Alec Vaezi

XPF expression correlates with clinical outcome in squamous cell carcinoma of the head and neck

Purpose: Tumor-specific biomarkers that predict resistance to DNA damaging agents may improve therapeutic outcomes by guiding the selection of effective therapies and limiting morbidity related to ineffective approaches. XPF (ERCC4) is an essential component of several DNA repair pathways and XPF-deficient cells are exquisitely sensitive to DNA damaging agents. The purpose of this study was to determine whether XPF expression levels predict clinical response to DNA damaging agents in head and neck squamous cell carcinoma (HNSCC). Experimental Design: Quantitative immunohistochemistry was used to measure XPF expression in tumors from a cohort of 80 patients with newly diagnosed HNSCC treated with radiation therapy with or without platinum-based chemotherapy; samples were collected prospectively. Genomic DNA isolated from blood samples was analyzed for nine single nucleotide polymorphisms (SNP) in the XPF gene by using a custom array. The primary endpoint was progression-free survival (PFS). Results: XPF expression was higher in tumors from the oral cavity than from the other sites (P < 0.01). High XPF expression correlated with early time to progression both by univariate (HR = 1.87, P = 0.03) and multivariate analysis (HR = 1.83, P = 0.05). The one year PFS for high expressers was 47% (95% CI = 31–62) compared with 72% (95% CI = 55–83) for low expressers. In addition, we identified four XPF SNPs that showed marginal association with treatment failure. Conclusions: Expression level of XPF in HNSCC tumors correlates with clinical response to DNA damaging agents. XPF has potential to guide next generation personalized cancer therapy. Clin Cancer Res; 17(16); 5513–22. ©2011 AACR.

ERCC1 and XRCC1 as biomarkers for lung and head and neck cancer

Advanced stage non-small cell lung cancer and head and neck squamous cell carcinoma are both treated with DNA damaging agents including platinum-based compounds and radiation therapy. However, at least one quarter of all tumors are resistant or refractory to these genotoxic agents. Yet the agents are extremely toxic, leading to undesirable side effects with potentially no benefit. Alternative therapies exist, but currently there are no tools to predict whether the first-line genotoxic agents will work in any given patient. To maximize therapeutic success and limit unnecessary toxicity, emerging clinical trials aim to inform personalized treatments tailored to the biology of individual tumors. Worldwide, significant resources have been invested in identifying biomarkers for guiding the treatment of lung and head and neck cancer. DNA repair proteins of the nucleotide excision repair pathway (ERCC1) and of the base excision repair pathway (XRCC1), which are instrumental in clearing DNA damage caused by platinum drugs and radiation, have been extensively studied as potential biomarkers of clinical outcomes in lung and head and neck cancers. The results are complex and contradictory. Here we summarize the current status of single nucleotide polymorphisms, mRNA, and protein expression of ERCC1 and XRCC1 in relation to cancer risk and patient outcomes.

Phase II Study of Cetuximab in Combination with Cisplatin and Radiation in Unresectable, Locally Advanced Head and Neck Squamous Cell Carcinoma: Eastern Cooperative Oncology Group Trial E3303

Purpose: Treatment with cisplatin or cetuximab combined with radiotherapy each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared with radiotherapy alone. Eastern Cooperative Oncology Group Trial E3303 evaluated the triple combination. Experimental Design: Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400 mg/m2) followed by 250 mg/m2/week and cisplatin 75 mg/m2 q 3 weeks ×3 cycles concurrent with standard fractionated radiotherapy. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6 to 12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival. Results: A total of 69 patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal primaries constituted the majority (66.7%), stage T4 48.3% and N2-3 91.7%. Median radiotherapy dose delivered was 70 Gy, 71.6% received all three cycles of cisplatin, and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% [95% confidence interval (CI), 33%–61%]. Two-year overall survival (OS) was 66% (95% CI, 53%–77%); median OS was not reached. Response rate was 66.7%. Most common grade ≥3 toxicities included mucositis (55%), dysphagia (46%), and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all oropharyngeal) were HPV positive. HPV+ patients had significantly longer OS and PFS (P = 0.004 and P = 0.036, respectively). Conclusions: Concurrent cetuximab, cisplatin, and radiotherapy were well tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV+ tumors. Clin Cancer Res; 20(19); 5041–51. ©2014 AACR.

Minimally invasive surgery for parapharyngeal space tumors

Parapharyngeal space (PS) tumors are surrounded by critical anatomical structures. Resection is often challenging due to limited surgical exposure. Herein, we report a novel transcervical, minimally invasive, video‐assisted technique that facilitates the resection of PS lesions.

Pseudomeningoceles of the sphenoid sinus masquerading as sinus pathology

To describe the clinical presentation, pathophysiology, and treatment of spontaneous cerebrospinal fluid (CSF) leaks of the sphenoid bone, with an emphasis on a previously undescribed form in this location, in which CSF is trapped under the mucosa of the sinonasal cavity or in the soft tissue of the skull base.

Choline phosphate cytidylyltransferase‐α is a novel antigen detected by the anti‐ERCC1 antibody 8F1 with biomarker value in patients with lung and head and neck squamous cell carcinomas

The determination of in situ protein levels of ERCC1 with the 8F1 monoclonal antibody is prognostic of survival in patients with non‐small cell lung cancer (NSCLC). The authors previously demonstrated that 8F1 recognizes a second nuclear antigen. This antigen was identified and its value as a biomarker of clinical outcomes analyzed.

Frailty Measurements and Dysphagia in the Outpatient Setting

Objective: Deconditioning and frailty may contribute to dysphagia and aspiration. Early identification of patients at risk of aspiration is important. Aspiration prevention would lead to reduced morbidity and health care costs. We therefore wondered whether objective measurements of frailty could help identify patients at risk for dysphagia and aspiration. Methods: Consecutive patients (n = 183) were enrolled. Patient characteristics and objective measures of frailty were recorded prospectively. Variables tested included age, body mass index, grip strength, and 5 meter walk pace. Statistical analysis tested for association between these parameters and dysphagia or aspiration, diagnosed by instrumental swallowing examination. Results: Of variables tested for association with grip strength, only age category (P = .003) and ambulatory status (P < .001) were significantly associated with grip strength in linear regression models. Whereas walk speed was not associated with dysphagia or aspiration, ambulatory status was significantly associated with dysphagia and aspiration in multivariable model building. Conclusion: Nonambulatory status is a predictor of aspiration and should be included in risk assessments for dysphagia. The relationship between frailty and dysphagia deserves further investigation. Frailty assessments may help identify those at risk for complications of dysphagia.

Classification of Sphenoid Sinus Pneumatization: Relevance for Endoscopic Skull Base Surgery

The goal of this study was to present a classification based on the degree of pneumatization of the sphenoid sinus in the coronal plane that can be used to instruct preoperative planning for endoscopic endonasal surgery (EES).

CCTα is a novel antigen detected by the anti-ERCC1 antibody 8F1 with biomarker value in lung and head and neck squamous cell carcinomas

The determination of in situ protein levels of ERCC1 with the 8F1 monoclonal antibody is prognostic of survival in patients with non‐small cell lung cancer (NSCLC). The authors previously demonstrated that 8F1 recognizes a second nuclear antigen. This antigen was identified and its value as a biomarker of clinical outcomes analyzed.

Head and Neck Quality Assurance 2014

Quality assurance (QA) in complex head and neck cancer trials is essential. The need for QA is made more relevant with trials comprised of multiple end points, worldwide participation, and increasing use of adaptive strategies/advanced technology to validate/verify outcome analyses. Integration is necessary for tissue analysis, biomarker assessment, imaging, radiation therapy, chemotherapy, and/or targeted therapy for patients with new diagnosis, relapse, and second head and neck malignancies.