RIG-I-like receptor LGP2 protects tumor cells from ionizing radiation.

An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNß. Specifically (i) suppression of LGP2 leads to enhanced IFNß, (ii) cytotoxic effects following IR correlated with expression of IFNß inasmuch as inhibition of IFNß by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNß and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNß.

Effect of postradiotherapy neck dissection on nonregional disease sites.

IMPORTANCE: After chemoradiation for head and neck cancer, more than 90% of patients who achieve a complete clinical response on imaging have their disease regionally controlled without postradiotherapy neck dissections (PRNDs). Because several groups have reported that lymph node involvement also predicts failure at both the primary and distant sites, the extent to which PRND affects nonregional sites of disease remains unclear. OBJECTIVE: To evaluate how PRND affects local control (LC) and distant control in patients who achieve a complete clinical response. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively reviewed 287 patients (74 of whom underwent PRND) from the University of Illinois at Chicago Medical Center who were treated for stage III/IV disease with definitive chemoradiation from January 1, 1990, through December 31, 2012. INTERVENTIONS: Chemoradiation followed by lymph node dissection or observation. MAIN OUTCOMES AND MEASURES: End points evaluated included LC, regional control, freedom from distant metastasis, progression-free survival (PFS), and overall survival using first-failure analysis. RESULTS: Patients with advanced nodal disease (stage N2b or greater; n = 176) had improved PFS (74.6% vs 39.1%; P < .001), whereas patients with lesser nodal disease had similar PFS. For patients with advanced nodal disease, PRND improved 2-year LC (85.5% vs 53.5%; P < .001), locoregional control with PRND (78.9% vs 45.7%; P < .001), freedom from distant metastasis (79.5% vs 67.5%; P = .03), and overall survival (84.5% vs 61.7%; P = .004) but not regional control (96.9% vs 90.1%; P = .21). The benefit in LC (87.4% vs 66.2%; P = .02) and PFS (80.7% vs 53.4%; P = .01) persisted for those with negative posttreatment imaging results who underwent PRND. On univariate analysis, PRND, alcohol use, nodal stage, and chemoradiation significantly affected 2-year LC and/or PFS. On multivariate analysis, PRND remained strongly prognostic for 2-year LC (hazard ratio, 0.22; 95% CI, 0.07-0.54; P < .001) and PFS (hazard ratio, 0.42; 95% CI, 0.23-0.74; P = .002). CONCLUSIONS AND RELEVANCE: Postradiotherapy neck dissection improved control of nonregional sites of disease in patients with advanced nodal disease who achieved a complete response after chemoradiation. Thus, PRND may affect the control of nonnodal sites through possible mechanisms, such as clearance of incompetent lymphatics and prevention of reseeding of the primary and distant sites.

Radiation oncology medical student clerkship: implementation and evaluation of a bi-institutional pilot curriculum.

PURPOSE: To develop and evaluate a structured didactic curriculum to complement clinical experiences during radiation oncology clerkships at 2 academic medical centers. METHODS AND MATERIALS: A structured didactic curriculum was developed to teach fundamentals of radiation oncology and improve confidence in clinical competence. Curriculum lectures included: (1) an overview of radiation oncology (history, types of treatments, and basic clinic flow); (2) fundamentals of radiation biology and physics; and (3) practical aspects of radiation treatment simulation and planning. In addition, a hands-on dosimetry session taught students fundamentals of treatment planning. The curriculum was implemented at 2 academic departments in 2012. Students completed anonymous evaluations using a Likert scale to rate the usefulness of curriculum components (1=not at all, 5=extremely). Likert scores are reported as (median [interquartile range]). RESULTS: Eighteen students completed the curriculum during their 4-week rotation (University of Chicago n=13, Harvard Longwood Campus n=5). All curriculum components were rated as extremely useful: introduction to radiation oncology (5 [4-5]); radiation biology and physics (5 [5-5]); practical aspects of radiation oncology (5 [4-5]); and the treatment planning session (5 [5-5]). Students rated the curriculum as "quite useful" to "extremely useful" (1) to help students understand radiation oncology as a specialty; (2) to increase student comfort with their specialty decision; and (3) to help students with their future transition to a radiation oncology residency. CONCLUSIONS: A standardized curriculum for medical students completing a 4-week radiation oncology clerkship was successfully implemented at 2 institutions. The curriculum was favorably reviewed. As a result of completing the curriculum, medical students felt more comfortable with their specialty decision and better prepared to begin radiation oncology residency.

Racial parities in outcomes after radiotherapy for head and neck cancer.

BACKGROUND: Although black patients experience worse outcomes after treatment for squamous cell carcinoma of the head and neck (HNSCC), these conclusions were based on populations in which blacks comprised a minority of patients. The objective of the current study was to determine the impact of race on outcomes in patients with HNSCC who received radiotherapy at an institution in which blacks comprised the majority of patients. METHODS: In this retrospective cohort study, the authors reviewed 366 black patients and 236 white patients who had nonmetastatic HNSCC for which they received radiotherapy between 1990 and 2012. The primary study outcome measures were locoregional control, freedom from distant metastasis, progression-free survival, and overall survival. RESULTS: The median follow-up was 18.3 months for all patients. The 2-year locoregional control rate was 71.9% for black patients compared with 64.2% for white patients (hazard ratio, 0.72; P=.03). There was no difference between blacks and whites regarding 2-year freedom from distant metastasis, progression-free survival, or overall survival. Among the patients who had stage III through IVB disease, blacks and whites had similar outcomes. On multivariate analysis, race was not statistically significant for locoregional control, freedom from distant metastasis, progression-free survival, or overall survival. Despite these similar outcomes, black patients had worse socioeconomic factors and increased comorbidities but had similar treatment compliance compared with white patients. CONCLUSIONS: With more adverse prognostic factors, black patients experienced oncologic outcomes similar to the outcomes of white patients after receiving radiotherapy for HNSCC. The current data suggest that centers that treat large percentages of minority patients who receive radiotherapy for HNSCCs may overcome existing health care disparities through improved treatment compliance.

Stereotactic body radiation therapy for curative treatment of adrenal metastases.

The detection of oligometastatic adrenal metastases is increasing and there are limited data supporting the use of curative intent stereotactic body radiation therapy (SBRT) to treat patients with limited metastatic disease with adrenal involvement. Therefore, we utilized a prospectively maintained database of consecutive patients treated with SBRT for limited metastatic disease (≤5 sites) to identify patients with adrenal metastases. Patients were either treated on a three-fraction dose escalation protocol or a ten fraction off-protocol regimen. Outcomes including treated-metastasis control (TMC), distant control (DC), and overall survival (OS) were calculated by the Kaplan-Meier method. Ten patients with 13 adrenal metastases were identified for this case series. The median follow-up was 14.9 months. No patient experienced grade 3 toxicity. The most common grade 1-2 acute toxicities were fatigue (80%) and GI toxicity (40%). One patient experienced late grade 2 adrenal insufficiency. Overall, the 1-year TMC rate was 73%, DC was 30%, and OS was 90%. Three treated adrenal metastases progressed, all receiving the lowest BED10 (43.2 Gy), corresponding to 24 Gy in 3 fractions. After treatment of adrenal metastases with SBRT, the median time to salvage chemotherapy was 5.3 months (range 1.0-38.8 months) and 1-year freedom from salvage chemotherapy was 44%. These results suggest that SBRT to adrenal metastases was tolerated with low toxicity in limited metastatic patients and control rates are promising. This study supports the growing body of literature treating patients with adrenal metastases with SBRT.

Animal models to study the mutational landscape for oral cavity and oropharyngeal cancers.

OBJECTIVES: Cancer is likely caused by alterations in gene structure or expression. Recently, next generation sequencing has documented mutations in 106 head and neck squamous cell cancer genomes, suggesting several new candidate genes. However, it remains difficult to determine which mutations directly contributed to cancer. Here, summarize the animal models which have already validated and may test cancer causing mutations identified by next generation sequencing approaches. MATERIAL AND METHODS: We reviewed the existing literature on genetically engineered mouse models and next generation sequencing (NGS), as it relates to animal models of squamous cell cancers of the head and neck (HNSCC) in PubMed. RESULTS: NSG has identified an average of 19 to 130 distinct mutations per HNSCC specimen. While many mutations likely had biological significance, it remains unclear which mutations were essential to, or "drive," carcinogenesis. In contrast, "passenger" mutations also exist that provide no selection advantage. The genes identified by NGS included p53, RAS, Human Papillomavirus oncogenes, as well as novel genes such as NOTCH1, DICER and SYNE1,2. Animal models of HNSCC have already validated some of these common gene mutations identified by NGS. CONCLUSIONS: The advent of next generation sequencing will provide new leads to the genetic changes occurring in squamous cell cancers of the head and neck. Animal models will enable us to validate these new leads in order to better elucidate the biology of squamous cell cancers of the head and neck.

Feasibility and toxicity of hypofractionated image guided radiation therapy for large volume limited metastatic disease.

PURPOSE: Hypofractionated image guided radiation therapy (HIGRT) is increasingly used for limited metastases. Reported studies have mostly treated small volume tumors. Here, we report the toxicity and oncologic outcomes following treatment of large volume metastases. METHODS AND MATERIALS: HIGRT patients treated from October 2005 to March 2010 were reviewed. Gross tumor volumes (GTV) and planning target volumes (PTV) were obtained from planning software. A metastasis was considered large volume if the treated PTV exceeded 50 cc. Patients were treated with either 10-fraction (4-5 Gy per fraction) or 3-5 fraction (8-14 Gy per fraction) regimens. Toxicity was obtained from both prospectively collected databases and retrospectively from patient charts. RESULTS: Sixty-four patients with 93 treated lesions >50 cc were identified. The median GTV and PTV volumes were 41 and 119 cc, respectively. The median number of treated large volume lesions was 1, and a maximum of 3 large volume lesions were treated in a single patient. Primary malignancies included non-small cell lung cancer, renal cell, colorectal, breast, bladder, pituitary, small cell lung cancer, sarcoma, head-and-neck cancer, and hepatocellular cancer. Treated sites included lung (n = 33), regional lymph nodes (n = 20), bone (n = 17), adrenal (n = 9), and liver (n = 6). The most frequently used treatment regimen was 50 Gy in 5 Gy fractions. The median follow-up was 27 months for surviving patients. Treated lesion control was 78%. Low rates of acute and late grade 3 or higher toxicity were reported, with 3 and 5 patients experiencing each, respectively. CONCLUSIONS: HIGRT to large volume oligometastatic disease is tolerable and feasible with promising tumor control. Local radiation therapy should be considered in patients with large volume, limited metastatic disease.

Stereotactic body radiotherapy for the treatment of oligometastatic renal cell carcinoma.

OBJECTIVES: Renal cell carcinoma (RCC) is considered radioresistant, but stereotactic radiosurgery can control intracranial metastases. Advances in radiotherapy, such as stereotactic body radiotherapy (SBRT), allow high-dose radiation delivery to extracranial sites. Herein, we report our experience treating oligometastatic RCC with SBRT. METHODS: Patients with RCC and limited metastases were treated on a 3-fraction dose-escalation protocol (8 to 14 Gy/fraction) or off protocol with 10 fractions (4 to 5 Gy/fraction). Disease control was evaluated with serial imaging, and the Kaplan-Meier method was used to estimate lesion control (LeC), distant control, and survival. RESULTS: Eighteen consecutively treated patients with 39 metastases were treated using SBRT; 12 underwent treatment for all metastatic sites. Median follow-up was 16.2 months. Treatment was well tolerated; the most common acute toxicity was fatigue (61.1%) and late toxicity was limited. At 2 years, LeC was 91.4% and overall survival was 85%. Those who underwent treatment for all metastatic sites had a 2-year LeC of 100% and distant control of 35.7%. A shorter interval from diagnosis to SBRT predicted for distant progression. Freedom from any post-SBRT therapy was 64.2% at 1 year. CONCLUSIONS: In metastatic RCC, SBRT produces promising LeC with minimal toxicity. Further study should be expanded beyond that of managing intracranial disease. Its selected use may delay the requirement for systemic therapies.