Mutational landscape of head and neck squamous cell carcinomas in a South Asian population.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type globally and contributes significantly to burden of disease in South Asia. In Pakistan, HNSCC is among the most commonly diagnosed cancer in males and females. The increasing regional burden of HNSCC along with a unique set of risk factors merited a deeper investigation of the disease at the genomic level. Whole exome sequencing of HNSCC samples and matched normal genomic DNA analysis (n=7) was performed. Significant somatic single nucleotide variants (SNVs) were identified and pathway analysis performed to determine frequently affected signaling pathways. We identified significant, novel recurrent mutations in ASNS (asparagine synthetase) that may affect substrate binding, and variants in driver genes including TP53, PIK3CA, FGFR2, ARID2, MLL3, MYC and ALK. Using the IntOGen platform, we identified MAP kinase, cell cycle, actin cytoskeleton regulation, PI3K-Akt signaling and other pathways in cancer as affected in the samples. This data is the first of its kind from the Pakistani population. The results of this study can guide a better mechanistic understanding of HNSCC in the population, ultimately contributing new, rational therapeutic targets for the treatment of the disease.

Effect of human papillomavirus on patterns of distant metastatic failure in oropharyngeal squamous cell carcinoma treated with chemoradiotherapy.

IMPORTANCE: Important differences exist in the pattern and timing of distant metastases between human papillomavirus-initiated (HPV+) and HPV- oropharyngeal squamous cell carcinoma (OPSCC). However, our understanding of the natural history of distant metastases in HPV+ OPSCC and its implications for surveillance is limited. OBJECTIVE: To investigate the rate, pattern, and timing of distant metastases in advanced-stage OPSCC treated definitively with concomitant chemoradiotherapy. DESIGN, SETTING, AND PARTICIPANTS: In a retrospective review, we identified 291 patients with pathologically diagnosed stages III to IVB OPSCC and known HPV status from a tumor registry at the Cleveland Clinic. Patients were treated from January 1, 1996, through December 31, 2013. Details of treatment failure and the natural history of the disease were retrieved from the electronic medical records. INTERVENTIONS: All patients were treated with definitive concomitant chemoradiotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate and timing of distant metastases. Secondary outcomes included the pattern of distant failure and survival after distant metastases. RESULTS: Thirty-seven patients developed distant metastatic disease after definitive treatment, including 28 of 252 patients with HPV+ disease and 9 of 39 patients with HPV- disease. The 3-year projected distant control rate was higher in the HPV+ group (88% vs 74%; P = .01). The median time to develop distant metastases was also longer after the completion of treatment for HPV+ disease compared with HPV- disease (16.4 vs 7.2 months; P = .008). We detected a trend in patients with HPV+ disease for more distant metastatic sites involved than in those with HPV- disease (2.04 vs 1.33 sites; P = .09). Although the lung was the most common distant site involved in HPV+ and HPV- disease (HPV+ group, 23 of 28 patients [82%]; HPV- group, 7 of 9 patients [78%]), the HPV+ group had metastases to several subsets atypical for head and neck squamous cell carcinoma, including the brain, kidney, skin, skeletal muscle, and axillary lymph nodes in 2 patients each and in the intra-abdominal lymph nodes in 3 patients. The rate of 3-year overall survival was higher in the HPV+ group (89.9% vs 62.0%; P < .001), as was the median survival after the occurrence of distant metastases regardless of additional treatment (25.6 vs 11.1 months; P < .001). CONCLUSIONS AND RELEVANCE: This retrospective review suggests that distant metastases in patients with HPV+ OPSCC occurs significantly later after completion of chemoradiotherapy than in patients with HPV- disease. Human papillomavirus-initiated OPSCC also appears to involve a greater number of subsites and metastatic sites infrequently seen in head and neck squamous cell carcinoma. Distant metastatic disease in HPV+ OPSCC has unique characteristics and a natural history that may require alternative surveillance strategies.

Impact of surgical resection on survival in patients with advanced head and neck cancer involving the carotid artery.

IMPORTANCE: The present study addresses the survival benefit of aggressive surgical treatment of head and neck cancer involving the carotid artery. OBJECTIVE: To assess survival outcomes in patients treated for advanced squamous cell carcinoma involving the carotid artery using different treatment strategies. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study at a tertiary care center of 44 consecutive patients with squamous cell carcinoma involving the carotid artery from 2005 to 2012 with a median follow-up of 12 months. The radiologist was blinded to the outcome of surgical procedures. INTERVENTIONS: Surgery with or without radiotherapy, and definitive chemoradiation. MAIN OUTCOMES AND MEASURES: Overall survival and rates of locoregional and distant failures. The hypothesis was formulated before data collection. RESULTS: Of 44 patients, 35 (80%) were treated with curative intent with surgery with or without adjuvant therapy (n = 27 [61%]) or definitive chemoradiation therapy (n = 8 [18%]), while 9 patients (21%) were treated in a palliative fashion. Patients treated with curative intent had improved overall survival (median survival, 13.5 months) compared with the palliative group (median survival, 3.6 months) (P = .001). Of patients treated with curative intent, those with previously untreated disease (n = 14 [40%]) had an improved outcome relative to patients with recurrent or persistent disease (n = 21 [60%]), with median survival of 38.7 and 9.6 months, respectively (P = .008). Patients were treated with curative intent using 3 different treatment strategies (ie, carotid artery resection with or without reanastamosis) (n = 6 [17%]), curative peeling with or without adjuvant therapy (n = 21 [ 60%]), and definitive chemoradiation therapy (n = 8 [23%]). Survival outcome was not significantly different between subgroups treated with curative intention (P = .47). When reviewed by a head and neck radiologist in a blinded fashion (n = 30), preintervention imaging had a positive predictive value of 72.7% for resectability of cancer involving the carotid artery. In cases with almost circumferential involvement (>270°) and narrowing of the carotid artery, the disease was unresectable (n = 3). CONCLUSIONS AND RELEVANCE: Advanced head and neck cancer involving the carotid artery can be treated with curative intent with favorable results in most patients. If disease burden merits, an aggressive approach involving resection with or without reanastamosis of the carotid artery can be used without significant added morbidity.

Anaplastic thyroid cancer in young patients: a contemporary review.

PURPOSE: Little is known about prognostic factors and treatment outcomes in young patients with anaplastic thyroid cancer (ATC). The goal of this study is to define the clinical features of this subgroup. MATERIAL AND METHODS: Patients age 55 or younger with either ATC or well-differentiated thyroid cancer (WDTC) with anaplastic changes were identified using electronic medical record at the Cleveland Clinic. The same number of patients older than 55 was randomly selected to serve as control. Progression-free survival (PFS), overall survival time (OST) and cause-specific mortality (CSM) were measured against age, tumor histology, extent of disease, and treatment modalities. RESULTS: Twelve patients age 55 or younger were identified. The median age was 51 years. Four patients had WDTC with anaplastic components--mixed tumor group (MTG). Their median PFS, OST, and CSM at 24 months were 21.5 months, 51 months, and 25%, respectively. For the other 8 patients who had pure ATC, their median PFS, OST, and CSM were 3.5 months, 6 months, and 100%, respectively. Patients in the MTG had better survival compared to the pure ATC and control group in terms of PFS (p = 0.0047 and p = 0.0053), OST (p = 0.0028 and p = 0.0029) and the CSM at 24 months (p = 0.0339 and p = 0.0096). In the pure ATC group, patients with positive cervical lymph node and distant metastases had similar overall survival outcomes (6 vs. 8 months, p = 0.4995). CONCLUSION: Prognostic factors favoring survival in young patients with ATC include ATC arising within WDTC. Once full anaplastic transformation occurs, age was not a significant factor in survival.

Salvage laryngectomy in patients with recurrent laryngeal cancer in the setting of nonoperative treatment failure.

OBJECTIVE: To investigate the effectiveness of salvage partial and total laryngectomy in the treatment of recurrent laryngeal cancer in the setting of initial nonoperative treatment failure and to identify factors influencing long-term survival. STUDY DESIGN: Case series with planned chart review. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Patients with recurrent squamous cell carcinoma of the larynx initially treated with either radiation or chemoradiation, who underwent salvage laryngectomy at the Cleveland Clinic Foundation from 1997 to 2011, were identified. The cohort was divided into an early-stage group and an advanced-stage group based on initial tumor staging. Survival outcome was evaluated separately in each group against tumor staging, methods of treatment, and nodal status. Secondary endpoints of speech and swallowing were also evaluated. RESULTS: A total of 100 patients were identified, with 72 patients in the early-stage group and 28 patients in the advanced-stage group. The overall postsalvage locoregional control rate was 70%, and the 5-year disease-specific survival was 70% and 55.2% in the early and advanced group, respectively (P = .39). The 5-year disease-specific survival was not significant in either group when compared with recurrent staging, initial treatment, salvage treatment, or nodal disease (P = ns). Using voice prostheses, good to excellent speech function was achieved postoperatively in most patients. CONCLUSION: Tumor staging, methods of initial and salvage treatment, and nodal disease were not significant predictors of survival. Both salvage partial and total laryngectomy were effective methods in the treatment of recurrent laryngeal cancer in carefully selected patients.

A comparative analysis of toluidine blue with frozen section in oral squamous cell carcinoma.

BACKGROUND: Surgical excision of the primary tumor with safe margins remains the mainstay of treatment for oral cavity squamous cell carcinoma (OSCC). The standard of care for assessment of intraoperative margins is frozen section histopathology. Unfortunately the facility is not available at most centers in limited resource countries. Toluidine blue, a metachromatic dye, has been well described in clinical identification of malignant and premalignant lesion in the oral cavity. Considering this we decided to explore intraoperative use of toluidine blue staining, in comparison with frozen sections, for the assessment of tumor-free margins. METHODS: After obtaining clearance from the in-house ethical review committee, a prospective study was conducted at Aga Khan University Hospital, Karachi, from August 15, 2009 to March 14, 2010. A sample of 56 consenting patients with biopsy-proven OSCC were included in the study, giving us 280 tumor margins. Margins were analyzed using toluidine blue staining and frozen section histopathology. A receiver operator curve (ROC) was then applied to compare assessment of margin status by toluidine blue and frozen section. RESULTS: Of the 280 examined margins 11 stained positive with toluidine blue, three were positive on frozen section biopsy, and three were positive on final histopathology. Toluidine blue staining had sensitivity and specificity of 100% and 97%, respectively. The diagnostic accuracy of toluidine blue was found to be 97.1% with a positive predictive value (PPV) of 27.2% and a negative predictive value (NPV) of 100%. CONCLUSIONS: Toluidine blue can be used as an effective screening modality for the assessment of intraoperative margins in resource limited environments and reducing the number of frozen section biopsies performed. Further by providing real-time clinical information within minutes it can reduce indirect costs such as operating room time. It may also be used as an ad hoc for frozen section biopsies where frozen section facilities are available.

Successful management of aggressive fibromatosis of the neck using wide surgical excision: a case report.

INTRODUCTION: Aggressive fibromatosis is a benign tumor, thought to arise from deep musculoaponeurotic structures, rarely found in the head or neck. However, when it does occur in the head and neck region, it tends to be more aggressive and associated with significant morbidity, which may be attributed to the vital vascular, neurological or anatomical structures in close proximity. CASE PRESENTATION: We report the case of a 39-year-old Pakistani man who presented with a two-month history of a lump on the right side of his neck. The mass was excised and histopathological analysis revealed a case of aggressive fibromatosis. CONCLUSION: Due to the rarity of the condition no guidelines are available on the indications and extent of each modality. Due to its aggressive behavior and tendency to invade local structures and recur, a multi-modality management strategy is usually employed. On the basis of this case, we suggest that aggressive surgery is a viable management option and may be successfully used as a single modality treatment.

Changes in quality of life over 1 year in patients with head and neck cancer.

OBJECTIVES: To characterize and compare quality of life (QOL) in patients with head and neck cancer shortly before initial treatment and 1 year later and to study the predictors of changes in QOL over 1 year. DESIGN: Prospective cohort study. SETTING: Three otolaryngology clinics. PATIENTS: Three hundred sixteen patients having newly diagnosed squamous cell head and neck cancer. MAIN OUTCOME MEASURE: Health-related QOL was assessed using the 36-item Short-Form Health Survey and a head and neck cancer-specific QOL scale. RESULTS: Over 1 year, QOL decreased for physical functioning measures and eating but improved for mental health QOL. Depression and smoking were major predictors of poor QOL at baseline. Major predictors of change in QOL from baseline to 1 year were treatment factors, especially feeding tube placement (9 scales), chemotherapy (3 scales), and radiation therapy (3 scales). Baseline smoking and depressive symptoms also remained significant predictors of several QOL scales at 1 year. CONCLUSIONS: Health-related physical QOL tended to decline over 1 year and mental health QOL improved. The major predictors of change in QOL were treatment factors, smoking, and depressive symptoms. Physicians should alert patients to the relative effects on QOL one may experience with different treatments.

Health behaviors of head and neck cancer patients the first year after diagnosis.

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.

Influence of lecithin on mitochondrial DNA and age-related hearing loss.

OBJECTIVES: Lecithin is a polyunsaturated phosphatidylcholine (PPC), which are high energy functional and structural elements of all biologic membranes. PPC play a rate-limiting role in the activation of numerous membrane-located enzymes, including superoxide dismutase and glutathione, which are important antioxidants protecting cell membranes from damage by reactive oxygen species (ROS). ROS-induced damage to mitochondrial DNA may lead to reduced mitochondrial function in the cochlea and resultant hearing loss. STUDY DESIGN AND SETTING: The effects of lecithin on aging and age-associated hearing loss were studied in rats by measuring hearing sensitivities using auditory brainstem responses (ABR). In addition, mitochondrial function as a measure of aging was assessed by determining mitochondrial membrane potentials using flow cytometry and by amplifying mitochondrial DNA deletions associated with aging. Harlan-Fischer rats aged 18 to 20 months (n = 14) were divided into 2 groups. The experimental group was supplemented orally for 6 months with lecithin, a purified extract of soybean phospholipid (Nutritional Therapeutics, Allendale, NJ). RESULTS: The data obtained were compared with the control group. ABRs were recorded at 2-month intervals and showed significant preservation of hearing sensitivities in the treated subjects. Flow cytometry revealed significantly higher mitochondrial membrane potentials in the treated subjects, suggesting preserved mitochondrial function. Finally, the common aging mitochondrial DNA deletion (mtDNA(4834)) were amplified from brain and cochlear tissue including stria vascularis and auditory nerve. This specific deletion was found significantly less frequent in all tissues in the treated group compared with the controls. CONCLUSION: These experiments support our hypothesis and provide evidence that lecithin may preserve cochlear mitochondrial function and protect hearing loss associated with aging.