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For treating peripheral brain lesions--where proton therapy would be expected to have the greatest depth-dose advantage over photon therapy--the lateral penumbra strongly impacts the SS plan quality relative to photon techniques: proton beamlet sigma at patient surface must be small (<7.1 mm for three-beam single-field optimized SS plans) in order to achieve comparable or smaller brain necrosis NTCP relative to photon radiosurgery techniques. Achieving such small in-air sigma values at low energy (<70 MeV) is a major technological challenge in commercially available proton therapy systems.

Purpose: Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH À ) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH À to standard RT/TMZ therapy.Patients and Methods: This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH À ) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH À phase). Eight P-AscH À dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (!20 mmol/L). In the ADJ phase, P-AscH À doses were escalated in each subject at each cycle until plasma concentrations were !20 mmol/L. P-AscH À was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03).Results: Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable MGMT promoter methylation (n ¼ 8), median PFS was 10 months and median OS was 23 months.Conclusions: P-AscH À /RT/TMZ is safe with promising clinical outcomes warranting further investigation.

Background Delays in postoperative radiotherapy (PORT) for head and neck cancer (HNC) increase the risk for recurrence and mortality. The multifactorial nature of delays calls for an in‐depth understanding of potential contributors from the patient's and provider's perspectives. We sought to identify causes of delays in adjuvant radiotherapy initiation for HNC. Methods We performed a mixed‐methods study including patients with HNC care team members. Forty in‐depth interviews were performed (26 patients; 14 care team members). Timing and demographic data were collected from medical records. Results Median time from surgery to radiotherapy initiation was 45 days; 15 participants began after 42 days. Process delays and failure to communicate the urgency and significance of PORT initiation contributes to delays. Patients with a strong social support system experience less delays. Conclusions Achieving reductions in PORT initiation requires efficient care coordination, improved communication between interdisciplinary teams, and strengthening social support systems for patients with HNC.

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Aging is a natural process involving complex interplay between environment, metabolism, and genes. Sirtuin genes and their downstream targets have been associated with lifespan in numerous organisms from nematodes to humans. Several target proteins of the sirtuin genes are key sensors and/or effectors of oxidative stress pathways including FOXO3, SOD3, and AKT1. To examine the relationship between single nucleotide polymorphisms (SNP) at candidate genes in these pathways and human lifespan, we performed a molecular epidemiologic study of an elderly cohort (≥65 years old.). Using age at death as a continuous outcome variable and assuming a co-dominant genetic model within the framework of multi-variable linear regression analysis, the genotype-specific adjusted mean age at death was estimated for individual SNP genotypes while controlling for age-related risk factors including smoking, body mass index, alcohol consumption and co-morbidity. Significant associations were detected between human lifespan and SNPs in genes SIRT3, SIRT5, SIRT6, FOXO3 and SOD3. Individuals with either the CC or CT genotype at rs107251 within SIRT6 displayed >5-year mean survival advantages compared to the TT genotype (5.5 and 5.9 years, respectively; q-value  = 0.012). Other SNPs revealed genotype-specific mean survival advantages ranging from 0.5 to 1.6 years. Gender also modified the effect of SNPs in SIRT3, SIRT5 and AKT1 on lifespan. Our novel findings highlight the impact of sirtuins and sirtuin-related genotypes on lifespan, the importance of evaluating gender and the advantage of using age as a continuous variable in analyses to report mean age at death.

PurposeHead and neck surgery and radiation cause tissue fibrosis that leads to functional limitations and lymphedema. The objective of this study was to determine whether lymphedema therapy after surgery and radiation for head and neck cancer decreases neck circumference, increases cervical range of motion, and improves pain scores.Methods and materialsA retrospective review of all patients with squamous cell carcinoma of the oral cavity, oropharynx, or larynx who were treated with high-dose radiation therapy at a single center between 2011 and 2012 was performed. Patients received definitive or postoperative radiation for squamous cell carcinoma of the oral cavity, oropharynx, or larynx. Patients were referred to a single, certified, lymphedema therapist with specialty training in head and neck cancer after completion of radiation treatment and healing of acute toxicity (typically 1-3 months). Patients underwent at least 3 months of manual lymphatic decongestion and skilled fibrotic techniques. Circumferential neck measurements and cervical range of motion were measured clinically at 1, 3, 6, 9, and 12 months after completion of radiation therapy. Pain scores were also recorded.ResultsThirty-four consecutive patients were eligible and underwent a median of 6 months of lymphedema therapy (Range, 3-12 months). Clinically measured total neck circumference decreased in all patients with 1 month of treatment. Cervical rotation increased by 30.2% on the left and 27.9% on the right at 1 month and continued to improve up to 44.6% and 55.3%, respectively, at 12 months. Patients undergoing therapy had improved pain scores from 4.3 at baseline to 2.0 after 1 month.ConclusionsLymphedema therapy is associated with objective improvements in range of motion, neck circumference, and pain scores in the majority of patients.

Objectives: Higher facility surgical volume predicts for improved outcomes in patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy. We investigated the association between facility radiotherapy (RT) case volume and overall survival (OS) for patients with MIBC who received bladder-preserving RT, and the relationship with adherence to National Comprehensive Cancer Network (NCCN) guidelines for bladder preservation. Methods: The National Cancer Database was used to identify patients diagnosed with nonmetastatic MIBC from 2004 to 2015 and received RT at the reporting center. Facility case volume was defined as the total MIBC patients treated with RT during the period. Facilities were stratified into high-volume facility (HVF) or low-volume facility at the 80th percentile of RT case volume. OS was assessed using Kaplan-Meier analysis. Rates of compliance with NCCN guidelines regarding the use of transurethral resection of the bladder tumor before RT, planned use of concurrent chemotherapy, and total RT dose were compared. Cox proportional hazard model was used to evaluate predictors of OS. Results: There were 7562 patients included. No differences in age, Charlson-Deyo score, T stage, or node-positive rates were observed between groups. HVFs exhibited greater compliance with NCCN guidelines for bladder preservation (P<0.0001). Treatment at an HVF was associated with the improved OS for all patients (P=0.001) and for the subset of patients receiving NCCN-recommended RT doses (P=0.0081). Volume was an independent predictor of OS (P=0.002). Conclusions: Treatment at an HVF is associated with improved OS and greater guideline-concordant management among patients with MIBC.