Faculty Bibliography

Objective: Current national guidelines include category 1 recommendations for perioperative chemotherapy or adjuvant chemoradiation with surgical resection for patients with stage IB-IIIB gastric cancer. We conducted a meta-analysis of randomized trials in which chemotherapy was prospectively tested against chemoradiation with surgical resection. Methods: We electronically searched PubMed and EMBASE for randomized, controlled clinical trials involving patients with gastric adenocarcinoma, status post-R0 resection. The interventions compared were adjuvant chemotherapy versus chemoradiation, with any chemotherapy regimen. The primary outcomes of interest were disease-free survival and overall survival. The Mantel-Haenszel random-effects model was used to calculate effect sizes. Results: Six trials that included 1,171 patients were evaluated; 599 were randomized to adjuvant chemoradiation and 572 to chemotherapy alone. Chemoradiation was associated with a significant increase in disease-free survival (odds ratio 1.48, 95% confidence interval 1.08-2.03) when compared to chemotherapy alone. However, there was no significant difference in overall survival (odds ratio 1.27, 95% confidence interval 0.95-1.71). Five trials found no statistically significant differences in toxicities between the two groups. Conclusion: In patients with gastric cancer status post-R0 resection, adjuvant chemoradiation was associated with higher disease-free survival when compared to chemotherapy alone. It remains appropriate to design trials testing new systemic agents with radiotherapy. (c) 2014 S. Karger AG, Basel.

PURPOSE: To present a novel method of tumor radiosensitization through Hsp27 knockdown using locked nucleic acid (LNA) and to investigate the role of Hsp27 in DNA double strand break (DSB) repair. METHODS AND MATERIALS: Clonogenic survival assays, immunoblotting, the proximity ligation assay, and gammaH2AX foci analysis were conducted in SQ20B and FaDu human head-and-neck cancer cell lines treated with Hsp27 LNA and Hsp27 short hairpin RNA (shRNA). Additionally, nude mice with FaDu flank tumors were treated with fractionated radiation therapy after pretreatment with Hsp27 LNA and monitored for tumor growth. RESULTS: Hsp27 LNA and Hsp27 shRNA radiosensitized head-and-neck cancer cell lines in an Hsp27-dependent manner. Ataxia-Telangectasia Mutated-mediated DNA repair signaling was impaired in irradiated cells with Hsp27 knockdown. ATM kinase inhibition abrogated the radiosensitizing effect of Hsp27. Furthermore, Hsp27 LNA and shRNA both attenuated DNA repair kinetics after radiation, and Hsp27 was found to colocalize with ATM in both untreated and irradiated cells. Last, combined radiation and Hsp27 LNA treatment in tumor xenografts in nude mice suppressed tumor growth compared with either treatment alone. CONCLUSIONS: These results support a radiosensitizing property of Hsp27 LNA in vitro and in vivo, implicate Hsp27 in double strand break repair, and suggest that Hsp27 LNA might eventually serve as an effective clinical agent in the radiotherapy of head-and-neck cancer.

INTRODUCTION: Previous studies by our group and others have demonstrated the importance of sociodemographic factors in cancer-related outcomes. The identification of these factors has led to novel approaches to the care of the high-risk cancer patient, specifically in the adoption of clinical interventions that convey similar benefits as favorable sociodemographic characteristics. This study examined the importance of marital status and race as prognostic indicators in men with prostate cancer. METHODS: This report is a meta-analysis of 3,570 patients with prostate cancer treated in three prospective RTOG clinical trials. The Kaplan-Meier method was used to estimate the survival rate and the cumulative incidence method was used to analyze biochemical failure rate. Hazard ratios were calculated for all covariates using either the Cox or Fine and Gray's proportional hazards model or logistic regression model with associated 95% confidence intervals and p values. RESULTS: Hazard ratio (HR) for overall survival (OS) for single status compared to married status was 1.36 (95% CI, 1.2 to 1.53). OS HR for non-White compared to White patients was 1.05 (CI 0.92 to 1.21). In contrast, the disease-free survival (DFS) HR and biochemical failure (BF) HR were both not significantly different neither between single and married patients nor between White patients and non-White patients. Median time to death for married men was 5.68 years and for single men was 4.73 years. Median time for DFS for married men was 7.25 years and for single men was 6.56 years. Median time for BF for married men was 7.81 years and for single men was 7.05 years. CONCLUSIONS: Race was not associated with statistically significant differences in this analysis. Congruent with our previous work in other cancer sites, marital status predicted improved prostate cancer outcomes including overall survival. IMPLICATIONS FOR CANCER SURVIVORS: Prostate cancer is the most common visceral cancer in men in the USA. The stratification of prostate cancer risk is currently modeled solely on pathologic prognostic factors including PSA and Gleason Score. Independent of these pathologic prognostic factors, our paper describes the central sociodemographic factor of being single as a negative prognostic indicator. Single men are at high risk of poorer outcomes after prostate cancer treatment. Intriguingly, in our group of patients, race was not a significant prognostic factor. The findings in this paper add to the body of work that describes important sociodemographic prognostic factors that are currently underappreciated in patients with cancer. Future steps will include the validation of these findings in prospective studies, and the incorporation of clinical strategies that identify and compensate for sociodemographic factors that predict for poorer cancer outcomes.

Intensity modulated radiation therapy (IMRT) has recently been proposed for the treatment of malignant pleural mesothelioma (MPM). Here, we describe our experience with a multimodality approach for the treatment of mesothelioma, incorporating extrapleural pneumonectomy, intraoperative photodynamic therapy and postoperative hemithoracic IMRT. From 2004-2007, we treated 11 MPM patients with hemithoracic IMRT, 7 of whom had undergone porfimer sodium-mediated PDT as an intraoperative adjuvant to surgical debulking. The median radiation dose to the planning treatment volume (PTV) ranged from 45.4-54.5 Gy. For the contralateral lung, V20 ranged from 1.4-28.5%, V5 from 42-100% and MLD from 6.8-16.5 Gy. In our series, 1 patient experienced respiratory failure secondary to radiation pneumonitis that did not require mechanical ventilation. Multimodality therapy combining surgery with increased doses of radiation using IMRT, and newer treatment modalities such as PDT , appears safe. Future prospective analysis will be needed to demonstrate efficacy of this approach in the treatment of malignant mesothelioma. Efforts to reduce lung toxicity and improve dose delivery are needed and provide the promise of improved local control and quality of life in a carefully chosen multidisciplinary approach.

The analysis of biomolecular interactions is key in the drug development process. Label-free biosensor methods provide information on binding, kinetics, concentration, and the affinity of an interaction. These techniques provide real-time monitoring of interactions between an immobilized ligand (such as a receptor) to an analyte in solution without the use of labels. Advances in biosensor design and detection using BioLayer Interferometry (BLI) provide a simple platform that enables label-free monitoring of biomolecular interactions without the use of flow cells. We review the applications of BLI in a wide variety of research and development environments for quantifying antibodies and proteins and measuring kinetics parameters.

PURPOSE: EF5, a 2-nitroimidazole hypoxia marker, was used to study the presence, levels, and prognostic significance of hypoxia in primary head and neck squamous cell tumors. METHODS AND MATERIALS: Twenty-two patients with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, or larynx with at least 2 years of clinical follow-up were included in this study. Quantitative analyses of EF5 immunofluorescence was carried out, and these data were compared with patient outcome. RESULTS: EF5 immunostaining showed substantial intra- and intertumoral hypoxic heterogeneity. The majority of cells in all tumors were well oxygenated. Three patterns of EF5 binding in cells were identified using criteria based on the cellular region that was stained (peripheral or central) and the relationship of binding to necrosis. We tested the association between EF5-binding levels with event-free and overall survival irrespective of the pattern of cellular binding or treatment regimen. Patients with tumors containing EF5-binding regions corresponding to severe hypoxia (< or =0.1% oxygen) had a shorter event-free survival time than patients with pO(2) values greater than 0.1% (p = 0.032). Nodal status was also predictive for outcome. CONCLUSIONS: These data illustrate the potential utility of EF5 binding based on quantitative immunohistochemistry of tissue pO(2) and provide support for the development of noninvasive hypoxia positron emission tomographic studies with fluorine 18-labeled EF5.