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Purpose: Scoring of radiation pneumonitis (RP), a dose-limiting toxicity after thoracic radiochemotherapy, is subjective and thus inconsistent among studies. Here we investigated whether the extent of change in diffusing capacity of the lung for carbon monoxide (DLCO) after radiation therapy (RT) for non-small-cell lung cancer (NSCLC) could be used as an objective means of quantifying RP.Patients and Methods: We analyzed potential correlations between DLCO and RP in 140 patients who received definitive RT (≥ 60 Gy) with or without chemotherapy for primary NSCLC. All underwent DLCO analysis before and after RT. Post-RT DLCO values within 1 week of the RP diagnosis (Grade 0, 1, 2, or 3) were selected and compared with that individual's preradiation values. Percent reductions in DLCO and RP grade were compared by point biserial correlation in the entire patient group and in subgroups stratified according to various clinical factors.Results: Patients experiencing Grade 0, 1, 2, or 3 RP had median percentage changes in DLCO after RT of 10.7%, 13%, 22.1%, or 35.2%. Percent reduction in DLCO correlated with RP Grade ≤ 1 vs. ≥ 2 (p = 0.0004). This association held for the following subgroups: age ≥ 65 years, advanced stage, smokers, use of chemotherapy, volume of normal lung receiving at least 20 Gy ≥ 30%, and baseline DLCO or forced expiratory volume in 1 second ≥ 60%.Conclusions: By correlating percent change in DLCO from pretreatment values at the time of diagnosis of RP with RP grade, we were able to identify categories of RP based on the change in DLCO. These criteria provide a basis for an objective scoring system for RP based on change in DLCO. [ABSTRACT FROM AUTHOR]

Obesity is a major burden on the health system in England and the rest of the UK. Obesity prevalence is high in adults and children and most of the UK population are consuming more energy than required, and not meeting other dietary recommendations, including those for saturated fat, free sugars, fibre, oily fish and fruit and vegetables. Over the past 5 years, a number of cross-government policies, both promoting voluntary action and legislative, have been put in place to tackle diet-related health and obesity. The food environment is complex with many influencing factors, some of which act through individual automatic choices. Other factors such as accessibility, advertising, promotion and nudging drive increased food and drink purchases. With continual changes in the food environment favouring fast-food outlets and meal delivery companies alongside the adverse impact of the COVID-19 pandemic on diets and physical activity levels, further governmental action is likely needed to deliver sustained improvements to diet and health.

Purpose: Hypofractionated radiotherapy delivers larger daily doses of radiation and may increase the biologically effective dose delivered to the prostate. We conducted a randomized trial testing the hypothesis that dose-escalated, moderately hypofractionated intensity-modulated radiation therapy (HIMRT) improves prostate cancer control compared with conventionally fractionated IMRT (CIMRT) for men with localized prostate cancer., Patients and Methods: Men were randomly assigned to 75.6 Gy in 1.8-Gy fractions delivered over 8.4 weeks (CIMRT) or 72 Gy in 2.4 Gy fractions delivered over 6 weeks (HIMRT, biologically equivalent to 85 Gy in 1.8-Gy fractions assuming prostate cancer α-to-β ratio of 1.5). Failure was defined as prostate-specific antigen (PSA) failure (nadir plus 2 ng/mL) or initiation of salvage therapy. Modified Radiation Therapy Oncology Group criteria were used to grade late (≥ 90 days after completion of radiotherapy) GI and genitourinary toxicity., Results: Most of the 206 men (72%) had cT1, Gleason score 6 or 7 (99%), and PSA level ≤ 10 ng/mL (90%) disease. Androgen deprivation therapy was received by 24%. With a median follow-up of 8.5 years, men treated with HIMRT experienced fewer treatment failures (n = 10) than men treated with CIMRT (n = 21; P = .036). The 8-year failure rate was 10.7% (95% CI, 5.8% to 19.1%) with HIMRT and 15.4% (95% CI, 9.1% to 25.4%) with CIMRT. There was no difference in overall survival ( P = .39). There was a nonsignificant increase in late grade 2 or 3 GI toxicity with HIMRT (8-year 5.0% v 12.6%; P = .08). However, GI toxicity was only 8.6% when rectal volume receiving 65 Gy of HIMRT was ≤ 15%. Late genitourinary toxicity was similar ( P = .84). There was no grade 4 toxicity., Conclusion: The results of this randomized trial demonstrate superior cancer control for men with localized prostate cancer who receive dose-escalated moderately hypofractionation radiotherapy while shortening treatment duration.

Public Health England has set a definition for free sugars in the UK in order to estimate intakes of free sugars in the National Diet and Nutrition Survey. This follows the recommendation from the Scientific Advisory Committee on Nutrition in its 2015 report on Carbohydrates and Health that a definition of free sugars should be adopted. The definition of free sugars includes: all added sugars in any form; all sugars naturally present in fruit and vegetable juices, purées and pastes and similar products in which the structure has been broken down; all sugars in drinks (except for dairy-based drinks); and lactose and galactose added as ingredients. The sugars naturally present in milk and dairy products, fresh and most types of processed fruit and vegetables and in cereal grains, nuts and seeds are excluded from the definition.

Objectives: Hypofractionated prostate radiotherapy may increase biologically effective dose delivered while shortening treatment duration, but information on patient-reported urinary, bowel, and sexual function after dose-escalated hypofractionated radiotherapy is limited. We report patient-reported outcomes (PROs) from a randomized trial comparing hypofractionated and conventional prostate radiotherapy., Methods: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity-modulated radiation therapy (CIMRT, 75.6 Gy in 1.8 Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4 Gy fractions). Questionnaires assessing urinary, bowel, and sexual function were completed pretreatment and at 2, 3, 4, and 5 years after treatment., Results: Of 203 eligible patients, 185 were evaluable for PROs. A total of 173 completed the pretreatment questionnaire (82 CIMRT, 91 HIMRT) and 102 completed the 2-year questionnaire (46 CIMRT, 56 HIMRT). Patients who completed PROs were similar to those who did not complete PROs (all P>0.05). Patient characteristics, clinical characteristics, and baseline symptoms were well balanced between the treatment arms (all P>0.05). There was no difference in patient-reported bowel (urgency, control, frequency, or blood per rectum), urinary (dysuria, hematuria, nocturia, leakage), or sexual symptoms (erections firm enough for intercourse) between treatment arms at 2, 3, 4, and 5 years after treatment (all P>0.01). Concordance between physician-assessed toxicity and PROs varied across urinary and bowel domains., Discussion: We did not detect an increase in patient-reported urinary, bowel, and sexual symptom burden after dose-escalated intensity-modulated prostate radiation therapy using a moderate hypofractionation regimen (72 Gy in 2.4 Gy fractions) compared with conventionally fractionated radiation.

The sensitivity of the Northeast Greenland Ice Stream (NEGIS) to prolonged warm periods is largely unknown and geological records documenting such long-term changes are needed to place current observations in perspective. Here we use cosmogenic surface exposure and radiocarbon ages to determine the magnitude of NEGIS margin fluctuations over the last 45 kyr (thousand years). We find that the NEGIS experienced slow early Holocene ice-margin retreat of 30-40 m a -1 , likely as a result of the buttressing effect of sea-ice or shelf-ice. The NEGIS was ~20-70 km behind its present ice-extent ~41-26 ka and ~7.8-1.2 ka; both periods of high orbital precession index and/or summer temperatures within the projected warming for the end of this century. We show that the NEGIS was smaller than present for approximately half of the last ~45 kyr and is susceptible to subtle changes in climate, which has implications for future stability of this ice stream.

Purpose: We analyzed overall and disease-free survival (OS and DFS) after definitive (chemo)radiation for stage III non-small cell lung cancer with 2 statistical methods: Kaplan-Meier (KM) analysis, with diagnosis as index date, and conditional survival (CS) analysis, with a variety of disease-free index dates, and determined whether prognostic factors varied based on the reference date., Materials and Methods: All 651 patients analyzed received definitive (chemo)radiotherapy for stage III non-small cell lung cancer in November 1998 to December 2010 at a single institution; all had Karnofsky performance status scores ≥60 and received ≥60 Gy. OS and DFS were first calculated with the KM method, and then CS was used to calculate 2 outcomes: OS conditioned on DFS time (OS|DFS) and DFS conditioned on DFS time (DFS|DFS). Factors predicting OS and DFS conditioned on 1-, 2-, and 3-year DFS were sought in univariate and multivariate analyses., Results: KM analysis produced 1-, 2-, and 3-year DFS rates of 48%, 30%, and 26%; OS rates were 64%, 41%, and 29%. By CS analysis, both OS|DFS and DFS|DFS showed an increase in 5-year OS after 6 months, and CS after 30 months approached 100%. On multivariate analyses, age and concurrent chemoradiation predicted OS|DFS; age, smoking history, tumor histology, disease stage, and radiation dose predicted DFS|DFS., Conclusions: CS analysis showed that the probability of long-term survival increases sharply after 6 months with no evidence of disease; factors predicting survival differed based on the method and endpoint used.

Background: Which men benefit most from adding androgen deprivation therapy (ADT) to salvage radiation therapy (SRT) after prostatectomy has not clearly been defined; therefore, we evaluated the impact of ADT to SRT on failure-free survival (FFS) in men with a rising or persistent PSA after prostatectomy., Methods: We identified 332 men who received SRT after prostatectomy from 1987 to 2010. Recursive partitioning analysis (RPA) identified favorable, intermediate and unfavorable groups based on the risk of failure after SRT alone. Kaplan-Meier and log-rank tests compared FFS with and without ADT., Results: Forty-three percent received SRT alone and 57% received SRT with ADT (median 6.6 months (interquartile range (IQR) 5.8-18.1) ADT). Median SRT dose was 70 Gy (IQR 70-70), and median follow-up after SRT was 6.7 years (IQR 4.5-10.8). On Cox's proportional hazard regression, ADT improved FFS (adjusted hazard ratio 0.60, 95% confidence interval: 0.42-0.86; P=0.006). RPA classified unfavorable disease as negative surgical margins (SMs) and preradiation PSA of ⩾0.5 ng ml -1 . Favorable disease had neither adverse factor, and intermediate disease had one adverse factor. The addition of ADT to SRT improved 5-year FFS for men with unfavorable disease (70.3% vs 23.4%; P<0.001) and intermediate disease (69.8% vs 48.0%; P=0.003), but not for men with favorable disease (81.2% vs 78.0%; P=0.971)., Conclusions: The addition of ADT to SRT appears to improve FFS for men with a preradiation PSA of ⩾0.5 ng ml -1 or with negative SM at prostatectomy. Men with involved surgical margins and PSA <0.5 ng ml -1 appear to be at a lower risk of failure after SRT alone and may not derive as much benefit from the administration of ADT with SRT. These results are hypothesis-generating only, and further prospective data are required to see if ADT can safely be omitted in this select group of men.

Objectives: Predictors of acute hematologic toxicities during definitive chemoradiation for non-small cell lung cancer (NSCLC) are incompletely defined., Materials and Methods: We retrospectively analyzed 604 patients treated with definitive platinum-based doublet chemoradiation therapy for stage III NSCLC. The outcome of interest was grade ≥3 acute hematologic toxicities, specifically white blood cell, hemoglobin, platelet, neutrophil, and lymphocyte decrease during chemoradiation therapy. We assessed the association between any grade ≥3 acute hematologic toxicity with patient demographic, disease, radiation factors (specifically modality and dose), and chemotherapy agents via stepwise multivariate logistic regression. Survival was compared via log-rank and univariate Cox regression analyses., Results: There was no significant association between radiation modality and any hematologic toxicity on multivariate analysis. However, use of etoposide was found to be significantly associated with white blood cell, platelet, and neutrophil decrease compared with paclitaxel and docetaxel (all P<0.05). No differences were found between platinum agents. Overall survival (OS) and event-free survival (EFS) were significantly worse in patients who experienced grade ≥3 hemoglobin (OS: hazard ratio [HR]=1.5; 95% confidence interval [CI], 1.05-2.26; P=0.03, EFS: HR=1.7; 95% CI, 1.2-2.4; P=0.0032) and lymphocyte (OS: HR=1.5; 95% CI, 1.1-2.1; P=0.01, EFS: HR=1.4; 95% CI, 1.1-1.9; P=0.02) decreases., Conclusions: Chemotherapy identity, specifically the nonplatinum agent, was significantly associated with grade ≥3 hematologic toxicities, whereas radiation modality was not.

Background: Patients with glioblastoma multiforme (GBM) require radiotherapy as part of definitive management. Our institution has adopted the use of volumetric arc therapy (VMAT) due to superior sparing of the adjacent organs at risk (OARs) compared to intensity modulated radiation therapy (IMRT). Here we report our clinical experience by analyzing target coverage and sparing of OARs for 90 clinical treatment plans., Methods: VMAT and IMRT patient cohorts comprising 45 patients each were included in this study. For all patients, the planning target volume (PTV) received 50 Gy in 30 fractions, and the simultaneous integrated boost PTV received 60 Gy. The characteristics of the two patient cohorts were examined for similarity. The doses to target volumes and OARs, including brain, brainstem, hippocampi, optic nerves, eyes, and cochleae were then compared using statistical analysis. Target coverage and normal tissue sparing for six patients with both clinical IMRT and VMAT plans were analyzed., Results: PTV coverage of at least 95% was achieved for all plans, and the median mean dose to the boost PTV differed by only 0.1 Gy between the IMRT and VMAT plans. Superior sparing of the brainstem was found with VMAT, with a median difference in mean dose being 9.4 Gy. The ipsilateral cochlear mean dose was lower by 19.7 Gy, and the contralateral cochlea was lower by 9.5 Gy. The total treatment time was reduced by 5 min. The difference in the ipsilateral hippocampal D 100% was 12 Gy, though this is not statistically significant (P = 0.03)., Conclusions: VMAT for GBM patients can provide similar target coverage, superior sparing of the brainstem and cochleae, and be delivered in a shorter period of time compared with IMRT. The shorter treatment time may improve clinical efficiency and the quality of the treatment experience. Based on institutional clinical experience, use of VMAT for the treatment of GBMs appears to offer no inferiority in comparison to IMRT and may offer distinct advantages, especially for patients who may require re-irradiation.

Background: MUC5B is glycoprotein secreted by bronchial glands. A promoter variant in MUC5B, rs35705950, was previously found to be strongly associated with the incidence of idiopathic pulmonary fibrosis (IPF) and also the overall survival (OS) of such patients. Patients with IPF and patients with radiation pneumonitis (RP) have the similar pathologic process and clinical symptoms. However, the role of rs35705950 in patients receiving thoracic radiotherapy remains unclear., Patients and Methods: In total, 664 patients with NSCLC receiving definitive radiotherapy (total dose ≥60 Gy) were included in our study. RP was scored via the Common Terminology Criteria for Adverse Events v3.0. OS was the second end point. MUC5B rs35705950 was genotyped, and Kaplan-Meier and Cox regression analyses were used to evaluate associations between MUC5B rs35705950 and the risk of RP or OS., Results: The median patient age was 66 years (range 35-88); most (488 [73.2%]) had stage III of the disease. Until the last follow-up, 250 patients developed grade≥2 RP, 82 patients developed grade≥3 RP, and 440 patients died. The median mean lung dose was 17.9 Gy (range 0.15-32.74). No statistically significant associations were observed between genotypes of MUC5B rs35705950 and the incidence of RP≥grade 2 either in univariate analysis (hazard ratio [HR] 1.009, 95% confidence interval [CI] 0.728-1.399, P=.958) or in multivariate analysis (HR 0.921, 95% CI 0.645-1.315, P=.65). Similar results were also observed for RP≥grade 3, while TT/GT genotypes in MUC5B were significantly associated with poor OS in both univariate analysis (HR 1.287, 95% CI 1.009-1.640, P=.042) and multivariate analysis (HR 1.561, 95% CI 1.193-2.042, P=.001)., Conclusion: MUC5B promoter polymorphism could be prognostic of the OS among NSCLC patients receiving definitive radiotherapy, although no significant associations were found with the risk of RP., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To identify factors associated with regional recurrence after lymph node dissection (LND) for squamous cell carcinoma (SCC) to determine which patients might benefit from adjuvant therapy., Patients and Methods: Men who underwent LND for penile SCC from 1977 to 2014 were identified from an institutional database. Kaplan-Meier curves estimated recurrence-free survival (RFS) calculated from the date of LND. Cox regression models evaluated the association between RFS and patient and tumour characteristics., Results: In all, 182 men who underwent LND for penile SCC were identified. The median patient age was 62 years and the median follow-up was 4.2 years. After LND 34 men had regional recurrence, of which 24 developed isolated regional recurrences without distant metastasis. The median RFS was 5.7 months, and the 3-year RFS rate was 70%. On univariate analysis, lymphovascular invasion, clinical and pathological nodal stage, pathological inguinal laterality, pelvic nodal involvement, lymph node density ≥5.2%, ≥3 pathologically involved lymph nodes, and extranodal extension (ENE) were associated with worse RFS (all P < 0.05). On multivariate analysis, clinical N3 disease [adjusted hazard ratio (AHR)] 3.53, 95% confidence interval (CI) 1.68-7.45; P = 0.001), ≥3 pathologically involved lymph nodes (AHR 3.78, 95% CI 2.12-6.65; P < 0.001), and ENE (AHR 3.32, 95% CI 1.93-5.76; P < 0.001) were associated with worse RFS. The 3-year RFS for patients with cN0, cN1, cN2, and cN3 disease was 91.7%, 64.5%, 54.7%, and 38.3%, respectively. For men with ≥3 involved nodes, the 3-year RFS was 17% vs 82.4% in men with <3 involved nodes. The 3-year RFS was 29.7% in men with ENE and 85.7% in men without ENE., Conclusion: The presence of clinical N3 disease, ≥3 pathologically involved lymph nodes, and ENE was associated with worse RFS. As regional recurrence portends a dismal prognosis with few salvage options, adjuvant therapies should be developed for men with the aforementioned adverse factors., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

The influence of major Quaternary climatic changes on growth and decay of the Greenland Ice Sheet, and associated erosional impact on the landscapes, is virtually unknown beyond the last deglaciation. Here we quantify exposure and denudation histories in west Greenland by applying a novel Markov-Chain Monte Carlo modelling approach to all available paired cosmogenic 10 Be- 26 Al bedrock data from Greenland. We find that long-term denudation rates in west Greenland range from >50 m Myr -1 in low-lying areas to ∼2 m Myr -1 at high elevations, hereby quantifying systematic variations in denudation rate among different glacial landforms caused by variations in ice thickness across the landscape. We furthermore show that the present day ice-free areas only were ice covered ca. 45% of the past 1 million years, and even less at high-elevation sites, implying that the Greenland Ice Sheet for much of the time was of similar size or even smaller than today.

Objective: To evaluate the impact on food purchasing behaviour of the 'Change4Life Smart Swaps' campaign to encourage families to make small changes to lower-fat or lower-sugar versions of commonly eaten foods and drinks., Design: Quasi-experimental study comparing the proportion of swaps made by an intervention group (267 families who had signed up to the 'Smart Swaps' campaign promoted through various media, including television and radio advertising in early 2014) and a comparison group (135 families resident in Wales, signed up for 'Change4Life' materials, but not directly exposed to the 'Smart Swaps' campaign). During weeks 1, 2 and 3 of the campaign participants were asked to record their purchases of dairy products, carbonated drinks and breakfast cereals, using a mobile phone app questionnaire, when making a purchase within the category., Setting: England and Wales., Subjects: Families registered with 'Change4Life'., Results: In weeks 2 and 3 a significantly higher percentage of the intervention group had made 'smart swaps' than the comparison group. After week 3, 58 % of participants had swapped to a lower-fat dairy product compared with 26 % of the comparison group (P<0·001), 32 % of the intervention group had purchased a lower-sugar drink compared with 19 % of the comparison group (P=0·01), and 24 % had made a change to a lower-sugar cereal compared with 12 % of the comparison group (P=0·009)., Conclusions: In the short term a national campaign to change purchase habits towards healthier products may have some merit but the sustainability of change requires further investigation.

Objective: Androgen deprivation therapy (ADT) can improve outcomes for men with intermediate-risk prostate cancer (IR-PrCa) receiving external-beam radiotherapy (EBRT). Older men and men with significant comorbidity may be more susceptible to the harms of ADT, therefore we aimed to determine whether these men benefit from ADT., Methods: The adult comorbidity evaluation-27 index categorized severity of comorbidity in 636 men treated for IR-PrCa with dose-escalated EBRT (>75 Gy). The cohort was dichotomized at median age of 70. Multivariate Cox proportional hazard analysis evaluated the association of ADT with failure-free survival (FFS) for each age and comorbidity subgroup., Results: A total of 48% of men were 70 years and above. After adjustment for tumor characteristics, the addition of ADT to EBRT was associated with improved FFS for both men below 70 years of age (adjusted hazard ratio [AHR] 0.44; 95% confidence interval [CI], 0.19-0.99; P=0.046) and men 70 years and above (AHR 0.23; 95% CI, 0.06-0.91; P=0.035). ADT improved FFS for men below 70 years who had no or mild comorbidity (AHR 0.25; 95% CI, 0.09-0.73; P=0.011) but not for men below 70 years who had moderate or severe comorbidity (AHR 1.62; 95% CI, 0.35-7.49; P=0.537). Similarly, in men 70 years and above, there was a trend for improved FFS with ADT in healthy men (AHR 0.10; 95% CI, 0.01-1.08; P=0.058) but not in men with moderate to severe comorbidity (AHR 0.38; 95% CI, 0.06-2.56; P=0.318)., Conclusions: The addition of ADT to dose-escalated EBRT can improve outcomes for both younger and older men with IR-PrCa. This benefit was more pronounced in healthy men.

Background: The purpose of this study was to report the outcomes of patients with Merkel cell carcinoma (MCC) of the head and neck using a radiation-based treatment approach., Methods: We reviewed records of 106 consecutive patients with MCC of the head and neck treated with radiation therapy (RT) at our institution between 1988 and 2011. The Kaplan-Meier method was used to estimate outcomes and hazard ratios (HRs) were calculated., Results: The 5-year actuarial local and regional control rates were 96% and 96%, respectively. There were no regional recurrences in 22 patients treated with RT to gross nodal disease without neck dissection. The 5-year cause-specific survival rate was 76%. Lymphadenopathy at presentation impacted distant metastatic-free survival outcomes (p < .001). Treatment was well tolerated with only 5 patients having grade ≥3 toxicities., Conclusion: For MCC of the head and neck, a management strategy that includes RT offers excellent locoregional control. Gross nodal disease can be successfully treated with RT. © 2015 Wiley Periodicals, Inc. Head Neck 38: E452-E458, 2016., (© 2015 Wiley Periodicals, Inc.)

Background and Purpose: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive malignancy. We report survival rates and toxicity associated with sequential multimodality treatment including whole abdominopelvic radiation therapy (WART)., Material and Methods: Medical records of 32 patients with DSRCT treated at our institution were reviewed. Patients underwent chemotherapy, cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (HIPEC), followed by WART with intensity-modulated radiation or volumetric-modulated arc therapy., Results: Median overall survival (OS) was 60months. After 18months of follow-up, 20 patients (62.5%) had disease recurrence and median disease-free survival (DFS) was 10months. Median time to extrahepatic abdominal failure was 19.4months. Factors affecting time to local progression included liver metastases at diagnosis, and an interval of greater than 5.6months between diagnosis and HIPEC or greater than 2.1months between HIPEC and WART. None of these factors altered OS. Grade 3 or higher toxicities occurred in 84% of patients., Conclusions: WART following chemotherapy, surgical cytoreduction and HIPEC is an aggressive treatment for DSRCT patients and can result in severe side effects. Our median OS of 5years is favorable compared to prior studies, despite a median DFS of only 10months, which may be due to improved salvage therapies., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Age-related skeletal muscle loss, sarcopenia, cachexia and wider malnutrition (under nutrition) are complex in aetiology with interaction of clinical, social and economic factors. Weight loss and loss of skeletal muscle mass in older people are associated with increased morbidity and mortality with implications for increasing health and social care costs. There is insufficient evidence to identify the ideal treatment options. However, preventing weight loss and loss of skeletal muscle in older age will be keys to reducing morbidity and mortality. This will require all those coming into contact with older people to identify and address weight loss early, including through diet, improving physical activity and increasing social interaction. Public health messages on diet should, in the main, continue to focus on older people achieving current UK dietary recommendations for their age as visually depicted in the eatwell plate together with associated messages regarding dietary supplements where appropriate.

Purpose: We report long-term disease control, survival, and toxicity for patients with locally advanced non-small cell lung cancer prospectively treated with concurrent proton therapy and chemotherapy on a nonrandomized case-only observational study., Methods: All patients received passive-scatter proton therapy, planned with 4D-CT-based simulation; all received proton therapy concurrent with weekly chemotherapy. Endpoints were local and distant control, disease-free survival (DFS), and overall survival (OS)., Results: The 134 patients (21 stage II, 113 stage III; median age 69 years) had a median gross tumor volume (GTV) of 70 cm(3) (range, 5-753 cm(3)); 77 patients (57%) received 74 Gy(RBE), and 57 (42%) received 60-72 Gy(RBE) (range, 60-74.1 Gy(RBE)). At a median follow-up time of 4.7 years, median OS times were 40.4 months (stage II) and 30.4 months (stage III). Five-year DFS rates were 17.3% (stage II) and 18.0% (stage III). OS, DFS, and local and distant control rates at 5 years did not differ by disease stage. Age and GTV were related to OS and DFS. Toxicity was tolerable, with 1 grade 4 esophagitis and 16 grade 3 events (2 pneumonitis, 6 esophagitis, 8 dermatitis)., Conclusion: This report of outcomes after proton therapy for 134 patients indicated that this regimen produced excellent OS with tolerable toxicity., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Inflammatory breast cancer (IBC) is an aggressive type of breast cancer, characterized by very rapid progression, enlargement of the breast, skin edema causing an orange peel appearance (peau d'orange), erythema, thickening, and dermal lymphatic invasion. It is characterized by E-cadherin overexpression in the primary and metastatic disease, but to date no robust molecular features that specifically identify IBC have been reported. Further, models that recapitulate all of these clinical findings are limited and as a result no studies have demonstrated modulation of these clinical features as opposed to simply tumor cell growth., Methods: Hypothesizing the clinical presentation of IBC may be mediated in part by the microenvironment, we examined the effect of co-injection of IBC xenografts with mesenchymal stem/stromal cells (MSCs)., Results: MSCs co-injection significantly increased the clinical features of skin invasion and metastasis in the SUM149 xenograft model. Primary tumors co-injected with MSCs expressed higher phospho-epidermal growth factor receptor (p-EGFR) and promoted metastasis development after tumor resection, effects that were abrogated by treatment with the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. E-cadherin expression was maintained in primary tumor xenografts with MSCs co-injection compared to control and erlotinib treatment dramatically decreased this expression in control and MSCs co-injected tumors. Tumor samples from patients demonstrate correlation between stromal and tumor p-EGFR staining only in IBC tumors., Conclusions: Our findings demonstrate that the IBC clinical phenotype is promoted by signaling from the microenvironment perhaps in addition to tumor cell drivers.

Background: Intensity-modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) has improved the local disease control at a variety of anatomic sites. However, little is known about its use in lung cancer, especially in the context of shorter treatment schedules (hypofractionation). We analyzed the feasibility, toxicity, and patterns of failure of this approach for patients with non-small-cell lung cancer (NSCLC) who were not candidates for surgery or standard concurrent chemoradiation therapy., Patients and Methods: We retrospectively identified 71 patients with NSCLC who received IMRT+SIB in 15 fractions to ≥ 52.5 Gy from January 2007 to February 2013. Toxicity and local control were evaluated for all patients., Results: Of the 71 patients, 11 (16%) had stage I to II NSCLC, 15 (21%) stage III, and 45 (63%) stage IV. The esophagitis rate was grade 0 to 1 in 55%, grade 2 in 39%, and grade ≥ 3 in 6%. One patient developed a bronchoesophageal fistula 6 months after radiation. The pneumonitis rate was grade 0 to 1 in 93%, grade 2 in 6%, and grade 3 in 1%. At the time of analysis, 17 (24%) patients had local failure at a median of 5.2 months (range, < 1-16.1) after treatment. All but 1 failure occurred within the higher dose region., Conclusion: Hypofractionated IMRT+SIB is a viable option for some patients with NSCLC, with little high-grade toxicity overall. Nearly all local failures occurred within the higher dose region, implying strong radioresistance or some other mechanism for recurrence in a subgroup of patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Preclinical and epidemiologic studies suggest that receipt of some cardiac medications such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers, or aspirin may have antiproliferative effects in several types of cancer. The aim of this study was to estimate survival outcomes in patients receiving incidental cardiac medications during treatment for lung cancer, and to compare outcomes with those patients not receiving these medications., Patients and Methods: We retrospectively reviewed 673 patients who had received definitive radiotherapy for stage III non-small-cell lung cancer (NSCLC). Cox proportional hazard models were used to assess associations between receipt of ACEIs, ARBs, β-blockers, or aspirin and locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS)., Results: Multivariate analyses showed that ACEI receipt was associated with poorer LRPFS but had no effect on DMFS, DFS, or OS. Aspirin receipt was associated only with improved DMFS, and β-blocker receipt was associated with improved DMFS, DFS, and OS., Conclusion: Incidental receipt of ACEIs was associated with a higher prevalence of local failure, whereas receipt of either β-blockers or aspirin had protective effects on survival outcomes in this large group of patients with lung cancer. This finding warrants further clinical and preclinical exploration, as it may have important implications for treating patients with lung cancer who are also receiving cardiac medications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Purpose: MicroRNAs (miRNAs) are small, highly conserved non-coding RNAs that regulate many biological processes. We sought to investigate whether three serum miRNAs related to immunity or inflammation were associated with esophagitis induced by chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC)., Material and Methods: We measured serum miR-155, miR-221 and miR-21, before and during week 1-2 of CRT for 101 NSCLC patients by real-time PCR. Associations between miRNA and severe radiation-induced esophageal toxicity (RIET) were analyzed by logistic regression., Results: We found that patients with stage IIIB-IV disease, higher mean esophagus dose or esophageal V50 had higher rates of severe RIET. Furthermore, high levels of miR-155 and miR-221 at week 1-2 of CRT were also risk factors for severe RIET (miR-155: OR=1.53, 95% CI: 1.04-2.25, P=0.03; miR-221: OR=2.07, 95% CI: 1.17-3.64, P=0.012). In addition, the fold change of miR-221 was also predictive of severe RIET (OR=1.18, 95% CI: 1.02-1.37, P=0.026). However, pretreatment miRNAs was not predictive of severe RIET., Conclusions: High serum miR-155 and miR-221 during the first 2 weeks of CRT were associated with the development of severe RIET, suggesting that these miRNAs may be useful as an early surrogate for this form of toxicity., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: SEER recently released patient Gleason scores at biopsy/transurethral resection of the prostate. For the first time this permits accurate assessment of prostate cancer presentation and treatment according to clinical factors at diagnosis., Materials and Methods: We used the SEER database to identify men diagnosed with localized prostate cancer in 2010 who were assigned NCCN(®) risk based on clinical factors. We identified sociodemographic factors associated with high risk disease and analyzed the impact of these factors along with NCCN risk on local treatment., Results: Of the 42,403 men identified disease was high, intermediate and low risk in 38%, 40% and 22%, respectively. On multivariate analysis patients who were older, nonwhite, unmarried or living in a county with a higher poverty rate were more likely to be diagnosed with high risk disease (each p <0.05). Of the 38,634 men in whom prostate cancer was the first malignancy 23% underwent no local treatment, 40% were treated with prostatectomy, 36% received radiation therapy and 1% underwent local tumor destruction, predominantly cryotherapy. On multivariate analysis patients who were older, black, unmarried or living in a county with a higher poverty rate, or who had low risk disease were less likely to receive local treatment (each p <0.05)., Conclusions: Our analysis provides information on the current clinical presentation and treatment of localized prostate cancer in the United States. Nonwhite and older men living in a county with a higher poverty rate were more likely to be diagnosed with high risk disease and less likely to receive local treatment., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment., Methods and Materials: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria., Results: 101 men received CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016)., Conclusions: Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this hypofractionation regimen., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Purpose: Radiation esophagitis (RE) represents an inflammatory reaction to radiation therapy (RT). We hypothesized that aspects of the physiologic acute phase response (APR) predicts RE., Material and Methods: We retrospectively analyzed 285 patients with non-small cell lung cancer (NSCLC) treated with definitive radiation. The primary analysis was the association of pretreatment lab values reflective of the APR with symptomatic (grade ⩾ 2) RE. Univariate and multivariate odds ratios (ORs) were calculated to test associations of clinical and pretreatment lab values with RE. Optimal cutpoints and multivariable risk stratification groupings were determined via recursive partitioning analysis., Results: Pretreatment platelet counts were higher and hemoglobin levels lower in patients who developed RE (P<0.05). Based on these two pre-treatment risk factors, an APR score was defined as 0 (no risk factors), 1 (either risk factor), or 2 (both risk factors). APR score was significantly associated with RE in both univariate (OR = 2.3 for each point, 95% confidence interval [CI] 1.5-3.4, P = 0.001) and multivariate (OR = 2.1, 95% CI 1.3-3.4, P = 0.002) analyses., Conclusions: The APR score may represent a novel metric to predict RE. However, pending validation in an independent dataset, caution is advised when interpreting these results given their retrospective and thus exploratory nature., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Radiation pneumonitis (RP) is an inflammatory response to radiation therapy (RT). We assessed the association between RP and white blood cell (WBC) count, an established metric of systemic inflammation, after RT for non-small cell lung cancer., Methods and Materials: We retrospectively analyzed 366 patients with non-small cell lung cancer who received ≥60 Gy as definitive therapy. The primary endpoint was whether WBC count after RT (defined as 2 weeks through 3 months after RT completion) was associated with grade ≥3 or grade ≥2 RP. Median lung volume receiving ≥20 Gy (V20) was 31%, and post-RT WBC counts ranged from 1.7 to 21.2 × 10(3) WBCs/μL. Odds ratios (ORs) associating clinical variables and post-RT WBC counts with RP were calculated via logistic regression. A recursive-partitioning algorithm was used to define optimal post-RT WBC count cut points., Results: Post-RT WBC counts were significantly higher in patients with grade ≥3 RP than without (P<.05). Optimal cut points for post-RT WBC count were found to be 7.4 and 8.0 × 10(3)/μL for grade ≥3 and ≥2 RP, respectively. Univariate analysis revealed significant associations between post-RT WBC count and grade ≥3 (n=46, OR=2.6, 95% confidence interval [CI] 1.4‒4.9, P=.003) and grade ≥2 RP (n=164, OR=2.0, 95% CI 1.2‒3.4, P=.01). This association held in a stepwise multivariate regression. Of note, V20 was found to be significantly associated with grade ≥2 RP (OR=2.2, 95% CI 1.2‒3.4, P=.01) and trended toward significance for grade ≥3 RP (OR=1.9, 95% CI 1.0-3.5, P=.06)., Conclusions: Post-RT WBC counts were significantly and independently associated with RP and have potential utility as a diagnostic or predictive marker for this toxicity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Preclinical studies have suggested that angiotensin-converting enzyme inhibitors (ACEIs) can mitigate radiation-induced lung injury. We sought here to investigate possible associations between ACEI use and the risk of symptomatic radiation pneumonitis (RP) among patients undergoing radiation therapy (RT) for non-small cell lung cancer (NSCLC)., Methods and Materials: We retrospectively identified patients who received definitive radiation therapy for stages I to III NSCLC between 2004 and 2010 at a single tertiary cancer center. Patients must have received a radiation dose of at least 60 Gy for a single primary lung tumor and have had imaging and dosimetric data available for analysis. RP was quantified according to Common Terminology Criteria for Adverse Events, version 3.0. A Cox proportional hazard model was used to assess potential associations between ACEI use and risk of symptomatic RP., Results: Of 413 patients analyzed, 65 were using ACEIs during RT. In univariate analysis, the rate of RP grade ≥2 seemed lower in ACEI users than in nonusers (34% vs 46%), but this apparent difference was not statistically significant (P=.06). In multivariate analysis of all patients, ACEI use was not associated with the risk of symptomatic RP (hazard ratio [HR] = 0.66; P=.07) after adjustment for sex, smoking status, mean lung dose (MLD), and concurrent carboplatin and paclitaxel chemotherapy. Subgroup analysis showed that ACEI use did have a protective effect from RP grade ≥2 among patients who received a low (≤20-Gy) MLD (P<.01) or were male (P=.04)., Conclusions: A trend toward reduction in symptomatic RP among patients taking ACEIs during RT for NSCLC was not statistically significant on univariate or multivariate analyses, although certain subgroups may benefit from use (ie, male patients and those receiving low MLD). The evidence at this point is insufficient to establish whether the use of ACEIs does or does not reduce the risk of RP., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Diet-related chronic diseases are major public health concerns in England and the associated costs to the National Health Service and society are considerable. Poor diet and other lifestyle factors are estimated to account for about one-third of all deaths from CVD in England. UK dietary recommendations were set by the Committee on Medical Aspects of Food Policy and are now set by the Scientific Advisory Committee on Nutrition. For cardiovascular health, dietary recommendations are set for nutrients (saturated fat, trans-fat and carbohydrates), foods (fruits, vegetables and oily fish) and salt. The National Diet and Nutrition Survey demonstrates that the majority of the UK population have poor diets. Average intakes of saturated fat and salt are above recommendations while fruit, vegetables, fibre and oily fish are below recommendations. The Department of Health in England is committed to working to improve diet and lifestyle. Current work includes the Public Health Responsibility Deal, under which organisations pledge to increase fruits and vegetables and reduce levels of salt, trans-fat and energy in manufactured foods and menus, the provision of information to help improve food choice through better food labels and provision of information, including a NHS Choices website and the social marketing campaign Change4Life.

Background: Men with high-risk prostate cancer are often thought to have very poor outcomes in terms of disease control and survival even after definitive treatment. However, results after external beam radiotherapy have improved significantly through dose escalation and the use of androgen deprivation therapy (ADT). This report describes long-term findings after low-dose (< 75.6 Gy) or high-dose (≥ 75.6 Gy) external beam radiation, with or without ADT., Methods: This analysis included 741 men with high-risk prostate cancer (clinical classification ≥ T3, Gleason score ≥ 8, or prostate-specific antigen level ≥ 20 ng/mL) treated with external beam radiotherapy at a single tertiary institution from 1987 through 2004. The radiation dose ranged from 60 to 79.3 Gy (median, 70 Gy); 295 men had received ADT for ≥ 2 years, and the median follow-up time was 8.3 years., Results: The 5- and 10-year actuarial overall survival rates were significantly better for men treated with the higher radiation dose (no ADT plus ≥ 75.6 Gy, 87.3% and 72.0%, respectively; and ADT plus ≥ 75.6 Gy, 92.3% and 72%, respectively) (P = .0035). The corresponding 5- and 10-year biochemical failure-free survival rates were significantly better for patients treated with both ADT and higher radiation dose (82% and 77%, P < .0001). At 5 years, men who had not received ADT and had received radiation dose < 75.6 Gy had higher clinical local failure rates than those given ADT and radiation dose ≥ 75.6 Gy (24.2% versus 0%, P < .0001). The 10-year symptomatic local failure rate was only 2% for all patients., Conclusions: Contrary to lingering historical perceptions, treatment of high-risk prostate cancer with modern, high-dose, external beam radiotherapy and ADT can produce better biochemical, clinical, and survival outcomes over those from previous eras. Specifically, symptomatic local failure is uncommon, and few men die of prostate cancer even 10 or more years after treatment., (© 2013 American Cancer Society.)

Purpose: To compare dose-volume histogram variables for the internal and external urinary sphincters (IUS/EUS) with urinary quality of life after prostate brachytherapy., Methods and Materials: Subjects were 42 consecutive men from a prospective study of brachytherapy as monotherapy with (125)I for intermediate-risk localized prostate cancer. No patient received hormonal therapy. Preplanning constraints included prostate V100 higher than 95%, V150 lower than 60%, and V200 lower than 20% and rectal R100 less than 1cm(3). Patients completed the Expanded Prostate Cancer Index Composite quality-of-life questionnaire before and at 1, 4, 8, and 12 months after implantation, and urinary domain scores were analyzed. All structures including the IUS and EUS were contoured on T2-weighted MRI at day 30, and doses received were calculated from identification of seeds on CT. Spearman's (nonparametric) rank correlation coefficient (ρ) was used for statistical analyses., Results: Overall urinary morbidity was worst at 1 month after the implant. Urinary function declined when the IUS V285 was 0.4% (ρ=-0.32, p=0.04); bother worsened when the IUS V35 was 99% (ρ=-0.31, p=0.05) or the EUS V240 was 63% (ρ=-0.31, p=0.05); irritation increased when the IUS V35 was 95% (ρ=-0.37, p=0.02) and the EUS V265 was 24% (ρ=-0.32, p=0.04); and urgency worsened when the IUS V35 was 99.5% (ρ=-0.38, p=0.02). Incontinence did not correlate with EUS or IUS dose., Conclusions: Doses to the IUS and EUS on MRI/CT predicted worse urinary function, with greater bother, irritative symptoms, and urgency. Incorporating MRI-based dose-volume histogram analysis into the treatment planning process may reduce acute urinary morbidity after brachytherapy., (Copyright © 2013. Published by Elsevier Inc.)

Background: Preclinical studies have shown that norepinephrine can directly stimulate tumor cell migration and that this effect is mediated by the beta-adrenergic receptor., Patients and Methods: We retrospectively reviewed 722 patients with non-small-cell lung cancer (NSCLC) who received definitive radiotherapy (RT). A Cox proportional hazard model was utilized to determine the association between beta-blocker intake and locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS)., Results: In univariate analysis, patients taking beta-blockers (n = 155) had improved DMFS (P < 0.01), DFS (P < 0.01), and OS (P = 0.01), but not LRPFS (P = 0.33) compared with patients not taking beta-blockers (n = 567). In multivariate analysis, beta-blocker intake was associated with a significantly better DMFS [hazard ratio (HR), 0.67; P = 0.01], DFS (HR, 0.74; P = 0.02), and OS (HR, 0.78; P = 0.02) with adjustment for age, Karnofsky performance score, stage, histology type, concurrent chemotherapy, radiation dose, gross tumor volume, hypertension, chronic obstructive pulmonary disease and the use of aspirin. There was no association of beta-blocker use with LRPFS (HR = 0.91, P = 0.63)., Conclusion: Beta-blocker use is associated with improved DMFS, DFS, and OS in this large cohort of NSCLC patients. Future prospective trials can validate these retrospective findings and determine whether the length and timing of beta-blocker use influence survival outcomes.

Objective: To prospectively evaluate tumor control, survival, and toxic effects in patients with International Federation of Gynecology and Obstetrics (1988) stage I-IIIA papillary serous carcinoma of the endometrium treated with concurrent chemoradiation and adjuvant chemotherapy., Methods: Thirty-two patients were enrolled from October 2001 through July 2009. Patients underwent full surgical disease staging and postoperative concurrent weekly paclitaxel (50 mg/m2) and pelvic RT to 45 Gy plus a vaginal cuff boost followed by 4 cycles of adjuvant paclitaxel (135 mg/m2)., Results: Thirty patients (94%) were evaluable (3 with stage IA disease, 11 IB, 3 IC, 1 IIB, and 12 IIIA). Eighteen patients (60%) received all 5 planned courses of concurrent chemotherapy, 10 (33%) received 4 courses, and 2 (7%) received 3 courses. All 30 patients received RT; 27 (90%) received the full dose, 2 received 43.2 Gy, and 1 received 39.6 Gy owing to toxic effects. Twenty-three patients (77%) completed all 4 cycles of adjuvant paclitaxel, 3 (10%) completed 3 cycles, 2 (7%) completed 2 cycles, and 2 received no adjuvant therapy. Overall survival (OS), progression-free survival (PFS), and local control rates for all patients were 93%, 87%, and 87%, respectively, at 2 years and 85%, 83%, and 87%, respectively, at 5years. Six patients developed (20%) grade 3/4 toxicities from the treatment. Four patients (13%) had grade 3 or more severe bowel complications and two patients developed symptomatic pelvic fractures., Conclusions: Treatment with concurrent paclitaxel and pelvic RT followed by 4 courses of systemic paclitaxel produced favorable results in patients with surgically staged I-III UPSC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To date, no biomarkers have been found to predict, before treatment, which patients will develop radiation pneumonitis (RP), a potentially fatal toxicity, after chemoradiation for lung cancer. We investigated potential associations between single nucleotide polymorphisms (SNPs) in HSPB1 and risk of RP after chemoradiation for non-small cell lung cancer (NSCLC)., Methods and Materials: Subjects were patients with NSCLC treated with chemoradiation at 1 institution. The training data set comprised 146 patients treated from 1999 to July 2004; the validation data set was 125 patients treated from August 2004 to March 2010. We genotyped 2 functional SNPs of HSPB1 (rs2868370 and rs2868371) from all patients. We used Kaplan-Meier analysis to assess the risk of grade ≥2 or ≥3 RP in both data sets and a parametric log-logistic survival model to evaluate the association of HSPB1 genotypes with that risk., Results: Grade ≥3 RP was experienced by 13% of those with CG/GG and 29% of those with CC genotype of HSPB1 rs2868371 in the training data set (P=.028); corresponding rates in the validation data set were 2% CG/GG and 14% CC (P=.02). Univariate and multivariate analysis confirmed the association of CC of HSPB1 rs2868371 with higher risk of grade ≥3 RP than CG/GG after adjustment for sex, age, performance status, and lung mean dose. This association was validated both in the validation data set and with Harrell's C statistic., Conclusions: The CC genotype of HSPB1 rs2868371 was associated with severe RP after chemoradiation for NSCLC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF)., Methods: Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF., Results: Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%)., Conclusions: Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease. In patients with GS 4+3 or T2c disease, the addition of ADT to dose-escalated RT did improve FFF., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to evaluate the actuarial risk of local and regional failure in patients with completely resected non-small-cell lung cancer (NSCLC), and to assess surgical and pathological factors affecting this risk., Patients and Methods: Between January 1998 and December 2009, 1402 consecutive stage I-III (N0-N1) NSCLC patients underwent complete resection without adjuvant radiation therapy. The median follow-up was 42 months., Results: Local-regional recurrence was identified in 9% of patients, with local failure alone in 3% of patients, regional failure alone in 4% of patients, and both local and regional failure simultaneously in 2% of patients. Patients who had local failure were found to be at increased risk of mortality. By multivariate analyses, three variables were shown to be independently significant risk factors for local [surgical procedure (single/multiple wedges+segmentectomy versus lobectomy+bilobectomy+pneumonectomy), tumor size>2.7 cm, and visceral pleural invasion] and regional (pathologic N1 stage, visceral pleural invasion, and lymphovascular space invasion, LVI) recurrence, respectively., Conclusion: Patients with N0-N1 disease have low rates of locoregional recurrence after surgical resection. However, several prognostic factors can be identified that increase this risk and identify patients who may benefit from adjuvant treatment.

Purpose: The aim of the study was to evaluate the prognostic value of prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) prior to dose-escalated radiation therapy (RT) and long-term ADT in high-risk prostate cancer., Methods and Materials: We reviewed the charts of all patients diagnosed with high-risk prostate cancer and treated with a combination of long-term ADT (median, 24 months) and dose-escalated (median, 75.6 Gy) RT between 1990 and 2007. The associations among patient, tumor, and treatment characteristics with biochemical response to neoadjuvant ADT and their effects on failure-free survival (FFS), time to distant metastasis (TDM), prostate cancer-specific mortality (PCSM) and overall survival (OS) were examined., Results: A total of 196 patients met criteria for inclusion. Median follow-up time for patients alive at last contact was 7.0 years (range, 0.5-18.1 years). Multivariate analysis identified the pre-RT PSA concentration (<0.5 vs ≥0.5 ng/mL) as a significant independent predictor of FFS (P=.021), TDM (P=.009), PCSM (P=.039), and OS (P=.037). On multivariate analysis, pretreatment PSA (iPSA) and African-American race were significantly associated with failure to achieve a pre-RT PSA of <0.5 ng/mL., Conclusions: For high-risk prostate cancer patients treated with long-term ADT and dose-escalated RT, a pre-RT PSA level≥0.5 ng/mL after neoadjuvant ADT predicts for worse survival measures. Both elevated iPSA and African-American race are associated with increased risk of having a pre-RT PSA level≥0.5 ng/mL. These patients should be considered for clinical trials that test newer, more potent androgen-depleting therapies such as abiraterone and MDV3100 in combination with radiation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: We investigated potential associations between single-nucleotide polymorphisms (SNPs) in the heat shock protein beta-1 (HSPB1) gene and overall survival in US patients with non-small cell lung cancer (NSCLC)., Methods and Materials: Using available genomic DNA samples from 224 patients with NSCLC treated with definitive radio(chemo)therapy, we genotyped 2 SNPs of HSPB1 (NCBI SNP nos. rs2868370 and rs2868371). We used both Kaplan-Meier cumulative probability and Cox proportional hazards analyses to evaluate the effect of HSPB1 genotypes on survival., Results: Our cohort consisted of 117 men and 107 women, mostly white (79.5%), with a median age of 70 years. The median radiation dose was 66 Gy (range, 63-87.5 Gy), and 183 patients (82%) received concurrent platinum-based chemotherapy. The most common genotype of the rs2868371 SNP was CC (61%). Univariate and multivariate analyses showed that this genotype was associated with poorer survival than CG and GG genotypes (univariate hazard ratio [HR] = 1.39, 95% confidence interval [CI], 1.02-1.90; P=.037; multivariate HR = 1.39; 95% CI, 1.01-1.92; P=.045)., Conclusions: Our results showed that the CC genotype of HSPB1 rs2868371 was associated with poorer overall survival in patients with NSCLC after radio(chemo)therapy, findings that contradict those of a previous study of Chinese patients. Validation of our findings with larger numbers of similar patients is needed, as are mechanical and clinical studies to determine the mechanism underlying these associations., (Published by Elsevier Inc.)

The Znt7 gene encodes a ubiquitously expressed zinc transporter that is involved in transporting cytoplasmic zinc into the Golgi apparatus and a ZnT7-containing vesicular compartment. Overexpression of ZnT7 in the pancreatic β-cell stimulates insulin synthesis and secretion through regulation of insulin gene transcription. In this study, we demonstrate that ZnT7 is expressed in the mouse skeletal muscle. The activity of the insulin signaling pathway was down-regulated in myocytes isolated from the femoral muscle of Znt7 knock-out (KO) mice. High fat diet consumption (45% kcal) induced weight gain in male Znt7 KO mice but not female Znt7 KO mice. Male Znt7 KO mice fed the high fat diet at 5 weeks of age for 10 weeks exhibited hyperglycemia in the non-fasting state. Oral glucose tolerance tests revealed that male Znt7 KO mice fed the high fat diet had severe glucose intolerance. Insulin tolerance tests showed that male Znt7 KO mice were insulin-resistant. Diet-induced insulin resistance in male Znt7 KO mice was paralleled by a reduction in mRNA expression of Insr, Irs2, and Akt1 in the primary skeletal myotubes isolated from the KO mice. Overexpression of ZnT7 in a rat skeletal muscle cell line (L6) increased Irs2 mRNA expression, Irs2 and Akt phosphorylation, and glucose uptake. We conclude that a combination of decreased insulin secretion and increased insulin resistance accounts for the glucose intolerance observed in Znt7 KO mice.

Background: Dose-escalated (DE) radiation therapy (RT) and androgen deprivation therapy (ADT) improve prostate cancer outcomes over standard-dose RT. The benefit of adding ADT to DE-RT for men with intermediate-risk prostate cancer (IR-PrCa) is uncertain., Patients and Methods: We identified 636 men treated for IR-PrCa with DE-RT (>75Gy). The adult comorbidity evaluation-27 index classifed comorbidity. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT., Results: Forty-five percent received DE-RT and 55% DE-RT with ADT (median 6 months). On Cox proportional hazard regression that adjusted for comorbidity and tumor characteristics, ADT improved FFS (adjusted hazard ratio 0.36; P = 0.004). Recursive partitioning analysis of men without ADT classified Gleason 4 + 3 = 7 or ≥50% positive cores as unfavorable disease. The addition of ADT to DE-RT improved 5-year FFS for men with unfavorable disease (81.6% versus 92.9%; P = 0.009) but did not improve FFS for men with favorable disease (96.3% versus 97.4%; P = 0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (P = 0.006) but did not improve FFS for men with unfavorable disease and moderate or severe comorbidity (P = 0.380)., Conclusion: The addition of ADT to DE-RT improves FFS for men with unfavorable IR-PrCa, especially those with no or minimal comorbidity.

Purpose: To investigate the extent of change in pulmonary function over time after definitive radiotherapy for non-small-cell lung cancer (NSCLC) with modern techniques and to identify predictors of changes in pulmonary function according to patient, tumor, and treatment characteristics., Patients and Methods: We analyzed 250 patients who had received ≥ 60 Gy radio(chemo)therapy for primary NSCLC in 1998-2010 and had undergone pulmonary function tests before and within 1 year after treatment. Ninety-three patients were treated with three-dimensional conformal radiotherapy, 97 with intensity-modulated radiotherapy, and 60 with proton beam therapy. Postradiation pulmonary function test values were evaluated among individual patients compared with the same patient's preradiation value at the following time intervals: 0-4 (T1), 5-8 (T2), and 9-12 (T3) months., Results: Lung diffusing capacity for carbon monoxide (DLCO) was reduced in the majority of patients along the three time periods after radiation, whereas the forced expiratory volume in 1 s per unit of vital capacity (FEV1/VC) showed an increase and decrease after radiation in a similar percentage of patients. There were baseline differences (stage, radiotherapy dose, concurrent chemotherapy) among the radiation technology groups. On multivariate analysis, the following features were associated with larger posttreatment declines in DLCO: pretreatment DLCO, gross tumor volume, lung and heart dosimetric data, and total radiation dose. Only pretreatment DLCO was associated with larger posttreatment declines in FEV1/VC., Conclusions: Lung diffusing capacity for carbon monoxide is reduced in the majority of patients after radiotherapy with modern techniques. Multiple factors, including gross tumor volume, preradiation lung function, and dosimetric parameters, are associated with the DLCO decline. Prospective studies are needed to better understand whether new radiation technology, such as proton beam therapy or intensity-modulated radiotherapy, may decrease the pulmonary impairment through greater lung sparing., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: A competing risks analysis was undertaken to identify subgroups at greatest risk of dying from prostate cancer (PC) after definitive external beam radiation therapy (RT)±androgen deprivation therapy (ADT) in the prostate specific antigen (PSA) era., Methods: Outcomes of 2675 men with localised PC treated with RT±ADT from 1987-2007 were analysed. Prostate cancer-specific mortality (PCSM) and non-PCSM rates were calculated after stratifying patients according to National Comprehensive Cancer Network (NCCN) risk-group, RT dose, use of ADT and age at treatment., Results: Only 0.2% of low-risk men died of PC 10 years after treatment. All of these deaths occurred in patients treated with < 72 Gy, and only one patient ≥ 70 years old who received ≥ 72 Gy died of PC at last follow-up. Likewise, none of the patients with intermediate-risk disease treated with ≥ 72 Gy and ADT died of PC at 10 years, and the highest 10-year rate of PCSM was seen in men ≥ 70 years old treated with < 72 Gy without ADT (5.1%). Among high-risk men < 70 years old, treatment with RT dose < 72 Gy without ADT yielded similar 10-year rates of PCSM (15.2%) and non-PCSM (18.5%), whereas men treated with ≥ 72 Gy and ADT were twice as likely to die from other causes (16.2%) than PC (9.4%). In high-risk men ≥ 70 years old, dose-escalation with ADT reduced 10-year PCSM from 14% to 4%, and most deaths were due to other causes., Conclusion: Low- and intermediate-risk patients treated with definitive RT are unlikely to die of PC. PCSM is higher in men with high-risk disease but may be reduced with dose-escalation and ADT, although patients are still twice as likely to die of other causes., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: Prospective evaluation of sexual outcomes after prostate brachytherapy with iodine-125 seeds as monotherapy at a tertiary cancer care center., Methods and Materials: Subjects were 129 men with prostate cancer with I-125 seed implants (prescribed dose, 145 Gy) without supplemental hormonal or external beam radiation therapy. Sexual function, potency, and bother were prospectively assessed at baseline and at 1, 4, 8, and 12 months using validated quality-of-life self-assessment surveys. Postimplant dosimetry values, including dose to 10% of the penile bulb (D10), D20, D33, D50, D75, D90, and penile volume receiving 100% of the prescribed dose (V100) were calculated., Results: At baseline, 56% of patients recorded having optimal erections; at 1 year, 62% of patients with baseline erectile function maintained optimal potency, 58% of whom with medically prescribed sexual aids or drugs. Variables associated with pretreatment-to-posttreatment decline in potency were time after implant (p = 0.04) and age (p = 0.01). Decline in urinary function may have been related to decline in potency. At 1 year, 69% of potent patients younger than 70 years maintained optimal potency, whereas 31% of patients older than 70 maintained optimal potency (p = 0.02). Diabetes was related to a decline in potency (p = 0.05), but neither smoking nor hypertension were. For patients with optimal potency at baseline, mean sexual bother scores had declined significantly at 1 year (p < 0.01). Sexual potency, sexual function, and sexual bother scores failed to correlate with any dosimetric variable tested., Conclusions: Erections firm enough for intercourse can be achieved at 1 year after treatment, but most men will require medical aids to optimize potency. Although younger men were better able to maintain erections firm enough for intercourse than older men, there was no correlation between potency, sexual function, or sexual bother and penile bulb dosimetry., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: During the first 3 years after prostate cancer treatment with radiation therapy, benign prostate-specific antigen (PSA) bounces are difficult for clinicians to distinguish from a biochemical recurrence, which can result in unnecessary interventions and erroneous predictions of outcomes. The objective of this study was to evaluate a commonly used PSA failure definition in a multinational, multi-institutional study after monotherapy with prostate brachytherapy., Methods: Participants were selected from 2919 men who underwent permanent prostate brachytherapy at the University Medical Center Utrecht, Princess Margaret Hospital, or Seattle Prostate Institute between 1998 and 2006. Inclusion required not having received androgen-deprivation therapy and having at least 30 months of follow-up. Failure was defined as any post-treatment use of hormone therapy, clinical relapse, or prostogram-defined biochemical (PSA) failure. Cases in which the nomogram predicted biochemical failure were evaluated at each institution to verify biochemical status over time and the actual clinical outcome at 5 years., Results: The median follow-up for the 1816 patients was 5.2 years. Concordance between the prostogram-predicted and actual outcomes, as measured by the Harrell c statistic, was 0.655 (95% confidence interval [CI], 0.536-0.774; P = .010) for the Princess Margaret group, 0.493 (95% CI, 0.259-0.648; P = .955) for the Seattle group, and 0.696 (95% CI, 0.648-0.744, P < .001) for the Utrecht group. The overall mean difference in biochemical recurrence-free survival at 5 years between actual outcomes and prostogram-defined outcomes was 9.2% (95% CI, 7.7%-10.6%). The total numbers of prostogram-defined and actual biochemical failures were 312 and 157, respectively (P = .001)., Conclusions: The widely used prostogram could not adequately distinguish a benign PSA bounce from a biochemical recurrence after prostate brachytherapy and could not be used to counsel patients about their predicted outcomes after treatment. The authors conclude that, to avoid unnecessary active interventions after treatment, clinicians should monitor PSA levels for at least 3 years and provide reassurance to patients that a PSA rise during this time is common and may not indicate a treatment failure., (Copyright © 2011 American Cancer Society.)

Purpose: This study aimed to evaluate the changes in outcome for men with localized prostate cancer treated with definitive external beam radiation therapy during a 20-year period at a comprehensive cancer center., Methods: We categorized 2675 men with prostate cancer treated at MD Anderson Cancer Center with definitive external beam radiation therapy with or without androgen deprivation therapy into 3 treatment eras: 1987 to 1993 (n = 722), 1994 to 1999 (n = 828), and 2000 to 2007 (n = 1125). To help adjust for stage migration, patients were stratified according to risk group as defined by the National Comprehensive Cancer Network. Biochemical (Phoenix definition), local, distant, and any clinical failure, prostate-cancer specific survival, and overall survival were analyzed according to the Kaplan-Meier method., Results: Median age was 68.5 years and median follow-up was 6.4 years. Fewer men in the most recent era had high-risk disease, and a higher proportion received 72 Gy or higher (99% vs 4%) and androgen deprivation therapy (60% vs 6%) than the earliest era. All risk groups treated in the modern era experienced improved rates of biochemical, local, and distant failure. In high-risk patients, decreased rates of distant failure and clinical failure led to improved prostate cancer-specific survival and overall survival. Local control was improved for intermediate- and high-risk patients, with a trend toward improvement in low-risk patients. On multivariate analysis, recent treatment era was closely correlated with a dose of 72 Gy or higher and treatment with androgen deprivation therapy and predicted for lower rates of biochemical, local, and distant failure. Androgen deprivation therapy, higher dose, and more recent treatment era predicted for improved prostate cancer-specific survival., Discussion: During the last 20 years of prostate cancer irradiation, disease control outcomes have improved in all patients, leading to improved prostate cancer-specific survival and overall survival for men with high-risk disease. This may reflect advances in workup, staging accuracy, and prostate cancer treatment in the modern era.

Objective: To quantify gastrointestinal (GI) and genitourinary (GU) toxicity associated with postprostatectomy radiation and to determine the relationships between dosimetry parameters and medical comorbidities and toxicity., Methods: We reviewed the records of 233 prostate cancer patients irradiated after prostatectomy between 1987 and 2002. Ninety-nine patients were treated with a volumetric 3-dimensional conformal approach and 134 patients were treated conventionally. Acute and late GI and GU toxicity was recorded and the relationships between dosimetry parameters and comorbidities and toxicity were examined., Results: Acute grade 2 to 3 GI toxicity was more common in the conventionally versus conformally treated patients (83% vs. 61%, P=0.01). The rates of acute grade 2 to 3 GU toxicity were not significantly different between the techniques. There were no acute grade 4 events. Most patients had no late GI toxicity (73% conformal and 75% conventional) and no late GU toxicity (64% conformal and 59% conventional). In an actuarial analysis, the 5-year rates of grade 2 to 4 GI and GU complications were not different between the treatment techniques. Two patients treated conventionally had late grade 4 complications. Hemorrhoids predicted for late GI toxicity, and renal stones and preirradiation urinary incontinence predicted for late GU complications. Delivery of 50 Gy to more than 38% of the rectal volume, 40 Gy to more than 58%, or 30 Gy to more than 72% was associated with an increased risk of late GI complications. Eighty-seven percent of the late GI complications occurred in patients with at least grade 2 acute GI toxicity., Conclusions: For prostate cancer patients treated with postoperative radiation, limited toxicity is seen with conventional or conformal techniques. The similar rates of toxicity between techniques may have been because of higher conformal median doses -70 Gy versus 62 Gy. Dose-volume parameters correlate with the risk of GI complications.

Purpose: To report long-term failure patterns and survival in a randomized radiotherapy dose escalation trial for prostate cancer., Materials and Methods: A total of 301 patients with Stage T1b-T3 prostate cancer treated to 70 Gy versus 78 Gy now have a median follow-up of 9 years. Failure patterns and survival were compared between dose levels. The cumulative incidence of death from prostate cancer versus other causes was examined and regression analysis was used to establish predictive factors., Results: Patients with pretreatment prostate-specific antigen (PSA) >10 ng/mL or high-risk disease had higher biochemical and clinical failures rates when treated to 70 Gy. These patients also had a significantly higher risk of dying of prostate cancer. Patients <70 years old at treatment died of prostate cancer nearly three times more frequently than of other causes when they were radiated to 70 Gy, whereas those treated to 78 Gy died of other causes more frequently. Patients age 70 or older treated to 70 Gy died of prostate cancer as often as other causes, and those receiving 78 Gy never died of prostate cancer within 10 years of follow-up. In regression analysis, factors predicting for death from prostate cancer were pretreatment PSA >10.5 ng/mL, Gleason score 9 and 10, recurrence within 2.6 years of radiation, and doubling time of <3.6 months at the time of recurrence., Conclusions: Moderate dose escalation (78 Gy) decreases biochemical and clinical failure as well as prostate cancer death in patients with pretreatment PSA >10 ng/mL or high-risk disease., (Copyright © 2011 Elsevier Inc. All rights reserved.)

As opioid prescribing has dramatically expanded over the past decade, so too has the problem of prescription drug abuse. In response to these now two major public health problems - the problem of poorly treated chronic pain and the problem of opioid abuse - a new paradigm has arisen in pain management, namely risk stratification. Once a prescriber has determined that opioids will be used (a medical decision based on how intense the pain is, what has been tried and failed and, to some extent, what type of pain the patient has), he/she must then decide how opioid therapy is to be delivered. Different models of delivery of opioid therapy can be utilized, beginning the process with a risk assessment that is highly individualized to each patient. Recently, researchers have produced a wide variety of literature regarding assessment tools to be used for this purpose. And while there remains a need for larger prospective studies to examine the ability of each tool to predict aberrant drug-taking behaviors, clinicians can and should utilize one or more of these screening tools and understand their benefits and limitations. This chapter will describe the nature of current screening assessments, their potential for use in the pain population in various settings, past clinical observations and suggestions for moving forward., (Copyright © 2011 S. Karger AG, Basel.)

Low-income women have very high rates of depression and also face a number of unique barriers that can prevent them from seeking, accepting, engaging in, or benefiting from psychotherapy treatment. Untreated depression often leads to deleterious psychological consequences for these women and their children, and may also diminish a woman's ability to improve her economic circumstances. We reviewed the literature on psychotherapeutic interventions for depressed, low-income women, identifying a number of practical, psychological, and cultural barriers that often prevent them from engaging in psychotherapy. Next, we assessed the degree to which established intervention programs help women overcome these barriers. The data suggest that it is quite difficult to engage depressed, low-income women in psychotherapy, but that a number of standard psychotherapy approaches do show promise. However, we found that many of the currently available interventions fail to fully address the barriers that prevent this population from engaging in treatment. Moreover, the impact these interventions have on engagement and attrition rates or clinical improvements is often inadequately reported. We provide preliminary recommendations for clinicians who work with low-income women as well as suggestions for bolstering the literature base., (Published by Elsevier Ltd.)