngeal carcinoma were treated with tamoxifen hormonal therapy. Rationale was based on previous in vitro data identifying estrogen receptors and progesterone receptors in some laryngeal carcinoma cell lines. Four patients received tamoxifen, 10 to 20 mg by mouth twice a day; eight received 40 mg by mouth four times a day. The drug was well tolerated at all dose levels. There were no clinical responses. Two patients' tumor tissue was assayed for estrogen and progesterone receptors. One was negative for both, and the other was indeterminate for estrogen receptors and negative for progesterone receptors. A review of literature and a discussion of the possible reasons for the negative results are presented.

    Title Interleukin 2 Receptor Expression in Patients with Head and Neck Squamous Carcinoma. Effects of Thymosin Alpha 1 in Vitro.
    Date November 1989
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    Altered cellular immunity in patients with advanced head and neck cancer includes impairments in lymphokine production, blastogenesis, in vitro cytotoxicity, and T-cell levels. Recent evidence for the potential importance of in lymphokine interleukin 2 (IL-2) in patients with cancer prompted a study of the kinetics of IL-2 receptor expression on lymphocytes from patients with untreated advanced head and neck cancer and normal subjects and an evaluation of the in vitro effects of the T-cell immune-reconstituting peptide, thymosin alpha 1. Concanavalin A-stimulated IL-2 receptor expression was maximal after 72 hours and was higher in normal subjects than in patients. This was due to lower levels of helper/inducer (CD4) cells expressing IL-2 receptors in the patients compared with the normal subjects. Thymosin alpha 1 further decreased levels of IL-2 receptor-positive (both CD4 and CD8) cells at 48 and at 72 hours. At 96 hours, levels of IL-2 receptor-positive cells and proportions of cells in G2 and M phases of the cell cycle were similar among both groups of subjects. Simultaneous cell kinetic studies indicated that thymosin alpha 1 down regulation of IL-2 receptors was not due to an effect on proliferation and that differences in IL-2 receptor expression at 72 hours among normal subjects and the patients with cancer were more likely related to differences in cell proliferation kinetics.

    Title Monocytes and Impaired Leukocyte Migration Inhibitory Factor Production in Head and Neck Squamous Carcinoma.
    Date May 1989
    Journal Head & Neck Surgery
    Excerpt

    Impaired cell-mediated immunity has been consistently associated with head and neck squamous carcinoma (HNSC). Previous work has implicated monocytes in this impairment. The present study shows that in a subgroup of untreated patients with advanced HNSC, monocytes are responsible for impaired in vitro lymphokine (leukocyte migration inhibitory factor) production. In view of recent studies suggesting interactions between lymphokines and monocytes in the immune response, the present findings may be relevant to future immunotherapeutic approaches.

    Title Labyrinthine Functional Tests and a Case of Midline Cerebellar Teratoma.
    Date April 1989
    Journal The American Journal of Otology
    Excerpt

    Electronystagmographic (ENG) examination may indicate clinically abnormal but nonspecific or even diagnostically deceptive results. Insights into the processes producing such observations sometimes can be suggested from correlations of findings to pathologic conditions in cases of demonstrated vestibular lesions. Such an opportunity occurred when unusual ENG results were obtained from a patient who had a history of equilibrium disturbances. The ENG revealed a direction-changing nystagmus in lateral head and body positions but not with the head similarly turned. Ocular counterroll measurements indicated hypofunctioning otolithic reactions despite normal vestibuloocular responses to calorizations. Radiologic follow-up showed a midline cerebellar tumor, later surgically confirmed, and found to be a rare teratoma. After partial excision and decompression, repeat tests revealed changes in both the positional nystagmus and ocular counterroll. These findings have implications for diagnosis, for mechanisms underlying ataxia, for inclusion of ocular counterroll testing in diagnostic evaluations, and for understanding the mechanisms underlying direction-changing positional nystagmus.

    Title Cisplatin and Mitoguazone. An Induction Chemotherapy Regimen in Advanced Head and Neck Cancer.
    Date December 1988
    Journal Cancer
    Excerpt

    The combination of cisplatin 100 mg/m2 every 3 weeks and mitoguazone 500 mg/m2 every week with dose escalation was administered as a 9-week induction regimen to 27 patients with previously untreated Stage III or IV squamous cell carcinoma of the head and neck. This was followed by full-course radiation therapy for unresectable patients or surgery and postoperative radiation therapy for those with resectable disease. Sixteen patients had bulky unresectable disease, and ten were candidates for curative resection at study entry. Of 26 patients evaluable for response to chemotherapy, there were seven complete responses (CR) (five of six pathologically confirmed) and ten partial responses (PR) (65% CR + PR). Toxicity was generally mild with Grade 3 or 4 nausea and vomiting occurring in 15% and diarrhea in 12%. Nineteen percent of the patients developed transient nephrotoxicity (serum creatinine greater than 2), 62% anemia (hemoglobin decrease greater than 2 g/dl), 23% leukopenia (leukocyte count less than 3500 cells/microliters) and 8% thrombocytopenia (platelets less than 50,000 cells/microliters). Anorexia, fatigue, and weight loss occurred in nearly all patients. The median survival time of all patients was 17.5 months; complete responders, 43 months; partial responders, 16 months; and nonresponders, 9 months (P = 0.0025). In a multivariate analysis of stage, primary site, resectability status, response to chemotherapy, and local treatment (surgery plus radiation versus radiation), complete response was the only statistically significant covariate for survival. In Phase II single agent trials, mitoguazone has been shown to have a 15% response rate in head and neck cancer and cisplatin, a 30% to 40% response rate (less than 10% CR). Thus, our results, both complete and overall response rates, were higher than would be expected from either drug alone. A possible mechanism for this high response rate may be mitoguazone-induced cell synchronization. In vitro studies demonstrate the accumulation of tumor cells exposed to mitoguazone in S- and G2-phases of the cell cycle. These results would support further evaluation of mitoguazone in combination to explore the theoretical potentiation of antitumor effects by sequencing with cycle-specific agents.

    Title In Vitro Immune Modulation by Thymosin Alpha 1 in Patients with Head and Neck Squamous Cell Carcinoma.
    Date May 1988
    Journal Head & Neck Surgery
    Excerpt

    To determine if patients with head and neck squamous cell carcinoma represent an appropriate population for immune reconstitution with thymosin alpha 1, leukocyte migration inhibition (LMI) in response to phytohemagglutinin was measured in 24 previously untreated patients with head and neck cancer, and the in vitro effects of thymosin alpha 1 on migration inhibition were assessed. Compared to normal subjects, LMI was impaired in the head and neck cancer patients. Thymosin alpha 1, in vitro, was associated with improvement in LMI in the cancer patients. Improvements in migration response with thymosin alpha 1 appeared to be independent of levels of various T-lymphocyte subpopulations. However, patients with a normal LMI response had lower suppressor/cytotoxic cell levels than normal subjects or patients with impaired LMI. The findings confirm prior reports of the effects of thymic hormones on lymphokine production in vitro and provide rationale for further clinical studies of thymosin alpha 1 in patients with head and neck squamous cell carcinoma.

    Title Flow Cytometry: Dna Analysis of Squamous Cell Carcinoma of the Upper Aerodigestive Tract.
    Date February 1988
    Journal The Journal of Otolaryngology
    Excerpt

    The flow cytometer is capable of analyzing a large number of cells or cell nuclei. The flow cytometer has been used to analyze the DNA content of tumor cells from squamous cell carcinomas of the upper aerodigestive tract using a modification of the Vindelov staining procedure. The main difficulty in analyzing solid tumors using flow cytometry technology is the disaggregation of the cells and the quantification of the diploid point (2N point). A set of internal standards was developed for establishing the 2N point, as well as a technique for disaggregation, which is described. A histogram characteristic of a more aggressive squamous cell carcinoma which tends to recur more quickly and more frequently than the other squamous cell carcinoma histogram types was identified. The flow cytometer proved to be a practical method of analysis allowing for quantitative measurement of DNA content from a large number of cells originating from a squamous cell carcinoma. The trend between recurrence and histogram type will require further study.

    Title Alterations in T-lymphocyte Subpopulations in Patients with Head and Neck Cancer. Correlations with Prognosis.
    Date November 1987
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    Impaired cell-mediated immunity has been consistently demonstrated in patients with advanced head and neck squamous cancer (HNSC); however, the results of prior studies of correlations of cellular immune parameters with treatment outcome have been inconsistent, and routine assessment of immune parameters has been of limited clinical use. To determine the prognostic importance of alterations in the proportions of various T-lymphocyte subpopulations in the peripheral blood of patients with HNSC, levels of T3, T4, T6, T8, T9, T10, T11, and Leu 7 cells were quantitated by flow cytometry in 80 previously untreated patients and prospectively correlated with tumor characteristics and clinical course (median length of follow-up, 27 months). The mean helper/suppressor cell ratio (T4/T8) increased progressively with increasing tumor stage and was significantly elevated among patients with cancer as a group and in patients with advanced (stage III or IV) disease compared with 40 normal subjects. Decreased disease-free survival was significantly associated with elevated T4/T8 ratios and low percent T8 and T11 cell levels. The prognostic significance of percent T8 (cytotoxic/suppressor) cell levels persisted even after adjusting for known prognostic factors of tumor stage, T class, N class, and tumor site. These correlations provide new insight into immune alterations in HNSC that may prove useful in identifying patients with early clinical disease who have a poor prognosis.

    Title Carcinoid (neuroendocrine Carcinoma) of the Larynx.
    Date July 1987
    Journal The Annals of Otology, Rhinology, and Laryngology
    Excerpt

    Carcinoid of the larynx is a rare aggressive malignancy with few long-term survivors. Three cases of laryngeal carcinoid treated at the University of Michigan and 23 cases reported previously are reviewed. The clinical behavior, patterns of metastasis, and response to therapy were analyzed to determine optimal therapeutic evaluation and treatment strategies. Patient survival did not correlate with clinically evident regional adenopathy, length of symptoms, extent of laryngeal surgery, or retrospective staging according to American Joint Committee guidelines on cancer of the larynx (AJC-1980). Distant metastatic spread occurred frequently and was the most common cause of death. Surgical therapy is currently the only effective treatment for primary or recurrent disease. Future treatment regimens must address distant spread of tumor.

    Title Expression of A9 Antigen and Loss of Blood Group Antigens As Determinants of Survival in Patients with Head and Neck Squamous Carcinoma.
    Date July 1987
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    The murine monoclonal antibody (A9), raised to the human squamous cell carcinoma (SCC) cell-line UM-SCC-1, defines a squamous cell antigen associated with aggressive biologic behavior of SCC cell lines in vivo and in vitro. In the present investigation, A9 antigen was detected in tissue sections from 37 consecutive, previously untreated patients with SCC of the head and neck. All tumors were positive for A9 binding, although three distinct patterns (reflecting different intensities of A9 expression) were identified. The intensity of A9 expression was independent of primary tumor site, tumor differentiation, keratinization, or growth pattern. The frequency of high expression (Pattern 1) grew with increasing T class, N class, and tumor stage, and was associated with loss of blood group expression in the tumor and with low levels of lymphocyte infiltration in the tumor. Strong A9 expression had a statistically significant association with low nuclear grade (i.e., tumors with more mature and fewer enlarged nuclei, P = 0.019), low vascular/stromal response (i.e., patchy response rather than continuous, P = 0.014), and impaired in vitro lymphokine production by peripheral blood leukocytes (P = 0.0011). Of greatest interest, however, was the strong association of high A9 expression with shortened disease-free interval (DFI) (P = 0.085) and survival (P = 0.081) relative to patients with weak A9 tumor staining (Patterns 2 and 3). Similarly, the loss of blood group antigen expression was strongly associated with decreased DFI (P = 0.038) and survival (P = 0.062). While neither Pattern 1 A9 expression nor loss of blood group reach statistical significance in prediction of survival, the combination of Pattern 1 A9 expression and loss of blood group expression in primary tumors was significantly associated, both with decreased disease-free interval (P = 0.017) and with decreased overall survival (P = 0.011) (median length of follow-up = 22 months). The length of follow-up (LFU) ranged from 2 to 38 months, with a median LFU of 22 months. While the number of patients (37) is small, the significant association between the expression of these cell-surface markers with relapse and survival indicates that immunohistologic staining of the primary tumor will be an important prognostic indicator useful in identification of individual patients at greatest risk of recurrence or early death from head and neck cancer, independent of tumor size, site, or stage at presentation. These markers may thus provide means of selecting patients who should receive adjuvant therapy and more intensive monitoring for the early detection of recurrent disease.

    Title Lymphocyte Subpopulations Infiltrating Squamous Carcinomas of the Head and Neck: Correlations with Extent of Tumor and Prognosis.
    Date June 1987
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    Because little is known about the mechanisms involved in local tumor-host immune reactions in squamous carcinoma of the head and neck, a study was undertaken to better characterize the types of immune cells present at the local tumor site and determine their relationship to tumor extent, systemic cellular immune parameters, and clinical outcome. In 40 untreated patients, lymphocyte subsets (LS) at the tumor-host interface were quantitated immunohistologically from serial sections of frozen tumor specimens and correlated with concurrently measured peripheral LS levels and in vitro lymphocyte reactivity to phytohemagglutinin (PHA). The majority of infiltrating lymphocytes were T cells with rare B or Leu 7 cells. Proportions of T4 and T8 were similar in peritumor stroma; however, T8 cells predominated tumor parenchyma. Stromal and parenchymal infiltration by LS were not related to peripheral blood LS levels, lymphocyte reactivity, or tumor site. However, parenchymal T11 and T4 cell infiltration was less in advanced primary tumors (T3, T4) than in early tumors (T1, T2) (P = 0.01, P = 0.067, respectively), as was peripheral lymphocyte reactivity to PHA (P = 0.013). Short-term disease-free interval and actuarial survival differed significantly--according to parenchymal T11 and T4 cell infiltration--and were not related to T8, Leu 7, and B-cell infiltration. The findings extend prior studies of lymphocytic infiltration in head and neck cancer and demonstrate the potential importance of differences in tumor stromal and parenchymal infiltration. Together with recent evidence that T4 cells are critical for lymphokine production and for the proliferation of cytotoxic effector cells, the current results suggest that T4 cells play a critical role in the local immune response in squamous carcinoma of the head and neck.

    Title High-dose Cisplatin in Advanced Head and Neck Cancer.
    Date June 1987
    Journal Cancer Chemotherapy and Pharmacology
    Excerpt

    In 22 patients with advanced squamous cell carcinoma of the head and neck we evaluated the efficacy and toxicity of 200 mg/m2 cisplatin administered in 3% NaCl with vigorous hydration. Six patients had previously untreated stage IV disease and 16 patients had recurrent disease, including eight with prior chemotherapy including low-dose cisplatin and carboplatin. Cisplatin was administered as a brief infusion, either 40 mg/m2/day X 5 or 50 mg/m2/day X4, every 28 days. Objective responses were observed in 16 of 22 (73%) patients, including 5 of 6 (83%) previously untreated patients and 11 of 16 (69%) patients with recurrent disease. This included two complete responses, one confirmed pathologically. Fifty-seven courses of drug were administered and toxicity was monitored with serial creatinine clearance determinations, audiograms, and sensorimotor exams. Neuropathy and ototoxicity were dose-limiting and led to the stopping of treatment in 12 of the 16 responders after one to four courses (median three courses). Only two responding patients continued treatment until disease progression occurred at 3 and 4 months after achieving maximum response. Acute, transient nephrotoxicity occurred in four patients; two were retreated. Moderate myelosuppression occurred in all patients but was not treatment-limiting. For most patients the maximally tolerated number of courses was three. The median survival time was 33.5 weeks for recurrent disease patients, 108 weeks for newly diagnosed patients. This regimen is not recommended for the palliation of recurrent disease. However, the very high response rate suggests that high-dose cisplatin may have a useful role in induction or adjuvant chemotherapy regimens.

    Title Small Cell Carcinoma of the Head and Neck.
    Date February 1987
    Journal Head & Neck Surgery
    Excerpt

    Treatment methods for patients with small cell carcinoma of the head and neck are changing. Increasing clinical experience with these tumors and a better appreciation of patterns of recurrence, the need for thorough tumor staging, and the importance of chemotherapy as a form of primary therapy have contributed to these changes. Current concepts regarding small cell carcinoma arising in the head and neck are reviewed. Reported results of treatment for a variety of head and neck sites and site-specific relapse rates are summarized. New cases of small cell carcinoma arising in the hypopharynx, paranasal sinus, and from an unknown primary are added to the reported experience in the literature.

    Title Eikenella Corrodens As a Cause of Recurrent and Persistent Infections of the Head and Neck.
    Date February 1987
    Journal American Journal of Otolaryngology
    Excerpt

    Four patients had Eikenella corrodens infections involving the head and neck in different ways. The organism is discussed as a pathogen in mixed infections and as the predominant organism in other processes. As part of the resident microflora of mucous membrane surfaces, it is an important potential pathogen in a number of otolaryngologic clinical settings. Careful microbiological culturing and susceptibility testing reveal the causative organism and guide the antibiotic therapy.

    Title Small Cell Carcinoma of the Larynx: Results of Therapy.
    Date December 1986
    Journal The Laryngoscope
    Excerpt

    Primary small cell carcinoma of the larynx is a rare malignancy with a dismal prognosis. A survey of the long-term follow-up from reported cases of small cell carcinoma of the larynx and a review of the recent experience with this tumor at the University of Michigan Hospitals was undertaken to determine if newer treatment approaches incorporating adjuvant chemotherapy were associated with prolonged survival. Median survival for those patients receiving adjuvant chemotherapy was 19 months compared to 11 months for patients treated with surgery and/or radiation therapy alone. Among patients treated initially with primary radiation therapy and adjuvant chemotherapy median survival was 55 months, which was significantly longer than any other treatment regimen (P = 0.02). Systemic chemotherapy and therapeutic irradiation appears to offer the least disabling and most efficacious form of current therapy.

    Title Beta Endorphin Enhances in Vitro Lymphokine Production in Patients with Squamous Carcinoma of the Head and Neck.
    Date April 1986
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    Recent studies of the effects of endorphins and other neuropeptides on immune mechanisms suggest that immune reactive cells have specific opioid-like and nonopioid endorphin receptors, and indicate that neuropeptides may participate in regulating in vivo immune functions. Earlier demonstrations of impaired cellular immunity and impaired lymphokine production in patients with cancer of the head and neck prompted an investigation of the in vitro effects of beta-endorphin on the production of leukocyte migration inhibitory factor (LIF) in 29 patients with head and neck cancer and in 45 normal subjects. LIF production in response to phytohemagglutinin was significantly less in the cancer patients compared to normal subjects (p less than .001). beta-endorphin significantly enhanced LIF production in the cancer patients (p = .01) to levels that did not differ significantly from normal levels. A correlation of levels of lymphocyte subpopulations in the cancer patients suggested that enhancement of lymphokine production by beta-endorphin was related to levels of T8 (suppressor/cytotoxic) cells. The results confirm earlier demonstrations of impaired lymphokine production in patients with head and neck cancer and indicate that beta-endorphin can modulate in vitro lymphokine responses in such patients. These findings suggest that neuroendocrine peptides may play an important role in regulating immune function. Further study of the role of neuropeptides in the immune response should provide additional insight into the characterization of cellular immune dysfunction associated with head and neck cancer and should lead to the development of innovative immunotherapeutic treatment strategies.

    Title Definite Vs Adjuvant Radiotherapy. Comparative Effects on Lymphocyte Subpopulations in Patients with Head and Neck Squamous Carcinoma.
    Date November 1985
    Journal Archives of Otolaryngology (chicago, Ill. : 1960)
    Excerpt

    The recent association of alterations in T-lymphocyte subpopulations and impaired cellular immunity prompted an investigation of the effects of radiotherapy (RT) on serial levels of lymphocyte subsets in 30 patients with head and neck squamous carcinoma. Percentage and absolute levels of T3, T4, T6, T8, T10, T11, and Leu 7 cells were measured before, during, and after RT at monthly intervals for six months and compared with levels in 40 normal subjects. Sixteen patients received curative and 14 postoperative adjuvant RT. Before treatment, mean subset levels were similar among the patient and normal groups except for elevated Leu 7 (natural killer) cells in patients with stage I and II disease. There were profound decreases in absolute levels of each subpopulation during and after RT. The percentage of T4 (helper/inducer) cells decreased, whereas that of T8 (cytotoxic/suppressor) and Leu 7 cells tended to increase. Compared with normal values, the mean T4/T8 ratio decreased significantly by six months after RT, when absolute levels of the subsets had rebounded to pretreatment levels in the definitive RT group but remained profoundly decreased in the adjuvant group. The differing recovery patterns suggest that factors other than RT may contribute to persistent immunosuppression following RT.

    Title Dna Content of Human Squamous Cell Carcinoma Cell Lines. Analysis by Flow Cytometry and Chromosome Enumeration.
    Date September 1985
    Journal Archives of Otolaryngology (chicago, Ill. : 1960)
    Excerpt

    Fifteen squamous cell carcinoma cell lines derived from nine patients were examined for DNA content by flow cytometry and chromosome counts. Using human peripheral blood leukocytes and nucleated trout and chicken red blood cells as standards, the DNA indexes of the squamous cell carcinoma cell lines were found to range from 1.1 to 3.3. The DNA content was a stable characteristic of individual cell lines in multiple passages over a seven-month period. Although flow cytometry could detect abnormal DNA content even in diploid tumor lines, the chromosome number correlated well with the DNA content by flow cytometry. In cases in which more than one cell line was established from the same patient, the individual cell lines were found to differ in their DNA content. The cell lines established from metastatic or recurrent tumors usually had a lower DNA content and chromosome number and exhibited a more aggressive in vitro growth pattern than the primary tumor or earlier recurrence. We hypothesize that "streamlined" and aggressive cell populations may evolve in vivo from more slowly growing hyperploid precursor tumor cell populations when in the course of random loss of DNA or chromosomes those that confer no growth advantage are lost, while those that do confer growth advantage are retained.

    Title Intramuscular Hemangioma of the Head and Neck.
    Date March 1985
    Journal The Laryngoscope
    Excerpt

    Intramuscular hemangiomas are unusual tumors in the head and neck region that occur most frequently in the masseter muscle and are often confused with parotid neoplasms. Four cases are described and the literature reviewed. The diagnosis and management of these tumors are discussed in view of the fact that accurate preoperative diagnosis is unusual and tumor recurrence rates high. Increased awareness of the clinical presentation of intramuscular hemangiomas should enhance diagnostic accuracy and facilitate optimal treatment planning.

    Title Predictive Factors for Tumor Response to Preoperative Chemotherapy in Patients with Head and Neck Squamous Carcinoma. The Head and Neck Contracts Program.
    Date January 1985
    Journal Cancer
    Excerpt

    The high tumor response rates associated with intensive chemotherapy in previously untreated patients with advanced head and neck squamous cell carcinoma (HNSCC) led to the initiation of a multi-institutional National Cancer Institute trial. This trial used preoperative chemotherapy in patients with resectable Stage III and IV squamous cell carcinoma of the oral cavity or larynx/hypopharynx. Response rates, toxicity, and a variety of patient and tumor characteristics were analyzed to determine which factors might be useful in predicting tumor response to preoperative chemotherapy. Two hundred eighty-two patients received one course of preoperative cisplatin and bleomycin chemotherapy and were evaluable. There were 22 complete responses (CR) and 114 partial responses (PR) at the primary site (48% response rate). Of 197 patients with clinically positive regional adenopathy, 29 CRs and 73 PRs were observed (52%). Toxicity associated with the chemotherapy regimen was minimal. Primary tumor and regional node responses to chemotherapy were strongly correlated. No significant differences were found in primary or nodal response rates with respect to differing tumor site, stage, histologic differentiation, patient performance status, nutritional status, leukocyte count, hemoglobin level, age, sex, or alcohol use. Primary tumor response, however, was significantly related to T classification (P = 0.048). Nodal response was strongly associated with N classification and nodal size (P = 0.02 and P = 0.075, respectively). These findings suggest that, of the patient and tumor characteristics analyzed, none were more useful in predicting tumor response than clinical tumor staging parameters.

    Title An Overview of Preoperative Chemotherapy: Where Do We Go from Here?
    Date December 1984
    Journal American Journal of Otolaryngology
    Title Lymphokine Production and Lymphocyte Subpopulations in Patients with Head and Neck Squamous Carcinoma.
    Date November 1984
    Journal Archives of Otolaryngology (chicago, Ill. : 1960)
    Excerpt

    Prior studies of impaired cellular immune reactivity in patients with head and neck squamous carcinoma (HNSC) suggest that immune deficiency associated with tumor growth may be related, in part, to alterations in immunoregulatory functions. To determine if production of soluble mediators of the immune response (lymphokines) is impaired in patients with HNSC, leukocyte migration inhibition in response to phytohemagglutinin was assessed in 32 patients with HNSC and 29 normal subjects and was correlated with levels of specific peripheral blood lymphocyte subpopulations to determine if quantitative levels of immunoregulatory lymphocyte subpopulations were related to in vitro lymphokine production. In the patients with cancer, leukocyte inhibitory factor production was consistently and significantly impaired and was directly related to levels of T4-positive (helper/inducer) lymphocytes. Substantial differences in levels of individual subpopulations were not detected among normal subjects and patients with cancer; however, the mean T4/T8 ratio was substantially increased in the patients with cancer. The findings confirm and extend prior observations of impaired cellular immune mechanisms in patients with HNSC and suggest that impaired lymphokine production may be related to quantitative and qualitative alterations in lymphocyte subpopulations.

    Title Total En Bloc Resection of the Temporal Bone and Carotid Artery for Malignant Tumors of the Ear and Temporal Bone.
    Date May 1984
    Journal The Laryngoscope
    Excerpt

    A technique for single stage total en bloc resection of the temporal bone and intratemporal carotid artery with immediate reconstruction has been described. This formidable procedure requires the collaborative efforts of neurotologic skull base surgeons, neurosurgeons, and head and neck surgeons. Two patients have undergone this procedure; one with squamous cell carcinoma and one with extensive basal cell carcinoma. The quality of life following this procedure is adequate and the cosmetic deformity can be minimized. Longer follow-up is necessary to determine the value and overall impact of this approach to cancer of the temporal bone on disease free interval and patient survival. Further experience with the technical aspects of this procedure should reduce the operating time, blood loss, and resultant morbidity.

    Title Effects of Smoking and Age on Serum Levels of Immune-reactive Proteins Altered in Cancer Patients.
    Date May 1983
    Journal Cancer Detection and Prevention
    Excerpt

    In patients with solid malignancies, such as those associated with chronic smoking, levels of immunosuppressive acute-phase proteins (haptoglobin, alpha 1-acid glycoprotein, alpha 1-antitrypsin) are increased and correlate directly with extent of tumor and inversely with immune reactivity. Other serum proteins with immunorestorative properties (alpha 2HS-glycoprotein, prealbumin) are decreased and correlate directly with immune reactivity. Serum levels of these glycoproteins and albumin were measured in normal volunteers (132 cigarette smoking and 140 nonsmoking) to determine the effects of smoking history, age, and sex on protein levels. The alpha 1-acid glycoprotein increased, whereas albumin decreased with age in both groups, and haptoglobin increased with age in smokers. The alpha 1-acid glycoprotein, haptoglobin, and albumin levels also correlated with the extent of smoking (pack-years). In a comparison of age- and sex-matched smokers and nonsmokers, alpha 1-antitrypsin uniquely and significantly increased (P less than 0.001) in smokers but was not related to age or extent of smoking. The diagnostic and immunological implications of smoking and age-related changes in serum protein levels are discussed.

    Title Effects of Smoking and Age on Serum Levels of Immune Reactive Proteins.
    Date December 1982
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    In patients with head and neck squamous carcinoma, prior studies demonstrating correlations among levels of certain immunosuppressive acute phase proteins, tumor extent, and immune reactivity suggest that these protein levels may be useful parameters for assessing tumor status and clinical course after treatment. Because of the consistent association of chronic smoking with the development of cancers of the head and neck, the effects of smoking and age on levels of acute phase proteins (alpha 1-antitrypsin, haptoglobin, alpha 1-acid glycoprotein) and other immune reactive proteins (alpha 2HS-glycoprotein, prealbumin) were determined in smoking and nonsmoking normal subjects. In smokers, levels of alpha 1-antitrypsin were uniquely and significantly elevated and were not related to smoking extent or age. Levels of haptoglobin increased with smoking extent and age. In comparisons of age- and sex-matched smokers and nonsmokers, levels of alpha 1-acid glycoprotein increased with age among both groups. The demonstration of correlations of levels of immunosuppressive acute phase proteins with smoking extent and age among normal subjects suggests that changes in the levels of these proteins may be related etiologically to the association of smoking and age with the development of head and neck cancers.

    Title Preoperative Cisplatin and Bleomycin Therapy in Head and Neck Squamous Carcinoma. Prognostic Factors for Tumor Response.
    Date December 1981
    Journal Archives of Otolaryngology (chicago, Ill. : 1960)
    Excerpt

    A multi-institutional National Cancer Institute trial of preoperative cisplatin (100 mg/sq m, day 1) and intravenous bleomycin sulfate (15-mg/sq m bolus, day 3, followed by 15 mg/sq m/day, 24-hour infusion, days 3 to 7) was carried out in patients with previously untreated, resectable stage III and IV squamous cell carcinoma of the oral cavity or larynx and hypopharynx. Of the first 113 patients who received a single course of induction chemotherapy, eight complete responses and 47 partial responses at the primary site were observed (49%). Of 76 patients who had clinically positive regional adenopathy, 11 complete responses and 31 partial responses of neck nodes were observed (55%). The response rates of the primary tumor and the regional nodes to induction chemotherapy were assessed with respect to several pretreatment patient and tumor characteristics and to reported toxic effects after chemotherapy. Of the factors examined, no prognostic indicators were highly useful to predict the response of the primary tumor. However, the response of regional adenopathy was associated with the initial N class, the site of primary tumor, and the response of the primary tumor to induction chemotherapy.

    Title Intraarterial Chemotherapy of Head and Neck Cancer: Worth Another Look?
    Date January 1981
    Journal Cancer Clinical Trials
    Excerpt

    Early studies of intraarterial chemotherapy in patients with squamous carcinoma of the head and neck resulted in tumor response rates similar to those achieved with systemic chemotherapy, but which were associated with unacceptable morbidity. The results of recent clinical trials suggest that intraarterial chemotherapy can achieve higher response rates than previously reported and that the frequency of morbid complications can be reduced. A summary of the discussions which took place at a recent NCI-OSITC Workshop on Intraarterial Chemotherapy of Head and Neck Cancer is presented. New therapeutic strategies and improved treatment techniques provide the rationale for a reevaluation of intraarterial chemotherapy in patients with head and neck cancer.

    Title Editorial: a Classification System for Protocol Deviations in Clinical Trials.
    Date January 1981
    Journal Cancer Clinical Trials
    Title Improvement of Impaired Leukocyte Migration Inhibition by Thymosin in Patients with Head and Neck Squamous Carcinoma.
    Date December 1980
    Journal American Journal of Surgery
    Excerpt

    In a preliminary study of the effects of SK-SD and thymosin on leukocyte migration inhibition in patients with squamous carcinoma of the head and neck, the cancer patients had significantly lower leukocyte migration inhibition of SK-SD than normal subjects. Thymosin increased the inhibition to SK-SD in the cancer patients to levels similar to those in normal subjects, and decreased the inhibition in normal subjects. These results confirm and extend the results of previous studies of the effects of thymosin in vitro, which show restoration of immune reactivity in patients with impaired cellular immunity and either no effect or a decrease in immune reactivity in subjects with normal cellular immunity. These combined observations provide a rationale for determining the clinical effects of thymosin in immunoincompetent patients with head and neck cancer and suggest that immunorestorative agents such as thymosin be used with caution in patients with normal cellular immunity.

    Title Correlation of Serum Immune-reactive Proteins with Clinical Tumor Stage in Patients with Squamous Carcinoma of the Head and Neck and Nasopharyngeal Carcinoma.
    Date May 1980
    Journal Surgical Forum
    Title Serum Glycoproteins in Head and Neck Squamous Carcinoma: Correlations with Tumor Extent, Clinical Tumor Stage, and T-cell Levels During Chemotherapy.
    Date November 1979
    Journal American Journal of Surgery
    Title Serum Glycoproteins and Immunoglobulins in Nasopharyngeal Carcinoma: Correlations with Epstein-barr Virus Associated Antibodies and Clinical Tumor Stage.
    Date November 1979
    Journal American Journal of Surgery
    Title Rupture of the Jejunum Secondary to Blunt Trauma in a Football Player.
    Date June 1976
    Journal Southern Medical Journal
    Title Head and Neck Cancers.
    Date
    Journal Journal of the National Comprehensive Cancer Network : Jnccn
    Title Immunotherapy of Head and Neck Cancer: Current and Future Considerations.
    Date
    Journal Journal of Oncology
    Excerpt

    Patients with head and neck squamous cell carcinoma (HNSCC) are at considerable risk for death, with 5-year relative survival rates of approximately 60%. The profound multifaceted deficiencies in cell-mediated immunity that persist in most patients after treatment may be related to the high rates of treatment failure and second primary malignancies. Radiotherapy and chemoradiotherapy commonly have severe acute and long-term side effects on immune responses. The development of immunotherapies reflects growing awareness that certain immune system deficiencies specific to HNSCC and some other cancers may contribute to the poor long-term outcomes. Systemic cell-mediated immunotherapy is intended to activate the entire immune system and mount a systemic and/or locoregional antitumor response. The delivery of cytokines, either by single cytokines, for example, interleukin-2, interleukin-12, interferon-gamma, interferon-alpha, or by a biologic mix of multiple cytokines, such as IRX-2, may result in tumor rejection and durable immune responses. Targeted immunotherapy makes use of monoclonal antibodies or vaccines. All immunotherapies for HNSCC except cetuximab remain investigational, but a number of agents whose efficacy and tolerability are promising have entered phase 2 or phase 3 development.

    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 Current Trends in Initial Management of Hypopharyngeal Cancer: The Declining Use of Open Surgery.
    Date
    Journal Head & Neck
    Excerpt

    Squamous cell carcinoma of the hypopharynx represents a distinct clinical entity. Most patients present with significant comorbidities and advanced-stage disease. The overall survival is relatively poor because of high rates of regional and distant metastasis at presentation or early in the course of the disease. A multidisciplinary approach is crucial in the overall management of these patients to achieve the best results and maintain or improve functional results. Traditionally, operable hypopharyngeal cancer has been treated by total (occasionally partial) laryngectomy and partial or circumferential pharyngectomy, followed by reconstruction and postoperative radiotherapy in most cases.Efforts to preserve speech and swallowing function in the surgical treatment of hypopharyngeal (and laryngeal) cancer have resulted in a declining use of total laryngopharyngectomy and improved reconstructive efforts, including microvascular free tissue transfer. There are many surgical, as well as nonsurgical, options available for organ and function preservation, which report equally effective tumor control and survival. The selection of appropriate treatment is of crucial importance in the achievement of optimal results for these patients. In this article, several aspects of surgical and nonsurgical approaches in the treatment of hypopharyngeal cancer are discussed. Future studies must be carefully designed within clearly defined populations and use uniform terminology and standardized functional assessment and declare appropriate patient or disease endpoints. These studies should focus on improvement of resultsx, without increasing patient morbidity. In this respect, technical improvements in radiotherapy such as intensity-modulated radiotherapy, advances in supportive care, and incorporation of newer systemic agents such as targeted therapy, are relevant developments. © 2010 Wiley Periodicals, Inc. Head Neck, 2010.

    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.

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