Mihir K. Bhayani

Eat and Exercise During Radiotherapy or Chemoradiotherapy for Pharyngeal Cancers: Use It or Lose It

IMPORTANCE Data support proactive swallowing therapy during radiotherapy (RT) or chemoradiotherapy (CRT) for pharyngeal cancers. The benefits of adherence to a regimen of swallowing exercises and maintaining oral intake throughout treatment are reported, but independent effects are unclear. OBJECTIVE To evaluate the independent effects of maintaining oral intake throughout radiotherapy and adherence to preventive swallowing exercise. DESIGN Retrospective observational study. SETTING The University of Texas MD Anderson Cancer Center, Houston. PATIENTS The study included 497 patients treated with definitive RT or CRT for pharyngeal cancer (458 oropharynx, 39 hypopharynx) between 2002 and 2008. MAIN OUTCOMES AND MEASURES Swallowing-related end points were final diet after RT or CRT and duration of gastrostomy dependence. Primary independent variables included oral intake status at the end of RT or CRT (no oral intake, partial oral intake, or full oral intake) and adherence to a swallowing exercise regimen. Multiple linear regression and ordered logistic regression models were analyzed. RESULTS At the conclusion of RT or CRT, 131 patients (26%) had no oral intake and 74% maintained oral intake (167 partial [34%], 199 full [40%]). Fifty-eight percent (286 of 497) reported adherence to swallowing exercises. Maintenance of oral intake during RT or CRT and swallowing exercise adherence were independently associated with better long-term diet after RT or CRT (P = .045 and P < .001, respectively) and shorter duration of gastrostomy dependence (P < .001 and P = .007, respectively) in models adjusted for tumor and treatment burden. CONCLUSIONS AND RELEVANCE The data indicate independent, positive associations of maintenance of oral intake throughout RT or CRT and swallowing exercise adherence with long-term swallowing outcomes. Patients who either eat or exercise fare better than those who do neither. Patients who both eat and exercise have the highest rate of return to a regular diet and shortest duration of gastrostomy dependence.

STAT1 Pathway Mediates Amplification of Metastatic Potential and Resistance to Therapy

Background Traditionally IFN/STAT1 signaling is connected with an anti-viral response and pro-apoptotic tumor-suppressor functions. Emerging functions of a constitutively activated IFN/STAT1 pathway suggest an association with an aggressive tumor phenotype. We hypothesized that tumor clones that constitutively overexpress this pathway are preferentially selected by the host microenvironment due to a resistance to STAT1-dependent cytotoxicity and demonstrate increased metastatic ability combined with increased resistance to genotoxic stress. Methodology/Principal Findings Here we report that clones of B16F1 tumors grown in the lungs of syngeneic C57BL/6 mice demonstrate variable transcriptional levels of IFN/STAT1 pathway expression. Tumor cells that constitutively overexpress the IFN/STAT1 pathway (STAT1H genotype) are selected by the lung microenvironment. STAT1H tumor cells also demonstrate resistance to IFN-gamma (IFNγ), ionizing radiation (IR), and doxorubicin relative to parental B16F1 and low expressors of the IFN/STAT1 pathway (STAT1L genotype). Stable knockdown of STAT1 reversed the aggressive phenotype and decreased both lung colonization and resistance to genotoxic stress. Conclusions Our results identify a pathway activated by tumor-stromal interactions thereby selecting for pro-metastatic and therapy-resistant tumor clones. New therapies targeted against the IFN/STAT1 signaling pathway may provide an effective strategy to treat or sensitize aggressive tumor clones to conventional cancer therapies and potentially prevent distant organ colonization.

Prognosis and risk factors for early-stage adenoid cystic carcinoma of the major salivary glands

Adenoid cystic carcinoma (ACC) is characterized by slow growth, frequent local recurrences, and distant metastasis (DM). However, these findings frequently are reported in patients with advanced‐stage tumors, but the outcomes of early‐stage tumors are poorly defined. We sought to evaluate the risk factors for the development of DM in early‐stage ACC.

Gastrostomy tube placement in patients with hypopharyngeal cancer treated with radiotherapy or chemoradiotherapy: factors affecting placement and dependence.

Placement of gastrostomy tubes (g‐tubes) in patients with hypopharyngeal cancers undergoing radiation and chemotherapy is generally empirically determined. We examined our experience to identify predictive factors for g‐tube placement and length of dependence.

Functional relevance of miRNA sequences in human disease.

MicroRNA (miRNA) processing in the cytoplasm produces a miRNA duplex containing the forward, miRNA strand and the reverse, miRNA strand, which was thought to be degraded. However, recent evidence is challenging this dogma that miRNA is simply a non-functional byproduct of miRNA biogenesis. We present a comprehensive review of evidence that miRNA plays a significant role in cellular function and assembled a table outlining all of the publications before September 2011 that have reported on miRNA activity in human disease. Furthermore, we will present unexpected diagnostic and therapeutic implications due to the active miRNA status.

Targeting STAT3 inhibits growth and enhances radiosensitivity in head and neck squamous cell carcinoma

OBJECTIVES Signal transducer and activator of transcription 3 (STAT3) has been implicated in the development and progression of various solid tumors. We examined the efficacy of STAT3 inhibition as a novel therapeutic option for head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS Activation and expression of STAT3 and hypoxia-inducible factor-1α (HIF-1α) in HNSCC cell lines were assessed by immunoblots. The small molecule inhibitor, Stattic, was used to target STAT3 in HNSCC cell lines. MTT assays were performed to determine the effect of STAT3 inhibition on HNSCC cell viability, while clonogenic survival assays were used to assess the ability of Stattic to sensitize HNSCC cells to radiation therapy. We also examined the effect of Stattic on tumor growth and radiosensitivity in vivo using an orthotopic xenograft model of HNSCC. RESULTS Stattic effectively inhibited STAT3 activation and expression, resulting in decreased cell survival and proliferation and increased radiosensitivity. STAT3-mediated HIF-1α expression was also reduced in response to Stattic treatment. Oral administration of Stattic significantly reduced the growth of HNSCC tumors in a murine orthotopic xenograft, and analysis of tumor lysates confirmed decreased STAT3 phosphorylation. CONCLUSION STAT3 inhibition modulates HIF-1α expression, resulting in decreased tumor growth and possible enhanced radiosensitivity in HNSCC. Our results provide support for further exploration of STAT3 as a novel molecular therapeutic target in HNSCC.

Sinonasal adenocarcinoma: a 16-year experience at a single institution.

Adenocarcinoma is a rare tumor of the sinonasal tract. The purpose of this study was to characterize a single institutions experience with this malignancy.

Sialendoscopy for Patients with Radioiodine-Induced Sialadenitis and Xerostomia

BACKGROUND We examined outcomes in patients treated for radioactive iodine-induced sialadenitis (RAIS) and xerostomia with sialendoscopy. METHODS Data was prospectively collected for all patients undergoing sialendoscopy for RAIS from a single institution. Interventional details and intraoperative findings were recorded. Qualitative data were obtained through patient examination, telephone interviews, and use of a standard quality of life questionnaire, Xerostomia Questionnaire. Quantitative data were obtained from patients who underwent sialometry. RESULTS Twenty-six patients (24 women and 2 men; median age, 43 years; age range, 19-57 years) underwent interventional sialendoscopy after conservative management of symptoms proved unsuccessful. Sialadenitis was present in 25 patients and xerostomia in 22 patients. Mucus plugging in the duct of the gland was the most common finding (22 patients) followed by stenosis (18 patients), inflammation (eight patients), and erythema (eight patients). Median follow-up time was 23.4±12.1 months. Sixteen patients (64%) reported complete resolution; seven (28%), partial resolution; one (4%), no change in symptoms; and one (4%), regression in RAIS-related symptoms. Patients subjectively noted the following regarding their xerostomia symptoms: seven (31.8%) had complete resolution; 10 (45.5%), partial resolution; four (18.2%), no change; and one (4.5%), regression. Statistical analysis of the available sialometry data revealed a statistically significant difference in saliva production at 6 months following sialendoscopy for unstimulated saliva production (p=0.028). CONCLUSION Sialendoscopy is an effective treatment option for the management of RAIS and xerostomia refractory to conservative therapy and medical management. Patients in our cohort report durable improvement in symptoms after intervention.

The national landscape of human papillomavirus-associated oropharynx squamous cell carcinoma.

The head and neck squamous cell carcinoma (HNC) landscape is evolving with human papillomavirus (HPV) being a rising cause of oropharynx carcinoma (OPC). This study seeks to investigate a national database for HPV‐associated oropharynx carcinoma (HPV‐OPC). Using the National Cancer Data Base, we analyzed 22,693 patients with HPV‐OPC and known HPV status. Chi‐square tests and logistic regression models were utilized to examine differences between HPV positive and HPV negative OPC. 14,805 (65.2%) patients were HPV positive. Mean age at presentation was 58.4 years with HPV‐HNC patients being 2.8 years younger compared to the HPV‐negative cohort (58.4 vs. 61.2 years, p < 0.001). 67.6% of white patients were HPV‐positive compared to 42.3% of African American patients and 57.1% of Hispanics (p < 0.001). When combining race and socioeconomic status (SES), we found African American patients in high SES groups had HPV‐OPC prevalence that was significantly higher than African American patients in low SES groups (56.9% vs. 36.3%, p < 0.001). Geographic distribution of HPV‐OPC was also analyzed and found to be most prevalent in Western states and least prevalent in the Southern states (p < 0.001). The distribution of HPV‐OPC is variable across the country and among racial and socioeconomic groups. A broad understanding of these differences in HPV‐OPC should drive educational programs and improve clinical trials that benefit both prevention and current treatments.

Assessment of adjuvant therapy in resected head and neck cancer with high-risk features

OBJECTIVES Subgroup analysis from two randomized trials showed a survival benefit for adjuvant chemoradiation (CRT) over radiation alone (RT) in patients with extracapsular spread (ECS) of involved lymph nodes and/or positive margins (PM) in resected head and neck cancer (HNSCC). However, results were not analyzed separately for patients with ECS or PM and were not stratified by tumor subsite/HPV status. We therefore sought to determine whether adjuvant CRT is associated with a survival benefit, separately among patients with ECS or PM and stratified by subsite/HPV status. METHODS Using the National Cancer Database (NCDB), we identified 6948 patients diagnosed with HNSCC between 2010 and 13 who underwent surgical resection and had either ECS or PM. The impact of adjuvant therapy on OS from surgery was evaluated using Cox proportional hazards regression adjusting for clinical and demographic factors. RESULTS Adjuvant CRT was associated with a significant survival benefit over RT alone among patients with ECS (aHR 0.83, 95%CI 0.71-0.97) but not among those with PM (aHR 0.89, 95%CI 0.77-1.04). In patients with HPV-negative tumors, CRT was associated with a benefit over RT alone in the setting of ECS (aHR 0.83, 95%CI 0.70-0.98) but not PM (aHR 0.91, 95%CI 0.78-1.06). However, in patients with HPV-positive oropharynx tumors, CRT was not associated with a benefit over RT in ECS (aHR 0.94, 95%CI 0.47-1.88) but appeared beneficial in PM (aHR 0.54, 95%CI 0.32-0.90). CONCLUSIONS CRT appears beneficial over RT in ECS among patients with HPV-negative tumors, and beneficial in PM among patients with HPV-positive tumors.