Publications by authors named "Anand K Sharma"

52 Publications

Challenges in tackling energy expenditure as obesity therapy: From preclinical models to clinical application.

Mol Metab 2021 Apr 18:101237. Epub 2021 Apr 18.

Cardio Metabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. Electronic address:

Background: A chronic imbalance of energy intake and energy expenditure results in excess fat storage. The obesity often caused by this overweight is detrimental to the health of millions of people. Understanding both sides of the energy balance equation and their counter-regulatory mechanisms is critical to the development of effective therapies to treat this epidemic.

Scope Of Review: Behaviors surrounding ingestion have been reviewed extensively. This review focuses more specifically on energy expenditure regarding bodyweight control, with a particular emphasis on the organs and attractive metabolic processes known to reduce bodyweight. Moreover, previous and current attempts at anti-obesity strategies focusing on energy expenditure are highlighted. Precise measurements of energy expenditure, which consist of cellular, animal, and human models, as well as measurements of their translatability, are required to provide the most effective therapies.

Major Conclusions: A precise understanding of the components surrounding energy expenditure, including tailored approaches based on genetic, biomarker, or physical characteristics, must be integrated into future anti-obesity treatments. Further comprehensive investigations are required to define suitable treatments, especially because the complex nature of the human perspective remains poorly understood.
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http://dx.doi.org/10.1016/j.molmet.2021.101237DOI Listing
April 2021

Development and Evaluation of a Navigation-Based, Multilevel Intervention to Improve the Delivery of Timely, Guideline-Adherent Adjuvant Therapy for Patients With Head and Neck Cancer.

JCO Oncol Pract 2021 Mar 10:OP2000943. Epub 2021 Mar 10.

Hollings Cancer Center, Medical University of South Carolina, Charleston, SC.

Purpose: More than half of patients with head and neck squamous cell carcinoma (HNSCC) experience a delay initiating guideline-adherent postoperative radiation therapy (PORT), contributing to excess mortality and racial disparities in survival. However, interventions to improve the delivery of timely, equitable PORT among patients with HNSCC are lacking. This study (1) describes the development of NDURE (Navigation for Disparities and Untimely Radiation thErapy), a navigation-based multilevel intervention (MLI) to improve guideline-adherent PORT and (2) evaluates its feasibility, acceptability, and preliminary efficacy.

Methods: NDURE was developed using the six steps of intervention mapping (IM). Subsequently, NDURE was evaluated by enrolling consecutive patients with locally advanced HNSCC undergoing surgery and PORT (n = 15) into a single-arm clinical trial with a mixed-methods approach to process evaluation.

Results: NDURE is a navigation-based MLI targeting barriers to timely, guideline-adherent PORT at the patient, healthcare team, and organizational levels. NDURE is delivered via three in-person navigation sessions anchored to case identification and surgical care transitions. Intervention components include the following: (1) patient education, (2) travel support, (3) a standardized process for initiating the discussion of expectations for PORT, (4) PORT care plans, (5) referral tracking and follow-up, and (6) organizational restructuring. NDURE was feasible, as judged by accrual (88% of eligible patients [100% Blacks] enrolled) and dropout (n = 0). One hundred percent of patients reported moderate or strong agreement that NDURE helped solve challenges starting PORT; 86% were highly likely to recommend NDURE. The rate of timely, guideline-adherent PORT was 86% overall and 100% for Black patients.

Conclusion: NDURE is a navigation-based MLI that is feasible, is acceptable, and has the potential to improve the timely, equitable, guideline-adherent PORT.
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http://dx.doi.org/10.1200/OP.20.00943DOI Listing
March 2021

Microscopic Extranodal Extension in HPV-Negative Head and Neck Cancer and the Role of Adjuvant Chemoradiation.

Otolaryngol Head Neck Surg 2021 Feb 23:194599821989637. Epub 2021 Feb 23.

Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.

Objective: Pathologic extranodal extension (ENE) is an important adverse feature for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), but the prognostic significance of microscopic ENE (ENE) and role of adjuvant concurrent chemoradiation (CRT) for ENE remain unclear. This study evaluates (1) the prognostic significance of ENE in HPV-negative HNSCC and (2) whether adjuvant CRT is associated with improved overall survival (OS) for these patients.

Study Design: Retrospective cohort study.

Setting: Commission on Cancer (CoC)-accredited facilities.

Methods: This retrospective cohort study included patients in the National Cancer Database from 2009 to 2015 with pathologic node-positive (pN+) HPV-negative HNSCC with either pathologic ENE or no ENE who had undergone margin-negative surgery. The association of ENE with OS was evaluated using Cox proportional hazard analyses. Analyses were repeated in patients with ENE receiving adjuvant therapy to evaluate the association of adjuvant CRT with OS.

Results: We included 5483 patients with pN+ HPV-negative HNSCC, of whom 24% had ENE. On multivariable analysis, ENE was associated with decreased OS relative to no ENE (adjusted hazard ratio [aHR], 1.43; 95% CI, 1.28-1.59). Among patients with ENE who received ≥60 Gy of adjuvant radiation therapy (RT) (n = 617), adjuvant CRT was not associated with improved OS relative to RT (aHR, 0.91; 95% CI, 0.66-1.27).

Conclusion: For patients with HPV-negative HNSCC, pN+ with ENE is associated with worse OS than pN+ without ENE. However, for patients with ENE, concurrent CRT is not associated with improved OS relative to RT. The optimal adjuvant paradigm for ENE requires additional investigation.
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http://dx.doi.org/10.1177/0194599821989637DOI Listing
February 2021

Barriers to the Delivery of Timely, Guideline-Adherent Adjuvant Therapy Among Patients With Head and Neck Cancer.

JCO Oncol Pract 2020 12 27;16(12):e1417-e1432. Epub 2020 Aug 27.

Hollings Cancer Center, Medical University of South Carolina, Charleston, SC.

Purpose: Delays initiating guideline-adherent postoperative radiation therapy (PORT) in head and neck squamous cell carcinoma (HNSCC) are common, contribute to excess mortality, and are a modifiable target for improving survival. However, the barriers that prevent the delivery of timely, guideline-adherent PORT remain unknown. This study aims to identify the multilevel barriers to timely, guideline-adherent PORT and organize them into a conceptual model.

Materials And Methods: Semi-structured interviews with key informants were conducted with a purposive sample of patients with HNSCC and oncology providers across diverse practice settings until thematic saturation (n = 45). Thematic analysis was performed to identify the themes that explain barriers to timely PORT and to develop a conceptual model.

Results: In all, 27 patients with HNSCC undergoing surgery and PORT were included, of whom 41% were African American, and 37% had surgery and PORT at different facilities. Eighteen clinicians representing a diverse mix of provider types from 7 oncology practices participated in key informant interviews. Five key themes representing barriers to timely PORT were identified across 5 health care delivery levels: (1) inadequate education about timely PORT, (2) postsurgical sequelae that interrupt the tight treatment timeline (both intrapersonal level), (3) insufficient coordination and communication during care transitions (interpersonal and health care team levels), (4) fragmentation of care across health care organizations (organizational level), and (5) travel burden for socioeconomically disadvantaged patients (community level).

Conclusion: This study provides a novel description of the multilevel barriers that contribute to delayed PORT. Interventions targeting these multilevel barriers could improve the delivery of timely, guideline-adherent PORT and decrease mortality for patients with HNSCC.
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http://dx.doi.org/10.1200/OP.20.00271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735037PMC
December 2020

Evaluating Adjuvant Therapy With Chemoradiation vs Radiation Alone for Patients With HPV-Negative N2a Head and Neck Cancer.

JAMA Otolaryngol Head Neck Surg 2020 12;146(12):1109-1119

Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston.

Importance: The American Joint Committee on Cancer staging system (Cancer Staging Manual, 8th Edition) for head and neck squamous cell carcinoma (HNSCC) now categorizes human papillomavirus (HPV)-negative HNSCC in a single positive lymph node smaller than 3 cm with pathologic extranodal extension (ENE) as N2a. The standard of care for pathologic ENE is adjuvant chemoradiation therapy (CRT). Whether adding chemotherapy concurrent with adjuvant radiation therapy improves survival in this clinical scenario is unknown.

Objective: To assess whether adjuvant CRT relative to radiation therapy alone is associated with improved survival among patients with pN2a HPV-negative HNSCC with ENE.

Design, Setting, And Participants: This retrospective cohort study included 504 patients with pN2a HPV-negative HNSCC with ENE who had undergone margin-negative surgery and adjuvant therapy. The patients were identified from the National Cancer Database from January 1, 2004, to December 31, 2015. Statistical analyses were conducted from September 1, 2019, to April 16, 2020.

Main Outcomes And Measures: The primary end point was overall survival. The association of adjuvant CRT with overall survival was analyzed using univariate and multivariate Cox proportional hazards regression analyses. Planned subset analyses were conducted in patients younger than 70 years with no comorbidities (the subset most likely to be eligible for a clinical trial of cisplatin-based chemoradiation) and in patients with pT3/T4 disease classification.

Results: Of 504 patients (mean [SD] age, 60.5 [12.7] years; 319 [63.3%] men; 434 [86.1%] White) with pN2a HPV-negative HNSCC with ENE who had undergone margin-negative surgery and adjuvant therapy, 298 patients (59.1%) received adjuvant CRT. For the overall cohort of patients with pN2a ENE, adjuvant CRT was not associated with improved overall survival relative to adjuvant radiation therapy alone in a multivariate analysis (adjusted hazard ratio, 0.98; 95% CI, 0.74-1.30). Adjuvant CRT was still not associated with improved overall survival in a subset analysis of 304 patients younger than 70 years with no comorbidities (adjusted hazard ratio, 0.98; 95% CI, 0.66-1.45) nor in a subset of 220 patients with pT3/T4 disease classification (adjusted hazard ratio, 1.03; 95% CI, 0.70-1.54).

Conclusions And Relevance: This study found that for patients with pN2a HPV-negative HNSCC with ENE who underwent margin-negative surgery and adjuvant therapy, adding chemotherapy concurrent with adjuvant radiation therapy was not associated with improved overall survival. Additional research is necessary to identify the optimal treatment paradigm for this clinical scenario.
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http://dx.doi.org/10.1001/jamaoto.2020.2107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426875PMC
December 2020

The Evolution of Care of Cancers of the Head and Neck Region: State of the Science in 2020.

Cancers (Basel) 2020 Jun 11;12(6). Epub 2020 Jun 11.

Head and Neck Tumor Center, Hollings Cancer Center, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.

Cancers that arise in the head and neck region are comprised of a heterogeneous group of malignancies that include carcinogen- and human papillomavirus (HPV)-driven mucosal squamous cell carcinoma as well as skin cancers such as cutaneous squamous cell carcinoma, basal cell carcinoma, melanoma, and Merkel cell carcinoma. These malignancies develop in critical areas for eating, talking, and breathing and are associated with substantial morbidity and mortality despite advances in treatment. Understanding of advances in the management of these various cancers is important for all multidisciplinary providers who care for patients across the cancer care continuum. Additionally, the recent Coronavirus Disease 2019 (COVID-19) pandemic has necessitated adaptations to head and neck cancer care to accommodate the mitigation of COVID-19 risk and ensure timely treatment. This review explores advances in diagnostic criteria, prognostic factors, and management for subsites including head and neck squamous cell carcinoma and the various forms of skin cancer (basal cell carcinoma, cutaneous squamous cell carcinoma, Merkel cell carcinoma, and melanoma). Then, this review summarizes emerging developments in immunotherapy, radiation therapy, cancer survivorship, and the delivery of care during the COVID-19 era.
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http://dx.doi.org/10.3390/cancers12061543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352543PMC
June 2020

Long-term outcome comparison for standard fractionation (>59 Gy) versus hyperfractionated (>45 Gy) radiotherapy plus concurrent chemotherapy for limited-stage small-cell lung cancer.

Rep Pract Oncol Radiother 2020 Jul-Aug;25(4):489-493. Epub 2020 Apr 27.

Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, US.

Background: Concurrent chemoradiotherapy (CCRT) is commonly employed in limited-stage small-cell lung cancer (LS-SCLC); however, the optimal radiotherapy regimen is still unknown. This 3-institution analysis compares long-term disease control and survival outcomes for once- (QD) versus twice-daily (BID) radiotherapy at contemporary doses.

Methods And Materials: Data were collected for LS-SCLC patients treated with platinum-based CCRT and planned RT doses of >5940 cGy at >180 cGy QD or >4500 cGy at 150 cGy BID. Comparative outcome analyses were performed for treatment groups.

Results: From 2005 through 2014, 132 patients met inclusion criteria for analysis (80 QD, 52 BID). Treatment groups were well-balanced, excepting higher rate of advanced mediastinal staging, longer interval from biopsy to treatment initiation, and lower rate of prophylactic cranial irradiation for the QD group, as well as institutional practice variation. At median survivor follow-up of 33.5 months (range, 4.6-105.8), 80 patients experienced disease failure (44 QD, 36 BID), and 106 died (62 QD, 44 BID). No differences in disease control or survival were demonstrated between treatment groups.

Conclusion: The present analysis did not detect a difference in disease control or survival outcomes for contemporary dose QD versus BID CCRT in LS-SCLC.
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http://dx.doi.org/10.1016/j.rpor.2020.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251533PMC
April 2020

Association of Care Processes With Timely, Equitable Postoperative Radiotherapy in Patients With Surgically Treated Head and Neck Squamous Cell Carcinoma.

JAMA Otolaryngol Head Neck Surg 2018 12;144(12):1105-1114

Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston.

Importance: Delays in initiation of postoperative radiotherapy (PORT) after surgery for head and neck squamous cell carcinoma (HNSCC) are common, predominantly affect racial minorities, and are associated with decreased survival. Details regarding the care processes that contribute to timely, equitable PORT remain unknown.

Objective: To determine care processes associated with timely, equitable PORT.

Design, Setting, And Participants: This retrospective cohort study included patients 18 years or older undergoing surgery for HNSCC at the Medical University of South Carolina (MUSC), Charleston, followed by PORT (at MUSC or elsewhere) with or without chemotherapy from January 1, 2014, through December 31, 2016. Data were analyzed from September 15, 2017, through June 28, 2018.

Main Outcomes And Measures: The main outcome measure was the proportion of timely, guideline-adherent initiation of PORT (≤6 weeks postoperatively). Secondary outcome measures included care processes associated with timely PORT. The association between process variables with timely PORT was explored using multivariable logistic regression analysis. Effect modification of the association between receipt of care processes and timely PORT by race was explored using interaction effects.

Results: A total of 197 patients were included in the analysis; they were predominantly white (157 [79.7%]) and male (136 [69.0%]) with a mean age of 59 years (range, 28-89 years). Overall, 89 patients (45.2%) experienced a delay initiating PORT. African American patients had a 13.5% absolute increase in the rate of delayed PORT relative to white patients (21 of 37 [56.8%] vs 68 of 157 [43.3%]). The adjusted multivariable regression showed that the following care processes were associated with timely PORT: preoperative radiotherapy consultation (odds ratio [OR], 8.94; 95% CI, 1.64-65.53), PORT at MUSC (OR, 6.21; 95% CI, 1.85-24.75), pathology report within 7 postoperative days (OR, 4.14; 95% CI, 1.21-15.86), time from surgery to PORT referral of no longer than 10 days (OR, 12.14; 95% CI, 3.14-63.00), time from PORT referral to consultation of no longer than 10 days (OR, 10.76; 95% CI, 3.01-49.70), and time from PORT consultation to its start of no longer than 21 days (OR, 4.80; 95% CI 1.41-18.44). Analysis of interactions revealed no statistically significant differences between African American and white patients in receipt of key processes associated with timely PORT.

Conclusions And Relevance: Specific care processes are associated with guideline-adherent initiation of PORT. Novel strategies appear to be needed to ensure that these processes are performed for all patients with HNSCC, thereby facilitating timely, equitable PORT.
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http://dx.doi.org/10.1001/jamaoto.2018.2225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472989PMC
December 2018

Racial and Ethnic Disparities in Travel for Head and Neck Cancer Treatment and the Impact of Travel Distance on Survival.

Cancer 2018 08 22;124(15):3181-3191. Epub 2018 Jun 22.

Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.

Background: Patients who travel a long distance (≥50 miles) for cancer care have improved outcomes. However, to the authors' knowledge, the prevalence of long travel distances for treatment by patients with head and neck squamous cell carcinoma (HNSCC), and the effect of travel distance on overall survival (OS), remains unknown.

Methods: The authors used the National Cancer Data base from 2004 through 2013 to identify patients with HNSCC undergoing definitive treatment. Travel distance for treatment was categorized as short (<12.5 miles), intermediate (12.5-49.9 miles), and long (50-249.9 miles). The primary outcome, OS, was evaluated using Cox shared-frailty modeling. A secondary outcome, factors associated with intermediate and long travel distances, was evaluated using multivariable hierarchical logistic regression.

Results: Among 118,000 patients with HNSCC, 62,753 (53.2%), 40,644 (34.4%), and 14,603 (12.4%) patients, respectively, traveled short, intermediate, and long distances for treatment. After adjusting for relevant covariates, long travel distance was associated with treatment at academic and high-volume centers. Patients of black race, of Hispanic ethnicity, with Medicaid insurance, and who were treated with nonsurgical treatment were less likely to travel long distances for treatment (P<.001). Traveling a long distance for treatment was associated with improved OS on multivariable analysis (adjusted hazard ratio, 0.93; 95% confidence interval, 0.89-0.96) compared with a short distance.

Conclusions: Traveling a long distance for HNSCC treatment is associated with improved survival, especially for patients receiving nonsurgical management. Racial and ethnic disparities in travel for HNSCC treatment exist. As regionalization of care continues, future work should identify and address reasons for racial and ethnic disparities in travel that may prevent access to care at high-volume facilities. Cancer 2018;000:000-000. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097948PMC
August 2018

Primary Surgery vs Radiotherapy for Early Stage Oral Cavity Cancer.

Otolaryngol Head Neck Surg 2018 04 19;158(4):649-659. Epub 2017 Dec 19.

1 Department of Otolaryngology-Head & Neck Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.

Objective The goal of this study is to determine the effect of primary surgery vs radiotherapy (RT) on overall survival (OS) in patients with early stage oral cavity squamous cell carcinoma (OCSCC). In addition, this study attempts to identify factors associated with receiving primary RT. Study Design Retrospective cohort study. Setting National Cancer Database (NCDB, 2004-2013). Subjects and Methods Reviewing the NCDB from 2004 to 2013, patients with early stage I to II OCSCC were identified. Kaplan-Meier estimates of survival, Cox regression analysis, and propensity score matching were used to examine differences in OS between primary surgery and primary RT. Multivariable logistic regression analysis was performed to identify factors associated with primary RT. Results Of the 20,779 patients included in the study, 95.4% (19,823 patients) underwent primary surgery and 4.6% (956 patients) underwent primary RT. After adjusting for covariates, primary RT was associated with an increased risk of mortality (adjusted hazard ratio [aHR], 1.97; 99% confidence interval [CI], 1.74-2.22). On multivariable analysis, factors associated with primary RT included age ≥70 years, black race, Medicaid or Medicare insurance, no insurance, oral cavity subsite other than tongue, clinical stage II disease, low-volume treatment facilities, and earlier treatment year. Conclusion Primary RT for early stage OCSCC is associated with increased mortality. Approximately 5% of patients receive primary RT; however, this percentage is decreasing. Patients at highest risk for receiving primary RT include those who are elderly, black, with public insurance, and treated at low-volume facilities.
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http://dx.doi.org/10.1177/0194599817746909DOI Listing
April 2018

Effect of time to initiation of postoperative radiation therapy on survival in surgically managed head and neck cancer.

Cancer 2017 Dec 25;123(24):4841-4850. Epub 2017 Aug 25.

Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina.

Background: The objective of this study was to determine the effects of National Comprehensive Cancer Network (NCCN) guideline-adherent initiation of postoperative radiation therapy (PORT) and different time-to-PORT intervals on the overall survival (OS) of patients with head and neck squamous cell carcinoma (HNSCC).

Methods: The National Cancer Data Base was reviewed for the period of 2006-2014, and patients with HNSCC undergoing surgery and PORT were identified. Kaplan-Meier survival estimates, Cox regression analysis, and propensity score matching were used to determine the effects of initiating PORT within 6 weeks of surgery and different time-to-PORT intervals on survival.

Results: This study included 41,291 patients. After adjustments for covariates, starting PORT >6 weeks postoperatively was associated with decreased OS (adjusted hazard ratio [aHR], 1.13; 99% confidence interval [CI], 1.08-1.19). This finding remained in the propensity score-matched subset (hazard ratio, 1.21; 99% CI, 1.15-1.28). In comparison with starting PORT 5 to 6 weeks postoperatively, initiating PORT earlier was not associated with improved survival (aHR for ≤ 4 weeks, 0.93; 99% CI, 0.85-1.02; aHR for 4-5 weeks, 0.92; 99% CI, 0.84-1.01). Increasing durations of delay beyond 7 weeks were associated with small, progressive survival decrements (aHR, 1.09, 1.10, and 1.12 for 7-8, 8-10, and >10 weeks, respectively).

Conclusions: Nonadherence to NCCN guidelines for initiating PORT within 6 weeks of surgery was associated with decreased survival. There was no survival benefit to initiating PORT earlier within the recommended 6-week timeframe. Increasing durations of delay beyond 7 weeks were associated with small, progressive survival decrements. Cancer 2017;123:4841-50. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759768PMC
December 2017

Adherence to National Comprehensive Cancer Network guidelines for time to initiation of postoperative radiation therapy for patients with head and neck cancer.

Cancer 2017 Jul 27;123(14):2651-2660. Epub 2017 Feb 27.

Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina.

Background: Adherence to evidence-based treatment guidelines has been proposed as a measure of cancer care quality. The objective of this study was to determine the rate and predictors of care that does not adhere to National Comprehensive Cancer Network guidelines regarding commencing postoperative radiation therapy (PORT) within 6 weeks of surgery for patients with head and neck squamous cell carcinoma (HNSCC).

Methods: The National Cancer Data Base was reviewed from 2006 to 2014, and patients with HNSCC who underwent curative-intent surgery followed by PORT were identified. Multivariable logistic regression analysis was used to determine the factors associated with nonadherence to guidelines regarding the timing of initiating PORT.

Results: In total, 47,273 patients were included in the study. 55.7% of patients (26,340/47,273) failed to commence PORT within 6 week of surgery. The percentage of patients who failed to initiate PORT within 6 week of surgery increased over time. On multivariable analysis, the factors associated with failure to initiate timely, guideline-adherent PORT included black race, public insurance [Medicare, Medicaid] or uninsured status, lower levels of education, increased severity of comorbidity, increased postoperative length of stay, 30-day unplanned hospital readmission, treatment at an academic medical center, and the receipt of surgery and PORT at different facilities.

Conclusions: Over 50% of patients with HNSCC who undergo surgery and PORT receive care that does not adhere to National Comprehensive Cancer Network guidelines with regard to initiating PORT within 6 weeks of surgery. Sociodemographic, oncologic, treatment, and hospital factors are all associated with failure to receive guideline-directed care and should be explored in future studies. Cancer 2017;123:2651-60. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30651DOI Listing
July 2017

Effect of postoperative radiotherapy on survival for surgically managed pT3N0 and pT4aN0 laryngeal cancer: Analysis of the National Cancer Data Base.

Cancer 2017 Jun 9;123(12):2248-2257. Epub 2017 Feb 9.

Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina.

Background: The current study was conducted to determine the effect of postoperative radiotherapy (PORT) on overall survival in patients with surgically managed pT3-T4aN0 laryngeal squamous cell carcinoma (SCC).

Methods: A review of the National Cancer Data Base from 2004 through 2013 was performed. Patients with surgically managed pT3-4aN0 laryngeal SCC with negative surgical margins were included. Univariable and multivariable Cox regression analyses were used to determine factors associated with survival.

Results: A total of 1460 patients were included, 46.2% of whom had pT3N0 disease (674 patients) and 53.8% of whom had pT4aN0 disease (786 patients). Approximately 72.0% of the patients with pT3N0 disease (485 patients) and 50.1% of the patients with pT4aN0 disease (394 patients) received PORT. PORT was not found to be associated with improved overall survival on univariable analysis for patients with pT3N0 disease (hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62-1.14), but was for patients with pT4aN0 disease (HR, 0.57; 95% CI, 0.45-0.71). For patients with pT3N0 SCC of the larynx, in a multivariable Cox regression analysis adjusting for age >65 years, severity of comorbidities, larynx subsite, extent of laryngectomy, and number of lymph nodes removed, PORT was not found to be associated with improved survival (adjusted HR, 0.88; 95% CI, 0.64-1.21). For patients with pT4aN0 disease, the administration of PORT was associated with improved survival on multivariable analysis adjusting for age >65 years, severity of comorbidities, larynx subsite, number of lymph nodes removed, and type of hospital (adjusted HR, 0.58; 95% CI, 0.46-0.73).

Conclusions: For patients with surgically managed pT3N0 laryngeal SCC with negative margins, PORT does not appear to be associated with improved survival. Despite a survival benefit, nearly 50% of patients with pT4aN0 laryngeal SCC and negative surgical margins do not receive standard-of-care PORT. Cancer 2017;123:2248-2257. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30586DOI Listing
June 2017

STAT3 Regulation By S-Nitrosylation: Implication In Cancer.

Redox Biol 2015 08 30;5:416-417. Epub 2015 Dec 30.

Departments of Pediatrics, Pathology and Laboratory Medicine and Radiation Oncology. Medical University of South Carolina, Charleston, SC, USA.

In this study, we assessed S-nitrosylation-based regulation of Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. Our studies show that STAT3 in stimulated microglia underwent two distinct redox-dependent modifications, S-nitrosylation and S-glutathionylation. STAT3 S-nitrosylation was associated with inducible nitric oxide synthase (iNOS)-produced nitric oxide (NO) and S-nitrosoglutathione (GSNO), whereas S-glutathionylation of STAT3 was associated with cellular oxidative stress. NO produced by iNOS or treatment of microglia with exogenous GSNO inhibited STAT3 activation via inhibiting STAT3 phosphorylation (Tyr705). Consequently, the interleukin-6 (IL-6)-induced microglial proliferation and associated gene expressions were also reduced. In cell-free kinase assay using purified JAK2 and STAT3, STAT3 phosphorylation was inhibited by its selective preincubation with GSNO, but not by preincubation of JAK2 with GSNO, indicating that GSNO-mediated mechanisms inhibit STAT3 phosphorylation through S-nitrosylation of STAT3 rather than JAK2. In this study, we identified that Cys259 was the target Cys residue of GSNO-mediated S-nitrosylation of STAT3. The replacement of Cys259 residue with Ala abolished the inhibitory role of GSNO in IL-6-induced STAT3 phosphorylation and transactivation, suggesting the role of Cys259S-nitrosylation in STAT3phosphorylation. Since STAT3 activation is involved in tumor progression and metastasis, we investigated the effect of GSNO in cell culture and mouse xenograft model of head and neck squamous cell carcinoma (HNSCC). GSNO treatment of HNSCCN cell lines reversibly decreases the activation (phosphorylation) of STAT3 in a concentration dependent manner. The reduced STAT3/NF-kB activity by GSNO correlated with decreased cell proliferation and increased apoptosis of HNSCC cells. In HNSCC mouse xenograft model, the tumor growth was reduced by systemic treatment with GSNO and was further reduced when the treatment combined with radiation and cisplatin. Accordingly, GSNO treatment also resulted in decreased levels of pSTAT3 and tumor growth regulators (ie. cyclin D2, VEGF and Bcl-2) in tumor tissue. In summary, these findings have implications for the development of new therapeutics targeting of STAT3 for treating diseases associated with inflammatory/immune responses and abnormal cell proliferation, including cancer.
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http://dx.doi.org/10.1016/j.redox.2015.09.021DOI Listing
August 2015

S-Nitrosoglutathione-mediated STAT3 regulation in efficacy of radiotherapy and cisplatin therapy in head and neck squamous cell carcinoma.

Redox Biol 2015 Dec 2;6:41-50. Epub 2015 Jul 2.

Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address:

S-nitrosoglutathione (GSNO) is an endogenous nitric oxide (NO) carrier that plays a critical role in redox based NO signaling. Recent studies have reported that GSNO regulates the activities of STAT3 and NF-κB via S-nitrosylation dependent mechanisms. Since STAT3 and NF-κB are key transcription factors involved in tumor progression, chemoresistance, and metastasis of head and neck cancer, we investigated the effect of GSNO in cell culture and mouse xenograft models of head and neck squamous cell carcinoma (HNSCC). For the cell culture studies, three HNSCC cell lines were tested (SCC1, SCC14a and SCC22a). All three cell lines had constitutively activated (phosphorylated) STAT3 (Tyr(705)). GSNO treatment of these cell lines reversibly decreased the STAT3 phosphorylation in a concentration dependent manner. GSNO treatment also decreased the basal and cytokine-stimulated activation of NF-κB in SCC14a cells and reduced the basal low degree of nitrotyrosine by inhibition of inducible NO synthase (iNOS) expression. The reduced STAT3/NF-κB activity by GSNO treatment was correlated with the decreased cell proliferation and increased apoptosis of HNSCC cells. In HNSCC mouse xenograft model, the tumor growth was reduced by systemic treatment with GSNO and was further reduced when the treatment was combined with radiation and cisplatin. Accordingly, GSNO treatment also resulted in decreased levels of phosphorylated STAT3. In summary, these studies demonstrate that GSNO treatment blocks the NF-κB and STAT3 pathways which are responsible for cell survival, proliferation and that GSNO mediated mechanisms complement cispaltin and radiation therapy, and thus could potentiate the therapeutic effect in HNSCC.
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http://dx.doi.org/10.1016/j.redox.2015.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511642PMC
December 2015

Requirement of percutaneous endoscopic gastrostomy tube placement in head-and-neck cancer treated with definitive concurrent chemoradiation therapy: An analysis of clinical and anatomic factors.

Pract Radiat Oncol 2013 Apr-Jun;3(2):e61-9. Epub 2012 Jul 24.

Department of Radiation Oncology, Medical University of South Carolina, Charleston, South Carolina.

Purpose: There is significant variation in recommendation for percutaneous endoscopic gastrostomy (PEG) tube placement in patients undergoing definitive chemoradiation therapy (CRT) for locally advanced squamous cell carcinoma of the head and neck (LAHNC), with some clinicians globally recommending prophylactic PEG and others waiting until toxicity has occurred. The present study was conceived to identify specific factors associated with PEG requirement, in a population of LAHNC patients who did not have up-front PEG placement.

Methods And Materials: Using a quality assurance database, we identified patients with oropharyngeal (ORP) or laryngeal-hypopharyngeal (LHP) LAHNC who were treated with CRT for inclusion in a cohort study of factors impacting PEG placement. Eligibility included stage III/IV squamous cell carcinoma of ORP and LHP. Patients were excluded if they had a PEG placement prior to commencement of CRT. The primary endpoint compared across groups was PEG placement, and multivariate analysis of factors was performed.

Results: We identified 107 patients with LAHNC who did not receive PEG tubes prior to treatment. After treatment initiation, 41% of patients with ORP tumors required PEG placement during treatment compared with 16% of LHP patients (P = .03). After adjusting for covariates, multivariate analysis revealed that the only predictor for PEG placement was ORP primary (odds ratio 4.77; 95% confidence interval 1.6-13.8, P = .009) using LHP as reference.

Conclusions: Our findings suggest that the patients with ORP cancers are more likely to require PEG placement during treatment and should be considered for prophylactic PEG placement, while LHP sites were associated with lower likelihood of PEG requirement. The primary reason for this difference appears to be severity of pharyngitis; proactive nutritional monitoring and supplementation should be implemented early. Patients with pretreatment risk stratification for PEG placement in LAHNC may improve quality of care and avoid unnecessary treatment breaks.
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http://dx.doi.org/10.1016/j.prro.2012.06.006DOI Listing
March 2014

Assessing the usefulness of 18F-fluorodeoxyglucose PET-CT scan after stereotactic body radiotherapy for early-stage non-small cell lung cancer.

Chest 2014 Aug;146(2):406-411

Division of Pulmonary/Critical Care, Medical University of South Carolina, Charleston, SC.

Background: Although stereotactic body radiation therapy (SBRT) is an established treatment option for early-stage lung cancer, there are no guidelines for reassessing patients for local treatment failure or intrathoracic recurrence after treatment. This study reports the sensitivity, specificity, and positive and negative predictive values for 18F-fluorodeoxyglucose (FDG) PET-CT scanning when used to evaluate patients after SBRT.

Methods: Charts were reviewed of all patients who received SBRT and a subsequent FDG PET-CT scan at a university hospital over a 5-year period. Pretreatment and 3-month posttreatment tumor characteristics on PET-CT scan and outcome data (adverse events from SBRT, need for repeat biopsy, rate of local treatment failure and recurrent disease, and all-cause mortality) were recorded.

Results: Eighty-eight patients were included in the study. Fourteen percent of patients (12 of 88) had positive 3-month PET scans. Of the positive results, 67% (eight of 12) were true positives. Eighty-six percent (76 of 88 patients) had negative 3-month FDG PET-CT scans, with 89% (68 of 76) true negatives. FDG PET-CT scan performed 3 months after SBRT for non-small cell lung cancer (NSCLC) had a sensitivity of 50% (95% CI, 0.26-0.75), a specificity of 94% (95% CI, 0.89-1.0), a positive predictive value of 67% (95% CI, 0.4-0.93), and a negative predictive value of 89% (95% CI, 0.83- 0.96).

Conclusions: FDG PET-CT scan 3 months after treatment of NSCLC with SBRT was a specific but insensitive test for the detection of recurrence or treatment failure. Serial CT scans should be used for early surveillance following SBRT, whereas FDG PET-CT scans should be reserved to define suspected metastatic disease or to evaluate new abnormalities on CT scan, or for possible reassessment later in the follow-up period after radiation-related inflammation subsides.
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http://dx.doi.org/10.1378/chest.13-2281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137590PMC
August 2014

A comparison of outcomes using intensity-modulated radiation therapy and 3-dimensional conformal radiation therapy in treatment of oropharyngeal cancer.

JAMA Otolaryngol Head Neck Surg 2014 Apr;140(4):331-7

Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston.

Importance: Approximately 50% of head and neck cancer survivors experience dysphagia and related morbidity. Intensity-modulated radiation therapy (IMRT) is increasingly used to treat oropharyngeal cancers with excellent oncologic outcomes, but few studies have compared it with conventional 3-dimensional conformal radiation therapy (3D-CRT) to determine whether it can decrease treatment-related toxic and adverse effects.

Objective: To determine whether IMRT improves percutaneous endoscopic gastrostomy (PEG) tube and treatment-related toxicity outcomes compared with 3D-CRT in patients with oropharyngeal squamous cell carcinoma.

Design, Setting, And Participants: Retrospective review of 159 patients with oropharyngeal primary tumors with no history of chemotherapy, radiation therapy, or surgery of the head and neck who underwent definitive treatment with radiotherapy for oropharyngeal squamous cell carcinoma at the Hollings Cancer Center outpatient clinic, Medical University of South Carolina, from 2000 to 2009.

Intervention: Doses of 70 Gy in 35 daily fractions of radiotherapy delivered via IMRT or 3D-CRT.

Main Outcomes And Measures: Primary end points included PEG tube dependence 1 year after radiotherapy start, weight loss during treatment, and change in Eastern Cooperative Oncology Group performance status. Secondary end points included overall and disease-free survival, disease recurrence, and toxic effect profiles.

Results: The IMRT group (n = 103) had a significantly lower rate of PEG tube dependence 1 year after treatment initiation than the 3D-CRT group (n = 56) for all patients (P = .02) and for those with advanced T stage (P = .01) and a shorter time to PEG tube removal (P < .001). Acute grade 3 or greater toxic effects to skin and mucous membranes occurred less frequently in the IMRT group (P = .02 and P < .001, respectively). The 2 groups did not differ significantly in weight loss, treatment failure (hazard ratio, 0.82 [95% CI, 0.47-1.41]), overall survival (P = .45), or disease-free survival (P = .26).

Conclusions And Relevance: The use of IMRT significantly improves PEG tube and toxicity-related outcomes compared with 3D-CRT in the treatment of oropharyngeal primary cancers. Given the association between mucosal toxic effects, PEG tube dependence, and dysphagia, these findings may be an indication of improved swallowing outcomes with IMRT.
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http://dx.doi.org/10.1001/jamaoto.2013.6777DOI Listing
April 2014

Salivary gland transfer to prevent radiation-induced xerostomia: a systematic review and meta-analysis.

Oral Oncol 2014 Feb 1;50(2):77-83. Epub 2013 Nov 1.

Department of Otolaryngology - Head and Neck Surgery, Medical University of South Carolina, United States. Electronic address:

Salivary gland transfer (SGT) has the potential to prevent radiation-induced xerostomia. We attempt to analyze the efficacy of SGT in prevention of xerostomia and maintenance of salivary flow rates after radiation treatment (XRT). Systematic review and meta-analysis. Primary endpoint was efficacy of SGT in prevention of radiation-induced xerostomia. Secondary endpoint was change from baseline of unstimulated and stimulated salivary flow rates after XRT. Seven articles, accruing data from 12 institutions, met inclusion criteria. In a total of 177 patients at mean follow-up of 22.7months, SGT prevented radiation-induced xerostomia in 82.7% (95% CI, 76.6-87.7%) of patients. Twelve months after XRT, unstimulated and stimulated salivary flow rates rose to 88% and 76% of baseline values, respectively. In comparison to control subjects twelve months after XRT, SGT subjects' unstimulated (75% vs. 11%) and stimulated (86% vs. 8%) salivary flow rates were drastically higher in SGT patients. Salivary gland transfer appears to be highly effective in preventing the incidence of xerostomia in patients receiving definitive head and neck radiation therapy.
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http://dx.doi.org/10.1016/j.oraloncology.2013.10.010DOI Listing
February 2014

STAT3 regulation by S-nitrosylation: implication for inflammatory disease.

Antioxid Redox Signal 2014 Jun 14;20(16):2514-27. Epub 2014 Feb 14.

1 Department of Pediatrics, Medical University of South Carolina , Charleston, South Carolina.

Aims: S-nitrosylation and S-glutathionylation, redox-based modifications of protein thiols, are recently emerging as important signaling mechanisms. In this study, we assessed S-nitrosylation-based regulation of Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway that plays critical roles in immune/inflammatory responses and tumorigenesis.

Results: Our studies show that STAT3 in stimulated microglia underwent two distinct redox-dependent modifications, S-nitrosylation and S-glutathionylation. STAT3 S-nitrosylation was associated with inducible nitric oxide synthase (iNOS)-produced nitric oxide (NO) and S-nitrosoglutathione (GSNO), whereas S-glutathionylation of STAT3 was associated with cellular oxidative stress. NO produced by iNOS or treatment of microglia with exogenous GSNO inhibited STAT3 activation via inhibiting STAT3 phosphorylation (Tyr(705)). Consequently, the interleukin-6 (IL-6)-induced microglial proliferation and associated gene expressions were also reduced. In cell-free kinase assay using purified JAK2 and STAT3, STAT3 phosphorylation was inhibited by its selective preincubation with GSNO, but not by preincubation of JAK2 with GSNO, indicating that GSNO-mediated mechanisms inhibit STAT3 phosphorylation through S-nitrosylation of STAT3 rather than JAK2. In this study, we identified that Cys(259) was the target Cys residue of GSNO-mediated S-nitrosylation of STAT3. The replacement of Cys(259) residue with Ala abolished the inhibitory role of GSNO in IL-6-induced STAT3 phosphorylation and transactivation, suggesting the role of Cys(259) S-nitrosylation in STAT3 phosphorylation.

Innovation: Microglial proliferation is regulated by NO via S-nitrosylation of STAT3 (Cys(259)) and inhibition of STAT3 (Tyr(705)) phosphorylation.

Conclusion: Our results indicate the regulation of STAT3 by NO-based post-translational modification (S-nitrosylation). These findings have important implications for the development of new therapeutics targeting STAT3 for treating diseases associated with inflammatory/immune responses and abnormal cell proliferation, including cancer.
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http://dx.doi.org/10.1089/ars.2013.5223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026100PMC
June 2014

Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II trial.

J Clin Oncol 2013 Apr 4;31(11):1415-21. Epub 2013 Mar 4.

University of Washington, Seattle Cancer Care Alliance, 825 Eastlake Ave E MS G4-940, Seattle, WA 98109, USA.

Purpose: The combination of cisplatin and radiotherapy is a standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Cetuximab-radiotherapy is superior to radiotherapy alone in this population, validating epidermal growth factor receptor (EGFR) as a target. Erlotinib is a small-molecule inhibitor of EGFR. Adding EGFR inhibition to standard cisplatin-radiotherapy may improve efficacy.

Patients And Methods: Patients with locally advanced SCCHN were randomly assigned to receive cisplatin 100 mg/m(2) on days 1, 22, and 43 combined with 70 Gy of radiotherapy (arm A) or the same chemoradiotherapy with erlotinib 150 mg per day, starting 1 week before radiotherapy and continued to its completion (arm B). The primary end point was complete response rate (CRR), evaluated by central review. The secondary end point was progression-free survival (PFS). Available tumors were tested for p16 and EGFR by fluorescent in situ hybridization.

Results: Between December 2006 and October 2011, 204 patients were randomly assigned. Arms were well balanced for all patient characteristics including p16, with the exception of more women on arm A. Patients on arm B had more rash, but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities. Arm A had a CRR of 40% and arm B had a CRR of 52% (P = .08) when evaluated by central review. With a median follow-up time of 26 months and 54 progression events, there was no difference in PFS (hazard ratio, 0.9; P = .71).

Conclusion: Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS.
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http://dx.doi.org/10.1200/JCO.2012.46.3299DOI Listing
April 2013

Synchronous bilateral inverted papilloma of the temporal bone: Case report and review of the literature.

Head Neck 2013 Aug 28;35(8):E240-5. Epub 2012 Jun 28.

College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.

Background: Temporal bone inverted papilloma (IP) is an extremely rare tumor. Its etiology is unknown and represents a source of debate. Only 2 previous cases of bilateral temporal bone IP have been reported. A case report and review of the literature via PubMed database search are presented.

Mathods And Results: A 52-year-old African-American man who initially underwent medial maxillectomy for right-sided nasal IP returned with bilateral temporal bone IP 7 months later without evidence of extension through the Eustachian tubes. Despite multiple resections and adjuvant radiation, the tumor transformed into squamous cell carcinoma and progressed to involve the intracranial dura, temporal lobe, and cervical dura.

Conclusions: Multiple origins may exist for temporal IP: direct extension, iatrogenic seeding, or development from ectopic Schneiderian epithelium. Temporal bone IP appears to represent a much more aggressive tumor than its nasal counterpart, necessitating aggressive early surgical intervention to decrease recurrence and transformation risk.
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http://dx.doi.org/10.1002/hed.23073DOI Listing
August 2013

A phase II study of submandibular gland transfer prior to radiation for prevention of radiation-induced xerostomia in head-and-neck cancer (RTOG 0244).

Int J Radiat Oncol Biol Phys 2012 Oct 27;84(2):437-42. Epub 2012 Apr 27.

University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada.

Purpose: We report the results of a phase II study to determine the reproducibility of a submandibular salivary gland transfer (SGT) surgical technique for prevention of radiation (XRT)-induced xerostomia in a multi-institutional setting and to assess severity of xerostomia.

Methods And Materials: Eligible patients had surgery for primary, neck dissection, and SGT, followed by XRT, during which the transferred salivary gland was shielded. Intensity modulated radiation therapy, amifostine, and pilocarpine were not allowed, but postoperative chemotherapy was allowed. Each operation was reviewed by 2 reviewers and radiation by 1 reviewer. If 13 or more (of 43) were "not per protocol," then the technique would be considered not reproducible as per study design. The secondary endpoint was the rate of acute xerostomia, grade 2 or higher, and a rate of ≤ 51% was acceptable.

Results: Forty-four of the total 49 patients were analyzable: male (81.8%), oropharynx (63.6%), stage IV (61.4%), median age 56.5 years. SGT was "per protocol" or within acceptable variation in 34 patients (77.3%) and XRT in 79.5%. Nine patients (20.9%) developed grade 2 acute xerostomia; 2 had grade 0-1 xerostomia (4.7%) but started on amifostine/pilocarpine. Treatment for these 11 patients (25.6%) was considered a failure for the xerostomia endpoint. Thirteen patients died; median follow-up for 31 surviving patients was 2.9 years. Two-year overall and disease-free survival rates were 76.4% and 71.7%, respectively.

Conclusions: The technique of submandibular SGT is reproducible in a multicenter setting. Seventy-four percent of patients were prevented from XRT-induced acute xerostomia.
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http://dx.doi.org/10.1016/j.ijrobp.2012.02.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746194PMC
October 2012

Cervical osteomyelitis after placement of a self-expanding plastic stent for palliation of dysphagia associated with chemoradiation-induced esophageal strictures.

Head Neck 2013 Jun 24;35(6):E197-201. Epub 2012 Feb 24.

Department of Radiation Oncology, Medical University of South Carolina, Charleston, South Carolina, USA.

Background: Esophageal strictures are a common sequela of chemoradiation and/or surgery to the head and neck cancers and can lead to stenosis and significant dysphagia. Endoscopic dilation endoscopic and placement of self-expanding stents are often to used relieve dysphagia symptoms. However, these stents are not without risks and complications.

Methods: We present a case of a 58-year-old man who had the rare complication of cervical osteomyelitis as a result of plastic esophageal stent placement for palliation of chemoradiation-induced strictures.

Results: The patient was successfully managed with immobilization of the cervical spine in a halo vest and appropriate antibiotics.

Conclusion: To the best of our knowledge, this is the first reported case of cervical spine osteomyelitis after self-expanding plastic stent (SEPS) placement for esophageal stricture. It was successfully treated with immobilization and antibiotic therapy. The treating physician should be aware of this rare complication to make an early diagnosis. Literature on esophageal stent-induced cervical osteomyelitis is reviewed.
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http://dx.doi.org/10.1002/hed.22975DOI Listing
June 2013

Salvage Resection for Isolated Local and/or Regional Failure of Head/Neck Cancer Following Definitive Concurrent Chemoradiotherapy Case Series and Review of the Literature.

Mcgill J Med 2011 Jun;13(2):29

Background: Primary management of advanced head/neck cancers involves concurrent chemoradiotherapy . Subsequently, regional and local failures are managed with resection but there have been few reports that describe the morbidity and disease control outcomes of surgical salvage in this setting.

Methods: Retrospective analysis describes complications, survival, and patterns of failure after salvage resection of isolated local and/or regional failures of head/neck cancer following definitive concurrent chemoradiotherapy.

Results: Sixteen patients were identified for inclusion: laryngectomy in 11 patients, oral cavity/oropharynx resection in 2 patients, and neck dissection alone in 4 patients. Ten patients required graft tissue reconstruction (6 pedicle and 4 free flap). Median post-operative hospitalization was 7 days (range 3-19), and 4 patients required hospital re-admission. At a median survivor follow-up of 15.8 months (range 4.3-34.9), 10 patients were alive (6 without evidence of disease). Seven patients experienced disease recurrence at a median 6.7 months (range 0-12.6) following salvage resection (2 with isolated distant failures). Estimated 2-year local/regional control, freedom from failure, and overall survival were 58%, 39%, and 58%, respectively.

Conclusions: Surgical salvage after primary definitive concurrent chemoradiotherapy is feasible with toxicity and outcomes similar to prior radiotherapy alone or sequential chemotherapy and radiation. Local andregional recurrence remains the predominant pattern of failure.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277417PMC
June 2011

Results of a phase II trial of gemcitabine plus doxorubicin in patients with recurrent head and neck cancers: serum C₁₈-ceramide as a novel biomarker for monitoring response.

Clin Cancer Res 2011 Sep 26;17(18):6097-105. Epub 2011 Jul 26.

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.

Purpose: Here we report a phase II clinical trial, which was designed to test a novel hypothesis that treatment with gemcitabine (GEM)/doxorubicin (DOX) would be efficacious via reconstitution of C(18)-ceramide signaling in head and neck squamous cell carcinoma (HNSCC) patients for whom first-line platinum-based therapy failed.

Experimental Design: Patients received GEM (1,000 mg/m²) and DOX (25 mg/m²) on days 1 and 8, every 21 days, until disease progression. After completion of 2 treatment cycles, patients were assessed radiographically, and serum samples were taken for sphingolipid measurements.

Results: We enrolled 18 patients in the trial, who were evaluable for toxicity, and 17 for response. The most common toxicity was neutropenia, observed in 9 of 18 patients, and there were no major nonhematologic toxicities. Of the 17 patients, 5 patients had progressive disease (PD), 1 had complete response (CR), 3 exhibited partial response (PR), and 8 had stable disease (SD). The median progression-free survival was 1.6 months (95% CI: 1.4-4.2) with a median survival of 5.6 months (95% CI: 3.8-18.2). Remarkably, serum sphingolipid analysis revealed significant differences in patterns of C₁₈-ceramide elevation in patients with CR/PR/SD in comparison with patients with PD, indicating the reconstitution of tumor suppressor ceramide generation by GEM/DOX treatment.

Conclusions: Our data suggest that the GEM/DOX combination could represent an effective treatment for some patients with recurrent or metastatic HNSCC, and that serum C₁₈-ceramide elevation might be a novel serum biomarker of chemotherapy response.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-0930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176980PMC
September 2011

Toxicity, response rates and survival outcomes of induction cisplatin and irinotecan followed by concurrent cisplatin, irinotecan and radiotherapy for locally advanced esophageal cancer.

Jpn J Clin Oncol 2011 Mar 17;41(3):334-42. Epub 2010 Nov 17.

Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA.

Objective: Cisplatin-based chemoradiotherapy is standard treatment for locally advanced esophageal and gastroesophageal cancers; however, the optimal chemotherapy regimen remains to be defined.

Methods: Retrospective single institution analysis of toxicities, response rates and survival outcomes in patients with cT3-4 or N1/M1a esophageal squamous cell or adenocarcinoma treated with induction cisplatin and irinotecan followed by concurrent cisplatin, irinotecan and radiotherapy. Secondary analysis for association of disease control and outcomes with demographic, tumor and treatment factors (including histology).

Results: Fifty-three patients were eligible for the present analysis. All patients underwent endoscopic ultrasonography and were either cT3-4 and/or cN1 disease. Fifty patients completed radiotherapy as planned (median dose 50.4 Gy, range 0-61.2), and 35 patients completed four cycles of chemotherapy as planned (range 1-4). Severe acute toxicities included Grade ≥ 3 neutropenia and esophagitis in 13 and 12 patients, respectively. There were no Grade 5 (fatal) toxicities noted. At mean survivor follow-up of 24.5 months (range 2.7-63), 17 patients were alive (8 without disease) and 36 deceased. Forty patients experienced disease recurrence, with initial loco-regional, distant or both failures in 28, 9 and 3 patients, respectively. Estimated 2-year overall survival and freedom from failure were 42 and 9%, respectively, without significant difference by histology.

Conclusions: Cisplatin/irinotecan chemoradiotherapy is tolerable, demonstrating similar efficacy for squamous cell and adenocarcinoma esophageal cancers.
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http://dx.doi.org/10.1093/jjco/hyq208DOI Listing
March 2011

Involved-field radiotherapy with concurrent chemotherapy for limited-stage small-cell lung cancer: disease control, patterns of failure and survival.

J Med Imaging Radiat Oncol 2010 Oct;54(5):483-9

Department of Radiation Oncology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.

Introduction: Major randomised trials have employed elective nodal irradiation as part of combined modality therapy for limited-stage small-cell lung cancer (SCLC). The present investigation describes patterns of failure, disease control, and survival outcomes for involved-field radiotherapy with concurrent chemotherapy, without elective irradiation of uninvolved mediastinal nodal regions.

Methods: Retrospective analysis of SCLC patients treated with curative-intent accelerated, twice-daily radiotherapy and concurrent platinum-based chemotherapy at an academic institution. Treatment fields were reviewed, and patients who completed ≥42 Gy in 1.5 Gy twice-daily fractions to involved fields (without elective irradiation of uninvolved mediastinal lymphatic regions) were included in the present analysis. Initial patterns of failure, disease control and overall survival were recorded.

Results: Fifty-two patients fulfilled study criteria and were included in the present analysis. All but one patient completed three to four cycles of chemotherapy, and 10 patients experienced grade 3 acute esophagitis. At a median survivor follow-up of 35 months (range 5.5-91.9), 22 patients were alive (15 without recurrence) and 30 had died (23 of/with disease, four of unknown cause, two of other cause and one of treatment toxicity). Initial site(s) of disease failure were loco-regional only (11 patients), distant only (14) and loco-regional plus distant (3). There were no cases of isolated out-of-field mediastinal recurrence in the absence of supraclavicular or more distant disease. The estimated 3-year disease-free and overall survivals were 36% and 44%, respectively.

Conclusions: Involved-field radiotherapy did not appear to have an adverse impact on the anticipated patterns of failure, disease control, or overall survival in this population of limited-stage SCLC patients.
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http://dx.doi.org/10.1111/j.1754-9485.2010.02201.xDOI Listing
October 2010

Once-daily radiotherapy to > or =59.4 Gy versus twice-daily radiotherapy to > or =45.0 Gy with concurrent chemotherapy for limited-stage small-cell lung cancer: a comparative analysis of toxicities and outcomes.

Jpn J Radiol 2010 Jun 30;28(5):340-8. Epub 2010 Jun 30.

Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA.

Purpose: The aim of this study was to compare toxicities, disease control, survival outcomes, and patterns of failure between groups of limited-stage small-cell lung cancer patients treated with once-daily versus twice-daily radiotherapy and concurrent chemotherapy.

Materials And Methods: This single-institution retrospective analysis included a comparison of two of radiotherapy regimens to planned doses of (1) > or =59.4 Gy at 1.8-2.0 Gy per once-daily fraction or (2) > or =45 Gy at 1.5 Gy per twice-daily fractions with concurrent platinum-based chemotherapy. Comparative analyses of toxicities and disease control were performed.

Results: A total of 71 patients were included in the present study (17 once-daily, 54 twice-daily). Patient, tumor, staging, and treatment factors were similar between the two treatment groups. Median planned radiotherapy doses were 60 Gy (range 59.4-70.0 Gy) and 45 Gy (range 45-51 Gy) for the once-daily and twice-daily groups, respectively. Acute toxicities were similar between the groups ( approximately 20% grade 3 esophagitis). At a median survival follow-up of 26.2 months (range 3.4-85.5 months), 42 patients had died. The 2-year overall survival estimates were similar at 43% and 49% for the once-daily versus twice-daily groups, respectively. Isolated in-field failures were similar between the two groups ( approximately 17%).

Conclusion: The present analysis did not detect a statistically significant difference in acute toxicities, disease control, or survival outcomes in limited-stage small-cell lung cancer patients treated with concurrent chemotherapy and once-daily versus twice-daily radiotherapy.
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http://dx.doi.org/10.1007/s11604-010-0429-xDOI Listing
June 2010

Treatment of eccrine porocarcinoma with metastasis to the parotid gland using intensity-modulated radiation therapy: a case report.

J Med Case Rep 2010 May 22;4:147. Epub 2010 May 22.

Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, USA.

Introduction: Cutaneous eccrine porocarcinomas are uncommon malignant tumors of the sweat gland.

Case Presentation: A 76-year-old Caucasian man presented to our hospital with a left temporal mass. We describe a case of eccrine porocarcinoma with metastasis to the parotid gland with special emphasis on the role of surgical resection and adjuvant radiation therapy.

Conclusion: Besides surgical resection, little is known about the role of adjuvant therapy in managing eccrine porocarcinomas. Radiation therapy should be considered within a multidisciplinary approach in patients with primary or recurrent eccrine porocarcinomas.
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http://dx.doi.org/10.1186/1752-1947-4-147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890019PMC
May 2010