Chromosomal aberrations in patients with head and neck squamous cell carcinoma do not vary based on severity of tobacco/alcohol exposure

BACKGROUND: Head and neck squamous cell carcinomas (HNSCC) have been causally associated with tobacco and alcohol exposure. However, 10–15% of HNSCC develop in absence of significant carcinogen exposure. Several lines of evidence suggest that the genetic composition of HNSCC varies based on the extent of tobacco/alcohol exposure, however, no genome wide measures have been applied to address this issue. We used comparative genomic hybridization (CGH) to screen for the genetic aberrations in 71 patients with head and neck squamous cell carcinoma and stratified the findings by the status of tobacco/alcohol exposure. RESULTS: Although the median number of abnormalities (9), gains (6) and losses (2) per case and the overall pattern of abnormalities did not vary significantly by the extent of tobacco/alcohol exposure, individual abnormalities segregating these patients were identified. Gain of 1p (p = 0.03) and 3q amplification (p = 0.05) was significantly more common in patients with a history of tobacco/alcohol exposure. CONCLUSIONS: This data suggests that the overall accumulated chromosomal aberrations in head and neck squamous cell carcinoma are not significantly influenced by the severity of tobacco/alcohol exposure with limited exceptions

Fanconi anemia and homologous recombination gene variants are associated with functional DNA repair defects in vitro and poor outcome in patients with advanced head and neck squamous cell carcinoma

Mutations in Fanconi Anemia or Homologous Recombination (FA/HR) genes can cause DNA repair defects and could therefore impact cancer treatment response and patient outcome. Their functional impact and clinical relevance in head and neck squamous cell carcinoma (HNSCC) is unknown. We therefore questioned whether functional FA/HR defects occurred in HNSCC and whether they are associated with FA/HR variants. We assayed a panel of 29 patient-derived HNSCC cell lines and found that a considerable fraction is hypersensitive to the crosslinker Mitomycin C and PARP inhibitors, a functional measure of FA/HR defects. DNA sequencing showed that these hypersensitivities are associated with the presence of bi-allelic rare germline and somatic FA/HR gene variants. We next questioned whether such variants are associated with prognosis and treatment response in HNSCC patients. DNA sequencing of 77 advanced stage HNSCC tumors revealed a 19% incidence of such variants. Importantly, these variants were associated with a poor prognosis (p = 0.027; HR = 2.6, 1.1–6.0) but favorable response to high cumulative cisplatin dose. We show how an integrated in vitro functional repair and genomic analysis can improve the prognostic value of genetic biomarkers. We conclude that repair defects are marked and frequent in HNSCC and are associated with clinical outcome.</p

Clinical impact of molecular analysis on thyroid cancer management

Thyroid cancer constitutes a progressive continuum of disease ranging from indolent well-differentiated carcinomas to aggressive poorly differentiated carcinomas and universally fatal anaplastic carcinomas. The wide divergence in clinical behavior is poorly predicted for by current clinicopathological factors. Moreover, therapeutic armentarium against aggressive thyroid cancers remains limited. Recent studies have identified a range of molecular alterations in thyroid cancers. Clinical implications of the molecular alterations include their utility in diagnostic evaluation, staging and targeted treatment. Continued molecular analysis of thyroid cancers promises to increase our understanding of its biologic behavior and is expected to have further impact on its clinical managemen

Patterns of expression of cell cycle/apoptosis genes along the spectrum of thyroid carcinoma progression

Genetic screening studies suggest that genetic changes underlie progression from well differentiated to anaplastic thyroid cancers. The aim of this study is to determine to what extent cell cycle/apoptosis regulators contribute to cancer progression. Tissue microarrarys (TMAs) were constructed from well-differentiated papillary thyroid carcinoma (WDPTC; n = 41), poorly differentiated thyroid carcinoma (PDTC; n = 43), and anaplastic thyroid carcinoma (ATC; n = 22). TMAs were immunostained for 7 different cell cycle/apoptosis-related genes (p53, Ki-67, bcl-2, mdm-2, cyclin D1, p21, and p27). p53 (0%, 12%, 32%) and Ki-67 (5%, 49%, 82%) were expressed with increasing frequency, and bcl-2 (68%, 42%, 0%) and p21 (40%, 7%, 0%) with decreasing frequency in WDPTC to PDTC and ATC, respectively (P < .001). Interestingly, mdm-2 (54%, 5%, 0%) showed decreased expression along the progression axis (P < .001). p27 and cyclin D1 were expressed in <15% of cases, with a trend toward decreasing expression from WDPTC to PDTC to ATC. These data confirm the presence of increasing genetic complexity with progressive dedifferentiation in thyroid cancer, with aberrant tumor suppressor activity and increased proliferative activity being most prevalent in ATC. The data also confirm the intermediate position of PDTC in the classification scheme of thyroid carcinoma

Closure of tracheoesophageal fistula with prefabricated revascularized bilaminar radial forearm free flap

BACKGROUND: Tracheoesophageal fistula (TEF) is a rare but serious complication associated with high mortality rates. Traditional management of TEF includes primary closure with or without interposition of regional tissue flaps but is associated with a significant recurrence risk, especially in case of larger fistulas. Application of microvascular free flap reconstruction is an emerging alternative in the surgical management of large TEFs, but may be limited by issues of flap bulkiness and requirement for neoepithelialization across the large inner flap surface. METHODS AND RESULTS: Here, we report prefabrication of a bilaminar radial forearm free flap to successfully close a large recurrent TEF that occurred years after tracheoesophageal puncture-based voice rehabilitation in a laryngectomized patient. CONCLUSION: The bilaminar radial forearm free flap may prove to be an important adjunct to the closure of large TEF

Oropharyngeal squamous cell carcinoma: a unique disease on the rise?

Despite successful efforts to control tobacco and alcohol consumption in the western world, several developed countries report rising oropharyngeal squamous cell carcinoma (OPSCC) incidence figures, specifically in young individuals. Similar to anogenital cancers, a significant proportion of OPSCC (up to 60%) is caused by sexually acquired HPV infection and the rise in OPSCC has been attributed to changing sexual behaviours in the Western World. Accordingly, patients with HPV-positive OPSCC report divergent sexual histories and absence of classical risk factors as tobacco and alcohol exposure compared to patients with HPV-negative OPSCC. The profile of HPV-positive OPSCC differs from HPV-negative OPSCC in several other significant aspects, including a unique molecular biologic tumor characteristics and improved clinical behaviour. Thus, a further increase in HPV-positive OPSCC will impact significantly upon clinical management of OPSCC, unless it is halted by adequate preventive measures aimed at reduction of HPV-associated disease. HPV vaccination has been recently offered to young females in an attempt to reduce HPV-induced cervical cancer and may ultimately result in a decline of OPSCC incidence as well. Until then, close collaboration between otolaryngologists/head and neck surgeons and anogenital/genitourinary specialists is warranted to optimize clinical management of HPV-induced malignancy and improve detection of second primary tumor developmen

Head and neck squamous cell carcinoma in young patients

Epidemiologic analyses have shown disproportional increases of head and neck squamous cell carcinoma (HNSCC) incidence in a younger age group (younger than 45 years old), compared to patients above 45 years old. Although this group is small (5%), it includes a significant subset of the HNSCC patient population, and is characterized by a distinct clinical and etiological phenotype. HNSCC in young patients often presents without significant exposure to alcohol and tobacco and primarily affects the oropharynx and oral cavity. Exposure to human papilloma virus (HPV) has been identified as a major contributor to the pathogenesis of oropharyngeal carcinomas, and explains part of the observed incidence variation. Specific hereditary influences, including genetic predispositions accounting for an increased mutagen sensibility and inherited syndromes like Fanconi Anemia and Bloom's syndrome, have been identified as causative factors in a subgroup of young-onset HNSCC, but their cumulative influence remains at present likely underestimated. Circumstantial evidence suggests that young-onset HNSCC patients have a clinically different phenotype compared to older patients, however, the true impact of young age on HNSCC clinical behavior will remain difficult to determine unless multi-institutional databases will be combined. The rising incidence of young-onset HNSCC mandates intensification of research endeavors into its etiology, clinical phenotype and optimal managemen

Repetitive endoscopic sinus surgery failure: a role for radical surgery?

OBJECTIVES: Endoscopic sinus surgery (ESS) is considered to be the golden standard for surgery in patients with chronic rhinosinusitis and nasal polyposis. However, there is still a small group of patients unresponsive despite repetitive surgery. Radical surgery aimed at reduction of the inflammatory burden and optimization of drainage of the sinuses has been suggested as a last resort for these patients. STUDY DESIGN: A prospective, questionnaire-based study was conducted in a group of 23 patients who underwent Denker's procedure for refractory chronic rhinosinusitis. Symptoms were evaluated before Denker's procedure and 12 months and 2 years after surgery. RESULTS: Patients reported improvement of feelings of congestion in 74%, rhinorrhea in 70%, and nasal obstruction in 60% of the cases. The following postoperative improvements were statistically significant: rhinorrhea (P = 0.001), feelings of congestion (P = 0.02), and nasal obstruction (P = 0.03). Reduced olfactory perception and asthma did not improve. CONCLUSION: Radical surgery may be a viable treatment option in case of recurrent ESS failure. EBM rating: C-