Tapan A. Padhya

HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment.

The hypoxic environment of tumors dictates the phenotype of local myeloid-derived suppressor cells (MDSCs) via HIF-1a expression; hypoxia converts splenic MDSCs from specific into nonspecific suppressors.

Mechanism Regulating Reactive Oxygen Species in Tumor-Induced Myeloid-Derived Suppressor Cells

Myeloid-derived suppressor cells (MDSC) are a major component of the immune suppressive network described in cancer and many other pathological conditions. Recent studies have demonstrated that one of the major mechanisms of MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). However, the mechanism of this phenomenon remained unknown. In this study, we observed a substantial up-regulation of ROS by MDSC in all of seven different tumor models and in patients with head and neck cancer. The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). MDSC from tumor-bearing mice had significantly higher expression of NOX2 subunits, primarily p47phox and gp91phox, compared with immature myeloid cells from tumor-free mice. Expression of NOX2 subunits in MDSC was controlled by the STAT3 transcription factor. In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. These findings expand our fundamental understanding of the biology of MDSC and may also open new opportunities for therapeutic regulation of these cells in cancer.

Lipid accumulation and dendritic cell dysfunction in cancer

Dendritic cells (DCs), a type of professional antigen-presenting cells, are responsible for initiation and maintenance of immune responses. Here we report that a substantial proportion of DCs in tumor-bearing mice and people with cancer have high amounts of triglycerides as compared with DCs from tumor-free mice and healthy individuals. In our studies, lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to upregulation of scavenger receptor A. DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens. DCs with high and normal lipid levels did not differ in expression of major histocompatibility complex and co-stimulatory molecules. However, lipid-laden DCs had a reduced capacity to process antigens. Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines. These findings suggest that immune responses in cancer can be improved by manipulating the lipid levels in DCs.

Prognostic Factors for Survival After Salvage Reirradiation of Head and Neck Cancer

PURPOSE Patients who develop recurrent or new primary head and neck cancer in a previously irradiated site have poor prognosis. Reirradiation is a treatment option, although it is associated with substantial toxicities. We investigated potential prognostic factors, including comorbidity and pre-existing organ dysfunction, for survival after reirradiation. METHODS Institutional electronic records of patients treated with reirradiation between January 1998 and 2008 were reviewed. Comorbidity was assessed by Charlson index and Adult Comorbidity Evaluation-27 (ACE-27) grading. Organ dysfunction was defined as feeding tube dependency, functioning tracheostomy, or soft tissue defect. RESULTS There were 103 patients, including 46 patients who underwent salvage surgery before reirradiation. Median progression-free and overall survivals were 12.1 months (95% CI, 9.7 to 16.6) and 19.3 months (95% CI, 13.9 to 29.9), respectively. Significant comorbidity was present in 36% of patients by Charlson index and 24% by ACE-27. Baseline organ dysfunction was present in 37% of patients. Median overall survivals were 5.5 months among those with both organ dysfunction and comorbidity per Charlson index, and 4.9 months per ACE-27, compared with 59.6 and 44.2 months, respectively, among the patients with neither organ dysfunction nor comorbidity (P < .001 and < .001). Other independent prognostic factors were interval from previous radiation, recurrent tumor stage, tumor bulk at reirradiation, and reirradiation dose. A nomogram to predict the probability of death within 24 months after reirradiation was developed (concordance index = 0.75). CONCLUSION Comorbidity and pre-existing organ dysfunction are among several important prognostic factors for patients undergoing reirradiation. For those with both comorbidity and organ dysfunction, reirradiation largely serves as a palliative therapy.

Three-Year Outcomes of Cranial Nerve Stimulation for Obstructive Sleep Apnea The STAR Trial

Objective To describe the 36-month clinical and polysomnography (PSG) outcomes in an obstructive sleep apnea (OSA) cohort treated with hypoglossal cranial nerve upper airway stimulation (UAS). Study Design A multicenter prospective cohort study. Setting Industry-supported multicenter academic and clinical setting. Subjects Participants (n = 116) at 36 months from a cohort of 126 implanted participants. Methods Participants were enrolled in a prospective phase III trial evaluating the efficacy of UAS for moderated to severe OSA. Prospective outcomes included apnea-hypopnea index, oxygen desaturation index, other PSG measures, self-reported measures of sleepiness, sleep-related quality of life, and snoring. Results Of 126 enrolled participants, 116 (92%) completed 36-month follow-up evaluation per protocol; 98 participants additionally agreed to a voluntary 36-month PSG. Self-report daily device usage was 81%. In the PSG group, 74% met the a priori definition of success with the primary outcomes of apnea-hypopnea index, reduced from the median value of 28.2 events per hour at baseline to 8.7 and 6.2 at 12 and 36 months, respectively. Similarly, self-reported outcomes improved from baseline to 12 months and were maintained at 36 months. Soft or no snoring reported by bed partner increased from 17% at baseline to 80% at 36 months. Serious device-related adverse events were rare, with 1 elective device explantation from 12 to 36 months. Conclusion Long-term 3-year improvements in objective respiratory and subjective quality-of-life outcome measures are maintained. Adverse events are uncommon. UAS is a successful and appropriate long-term treatment for individuals with moderate to severe OSA.

Outcomes of Postoperative Concurrent Chemoradiotherapy for Locally Advanced Major Salivary Gland Carcinoma

OBJECTIVE To investigate the potential value of postoperative concurrent chemoradiation among patients with high-risk salivary gland carcinomas. DESIGN Case control study based on retrospective medical record review. SETTING A tertiary care comprehensive cancer center. PATIENTS A total of 24 patients, 12 with major salivary gland carcinoma who were treated with postoperative concurrent chemoradiotherapy from 1998 to 2007 (chemoradiation group), and a control group of 12 patients treated with postoperative radiation alone. MAIN OUTCOME MEASURES Overall survival, progression-free survival, toxic effects. RESULTS All but 1 patient had stage III or IV disease; close or positive surgical margins were identified in 20 patients (83%). The median radiation dose was 63 Gy. In the chemoradiation group, platinum-based regimens were used in all. Treatment was well tolerated, but toxic effects, predominantly hematologic, were increased in the chemoradiation group. To date, 8 patients have died; the median overall survival was 53 months. The overall survival in the chemoradiation group was significantly better than in the radiation-alone group: 3-year survival rates were 83% and 44%, respectively (P = .05). CONCLUSIONS Locally advanced or high-grade salivary gland carcinomas follow an aggressive clinical course. Based on our limited experience, postoperative chemoradiation with a platinum-based regimen seems to be effective in selected patients and warrants further investigation.

Electronic Nicotine Delivery Systems (''E-cigarettes''): Review of Safety and Smoking Cessation Efficacy

Background and Objectives Cigarette smoking is common among cancer patients and is associated with negative outcomes. Electronic nicotine delivery systems (“e-cigarettes”) are rapidly growing in popularity and use, but there is limited information on their safety or effectiveness in helping individuals quit smoking. Data Sources The authors searched PubMed, Web of Science, and additional sources for published empirical data on safety and use of electronic cigarettes as an aid to quit smoking. Review Methods We conducted a structured search of the current literature up to and including November 2013. Results E-cigarettes currently vary widely in their contents and are sometimes inconsistent with labeling. Compared to tobacco cigarettes, available evidence suggests that e-cigarettes are often substantially lower in toxic content, cytotoxicity, associated adverse effects, and secondhand toxicity exposure. Data on the use of e-cigarettes for quitting smoking are suggestive but ultimately inconclusive. Conclusions Clinicians are advised to be aware that the use of e-cigarettes, especially among cigarette smokers, is growing rapidly. These devices are unregulated, of unknown safety, and of uncertain benefit in quitting smoking. Implications for Practice In the absence of further data or regulation, oncologists are advised to discuss the known and unknown safety and efficacy information on e-cigarettes with interested patients and to encourage patients to first try FDA-approved pharmacotherapies for smoking cessation.

Head and Neck Melanoma

BACKGROUND Melanoma of the head and neck and its treatment are complex issues. The behavior of head and neck melanoma is aggressive, and it has an overall poorer prognosis than that of other skin sites. METHODS The authors review current data on the treatment of head and neck melanoma, including both cutaneous and mucosal melanoma. RESULTS Current understanding of the behavior of head and neck melanoma is reviewed and treatment stratagems are presented. Controversies in treatment include lymphoscintigraphy with sentinel node biopsy, nodal dissection, margin size, role of radiation therapy, and reconstruction. The management goal is to treat melanoma aggressively while minimizing the effects of treatment on patient quality of life. CONCLUSIONS Due to its aggressiveness, head and neck melanoma should be treated aggressively when morbidity is not significantly increased. Patient specific treatment is imperative.

Randomized Controlled Withdrawal Study of Upper Airway Stimulation on OSA: Short- and Long-term Effect

Objective To assess the efficacy and durability of upper airway stimulation via the hypoglossal nerve on obstructive sleep apnea (OSA) severity including objective and subjective clinical outcome measures. Study Design A randomized controlled therapy withdrawal study. Setting Industry-supported multicenter academic and clinical setting. Subjects A consecutive cohort of 46 responders at 12 months from a prospective phase III trial of 126 implanted participants. Methods Participants were randomized to either therapy maintenance (“ON”) group or therapy withdrawal (“OFF”) group for a minimum of 1 week. Short-term withdrawal effect as well as durability at 18 months of primary (apnea hypopnea index and oxygen desaturation index) and secondary outcomes (arousal index, oxygen desaturation metrics, Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, snoring, and blood pressure) were assessed. Results Both therapy withdrawal group and maintenance group demonstrated significant improvements in outcomes at 12 months compared to study baseline. In the randomized assessment, therapy withdrawal group returned to baseline, and therapy maintenance group demonstrated no change. At 18 months with therapy on in both groups, all objective respiratory and subjective outcome measures showed sustained improvement similar to those observed at 12 months. Conclusion Withdrawal of therapeutic upper airway stimulation results in worsening of both objective and subjective measures of sleep and breathing, which when resumed results in sustained effect at 18 months. Reduction of obstructive sleep apnea severity and improvement of quality of life were attributed directly to the effects of the electrical stimulation of the hypoglossal nerve.

Endothelin receptor type B gene promoter hypermethylation in salivary rinses is independently associated with risk of oral cavity cancer and premalignancy.

Endothelin receptor type B (EDNRB) and kinesin family member 1A (KIF1A) are candidate tumor suppressor genes that are inactivated in cancers. In this study, we evaluated the promoter hypermethylation of EDNRB and KIF1A and their potential use for risk classification in prospectively collected salivary rinses from patients with premalignant/malignant oral cavity lesions. Quantitative methylation-specific PCR was performed to analyze the methylation status of EDNRB and KIF1A in salivary rinses of 191 patients. We proceeded to determine the association of methylation status with histologic diagnosis and estimate classification accuracy. On univariate analysis, diagnosis of dysplasia/cancer was associated with age and KIF1A or EDNRB methylation. Methylation of EDNRB highly correlated with that of KIF1A (P < 0.0001). On multivariable modeling, histologic diagnosis was independently associated with EDNRB (P = 0.0003) or KIF1A (P = 0.027) methylation. A subset of patients analyzed (n = 161) without prior biopsy-proven malignancy received clinical risk classification based on examination. On univariate analysis, EDNRB and risk classification were associated with diagnosis of dysplasia/cancer and remained significant on multivariate analysis (EDNRB: P = 0.047, risk classification: P = 0.008). Clinical risk classification identified dysplasia/cancer with a sensitivity of 71% and a specificity of 58%. The sensitivity of clinical risk classification combined with EDNRB methylation improved to 75%. EDNRB methylation in salivary rinses was independently associated with histologic diagnosis of premalignancy and malignancy and may have potential in classifying patients at risk for oral premalignant and malignant lesions in settings without access to a skilled dental practitioner. This may also potentially identify patients with premalignant and malignant lesions that do not meet the criteria for high clinical risk based on skilled dental examination. Cancer Prev Res; 3(9); 1093–103. ©2010 AACR.