Variation of the relative biological effectiveness with fractionation in proton therapy: analysis of prostate cancer response

Purpose: To present a methodology to analyze the variation of RBE with fractionation from clinical data of tumor control probability (TCP) and to apply it to study the response of prostate cancer to proton therapy. M&M: We analyzed the dependence of the RBE on the dose per fraction by using the LQ model and the Poisson TCP formalism. Clinical TCPs for prostate cancer treated with photon and proton therapy for conventional fractionation (2 Gy(RBE)x37 fractions), moderate hypofractionation (3 Gy(RBE)x20 fractions) and hypofractionation (7.25 Gy(RBE)x5 fractions) were obtained from the literature and analyzed. Results: The theoretical analysis showed three distinct regions with RBE monotonically decreasing, increasing or staying constant with the dose per fraction, depending on the change of ({\alpha}, \{beta}) values between photon and proton irradiation (the equilibrium point being at({\alpha}_p/\{beta}_p)=({\alpha}_X/\{beta}_X)({\alpha}_X/{\alpha}_p)). An analysis of the clinical data showed RBE values that decline with increasing dose per fraction: for low risk RBE=1.124, 1.119, and 1.102 for 1.82 Gy, 2.73 Gy and 6.59 Gy per fraction (physical proton doses), respectively; for intermediate risk RBE=1.119, and 1.102 for 1.82 Gy, and 6.59 Gy per fraction (physical proton doses), respectively. These values are nonetheless very close to the nominal 1.1 value. Conclusions: We presented a methodology to analyze the RBE for different fractionations, and we used it to study clinical data for prostate cancer. The analysis shows a monotonically decreasing RBE with increasing dose per fraction, which is expected from the LQ formalism and the changes in ({\alpha}, \{beta}) between photon and proton irradiation. However, the calculations in this study have to be considered with care as they may be biased by limitations in the modeling and/or by the clinical data set used for the analysis.Comment: Minor changes to match accepted manuscript; in press Medical Physic

Health-related quality of life in men with localized prostate cancer treated with radiotherapy: validation of an abbreviated version of the Expanded Prostate Cancer Index Composite for Clinical Practice in Spain

Cáncer de próstata; Evaluación de la calidad de vida; RadioterapiaCàncer de pròstata; Avaluació de la qualitat de vida; RadioteràpiaProstate cancer; Quality-of-life assessment; RadiotherapyBackground Health-related quality of life (HRQoL) is greatly affected by prostate cancer (PCa) and associated treatments. This study aimed to measure the impact of radiotherapy on HRQoL and to further validate the Spanish version of the 16-item Expanded Prostate Cancer Index Composite (EPIC-16) in routine clinical practice. Methods An observational, non-interventional, multicenter study was conducted in Spain with localized PCa patients initiating treatment with external beam radiotherapy (EBRT) or brachytherapy (BQT). Changes from baseline in EPIC-16, University of California-Los Angeles Prostate Cancer Index (UCLA-PCI), and patient-perceived health status were longitudinally assessed at end of radiotherapy (V2) and 90 days thereafter (V3). Psychometric evaluations of the Spanish EPIC-16 were conducted. Results Of 516 patients enrolled, 495 were included in the analysis (EBRT, n = 361; BQT, n = 134). At baseline, mean (standard deviation [SD]) EPIC-16 global scores were 11.9 (7.5) and 10.3 (7.7) for EBRT and BQT patients, respectively; scores increased, i.e., HRQoL worsened, from baseline, by mean (SD) of 6.8 (7.6) at V2 and 2.4 (7.4) at V3 for EBRT and 4.2 (7.6) and 3.9 (8.2) for BQT patients. Changes in Spanish EPIC-16 domains correlated well with urinary, bowel, and sexual UCLA-PCI domains. EPIC-16 showed good internal consistency (Cronbach’s alpha = .84), reliability, and construct validity. Conclusion The Spanish EPIC-16 questionnaire demonstrated sensitivity, strong discriminative properties and reliability, and validity for use in clinical practice. EPIC-16 scores worsened after radiotherapy in different HRQoL domains; however, a strong tendency towards recovery was seen at the 3-month follow-up visit.This study was funded by Astellas Pharma Inc

Environmental factors related to fungal infection and fumonisin accumulation during the development and drying of white maize kernels

In Southern Europe where whole maize kernels are ground and used for making bread and other food products, infection of the kernels by Fusarium verticillioides and subsequent fumonisin contamination pose a serious safety issue. The influence of environmental factors on this fungal infection and mycotoxin accumulation as the kernel develops has not been fully determined, especially in such food grade maize. The objectives of the present study were to determine which environmental factors may contribute to kernel invasion by F. verticillioides and fumonisin accumulation as kernels develop and dry in naturally infected white maize. Three maize hybrids were planted at two different sowing dates and kernel samples were collected 20, 40, 60, 80 and 100. days after silking. The percentage of kernels infected, and ergosterol and fumonisin contents were recorded for each sampling. F. verticillioides was the most prevalent species identified as the kernels developed. Temperature and moisture conditions during the first 80. days after silking favored natural kernel infection by F. verticillioides rather than by Aspergillus or Penicillium species. Fumonisin was found in kernels as early as 20. days after silking however significant fumonisin accumulation above levels acceptable in the EU did not occur until after physiological maturity of the kernel indicating that kernel drying in the field poses a high risk. Our results suggest that this could be due to increasing kernel damage by insects that favor fungal development, such as the damage by the moth Sitotroga cerealella, and to the occurrence of stress conditions for F. verticillioides growth that could trigger fumonisin biosynthesis, such as exposure to suboptimal temperatures for growth simultaneously with low water activity. © 2013 Elsevier B.V.MICINNSpanish Council of ResearchAutonomous Government of GaliciaEuropean Social FundThis research was supported by the National Plan for Research and Development of Spain (AGL2009-12770). A. Cao acknowledges funding from the JAE Program of the Spanish Council of Research. R. Santiago acknowledges postdoctoral contract “Isidro Parga Pondal” supported by the Autonomous Government of Galicia and the European Social Fund.Peer Reviewe

Patterns of Alcohol Consumption in Spanish University Alumni: Nine Years of Follow-Up

The aim of this study was to empirically identify different profiles of Spanish university alumni, based on their alcohol use over 9 years, and to further characterize them. A cohort study was carried out between 2005 and 2015 among university students (Compostela Cohort-Spain; n2015 = 415). Alcohol consumption was measured using the Alcohol Use Disorder Identification Test (AUDIT). A two-stage cluster analysis, based on their AUDIT total scores was carried out separately for males and females. The further characterization of every profile was based on demographic data, age at onset of alcohol use, positive alcohol-related expectancies, tobacco and cannabis use, as well as their answers to some European Addiction Severity Index items. Five different clusters were identified: Low users (29.2%), Moderated users (37.2%), At-risk users (14.2%), Decreasing users (13.2%) and Large users (6.2%) for females, and Low users (34.4%), At-risk users (25.6%), High-risk users (15.6%), Decreasing users (14.4%) and Large users (10.0%) for males. Being a cannabis user or a smoker was positively associated to those more hazardous clusters in both genders. Regarding females, significant differences in the age of onset and high positive expectancies were found. However, there were few significant differences among the groups in relation to their employment status and social relations. The results reveal the existence of different typologies of alcohol users among university alumni, with differences among males and females. Modifying positive expectancies, limiting access to alcohol at a young age, and reducing uses of other substances uses are key to promote healthier alcohol use profiles and to prevent hazardous usesThis work was supported by a grant from the Plan Nacional sobre Drogas (Spain) (2005/PN014) and from Fondo de Investigación Sanitaria (Spain) (PI15/00165). Eduardo López-Caneda was supported by the SFRH/BPD/109750/2015 Postdoctoral Fellowship of the Portuguese Foundation for Science and Technology as well as by the Psychology Research Centre (UID/PSI/01662/2013), co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007653)S

Effect of LHRH analogs on lower urinary tract symptoms associated with advanced prostate cancer in real clinical practice: ANALUTS study

Androgen deprivation; Hormonal therapy; RadiotherapyPrivación de andrógenos; Terapia hormonal; RadioterapiaPrivació d'andrògens; Teràpia hormonal; RadioteràpiaAims To estimate the prevalence of lower urinary tract symptoms (LUTS) in patients with prostate cancer scheduled to receive LHRH analogs, and to assess the effectiveness of LHRH analogs on LUTS in patients presenting moderate/severe symptoms. Methods Prospective, noninterventional, multicenter study conducted at 28 centers in Spain and Portugal. LUTS were evaluated using the International Prostate Symptom Score (IPSS) at baseline, 24 and 48 weeks after initiation of treatment. Subanalyses were performed according to age and concomitant treatment (radiotherapy, alpha-blockers, and antiandrogens). Results A total of 354 patients were treated with LHRH analogs for 48 weeks. The percentage of patients with moderate/severe LUTS (IPSS > 7) decreased from 60.2% (n = 213/354) at baseline to 52.8% (n = 187/354) at Week 48. Among patients with moderate/severe LUTS at baseline: 73.7% (n = 157/213) still had moderate/severe LUTS at Week 48; percentage reductions of patients with LUTS at Week 48 were statistically significant (p < 0.05) overall and by age or concomitant treatment, except for alpha-blockers (84.2% patients receiving them still had moderate/severe LUTS at Week 48). All IPSS items, including quality of life for urinary symptoms, improved throughout the study. The only predictor of response to treatment with LHRH analogs that improved IPSS by 3 points after 48 weeks was baseline testosterone levels. Lower baseline testosterone levels were associated with greater improvement in IPSS after treatment with LHRH analogs (odds ratio 0.998, 95% confidence interval 0.996–1.000, p = 0.0277). Conclusion LHRH analogs have a positive effect in patients with locally advanced or metastatic prostate cancer presenting moderate/severe LUTS regardless of age or concomitant treatment received (radiotherapy, antiandrogens, or alpha-blockers).The study was funded by Ipsen Pharma S.A.U

A case study on polypharmacy and depression in a 75-year-old woman with visual deficits and charles bonnet syndrome

Depression is one of the most prevalent pathologies in older adults. Its diagnosis and treatment are complex due to different factors that intervene in its development and progression, including intercurrent organic diseases, perceptual deficits, use of drugs, and psycho-social conditions associated with the aging process. We present the case of a 75-year-old woman (who lives in the community) with a diagnosis of major depression with more than 10 years of history, analyzing her evolution and therapeutic approachS

Effect of LHRH analogs on lower urinary tract symptoms associated with advanced prostate cancer in real clinical practice : ANALUTS study

To estimate the prevalence of lower urinary tract symptoms (LUTS) in patients with prostate cancer scheduled to receive LHRH analogs, and to assess the effectiveness of LHRH analogs on LUTS in patients presenting moderate/severe symptoms. Prospective, noninterventional, multicenter study conducted at 28 centers in Spain and Portugal. LUTS were evaluated using the International Prostate Symptom Score (IPSS) at baseline, 24 and 48 weeks after initiation of treatment. Subanalyses were performed according to age and concomitant treatment (radiotherapy, alpha-blockers, and antiandrogens). A total of 354 patients were treated with LHRH analogs for 48 weeks. The percentage of patients with moderate/severe LUTS (IPSS > 7) decreased from 60.2% (n = 213/354) at baseline to 52.8% (n = 187/354) at Week 48. Among patients with moderate/severe LUTS at baseline: 73.7% (n = 157/213) still had moderate/severe LUTS at Week 48; percentage reductions of patients with LUTS at Week 48 were statistically significant (p < 0.05) overall and by age or concomitant treatment, except for alpha-blockers (84.2% patients receiving them still had moderate/severe LUTS at Week 48). All IPSS items, including quality of life for urinary symptoms, improved throughout the study. The only predictor of response to treatment with LHRH analogs that improved IPSS by 3 points after 48 weeks was baseline testosterone levels. Lower baseline testosterone levels were associated with greater improvement in IPSS after treatment with LHRH analogs (odds ratio 0.998, 95% confidence interval 0.996-1.000, p = 0.0277). LHRH analogs have a positive effect in patients with locally advanced or metastatic prostate cancer presenting moderate/severe LUTS regardless of age or concomitant treatment received (radiotherapy, antiandrogens, or alpha-blockers)

Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity.

BACKGROUND: Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy. METHODS: The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studies were imputed with the 1000 Genomes reference panel. Individuals were genetically similar with a European ancestry based on principal component analysis. Genetic risks were quantified using polygenic risk scores. Regression models tested associations between risk scores and 2-year toxicity (overall, urinary frequency, decreased stream, rectal bleeding). Results were combined across studies using standard inverse-variance fixed effects meta-analysis methods. RESULTS: A total of 75 variants were genotyped/imputed successfully. Neither non-weighted nor weighted polygenic risk scores were associated with late radiation toxicity in individual studies (P>0.11) or after meta-analysis (P>0.24). No individual variant was associated with 2-year toxicity. CONCLUSION: Patients with a high polygenic susceptibility for prostate cancer have no increased risk for developing late radiotherapy toxicity. These findings suggest that patients with a genetic predisposition for prostate cancer, inferred by common variants, can be safely treated using current standard radiotherapy regimens.This work was supported by Cancer Research UK (C1094/A11728 to CMLW and NGB for the RAPPER study, C26900/A8740 to GCB, C5047A17528 to RE), the Royal College of Radiologists (GCB), Prostate Cancer UK (P2012148 to RE), The ELLIPSE Consortium on behalf of the GAME-ON Network, The National Institute for Health Research (GCB), Addenbrooke’s Charitable Trust (GCB), NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, The National Institute for Health Research Cambridge Biomedical Research Centre (NGB), UK Medical Research Council (LD), the Experimental Cancer Medicine Centre (CMLW), the Royal Marsden NHS Foundation Trust (DPD), the United States National Institutes of Health (1R01CA134444 to BSR), the American Cancer Society (RSGT-05-200-01-CCE to BSR), the United States Department of Defense (PC074201 to BSR), Mount Sinai Tisch Cancer Institute Developmental Fund Award (BSR), the Instituto de Salud Carlos III (FIS PI10/00164 and PI13/02030 to AV), Fondo Europeo de Desarrollo Regional (FEDER 2007-2013 to AV), Xunta de Galicia and the European Social Fund (POS-A/2013/034 to LF), and the Alberta Cancer Board Research Initiative Program (103.0393.71760001404 to MP). Laboratory infrastructure for the RAPPER study was funded by Cancer Research UK [C8197/A10123]. DD acknowledges support from the National Institute for Health Research RM/ICR Biomedical Research Centre and all the researchers at the Royal Marsden Hospital and the Institute of Cancer Research. The RAPPER cohort comprises patients and data recruited into the RT01 and CHHiP UK radiotherapy trials. The RT01 trial was supported by the UK Medical Research Council. The CHHiP trial (CRUK/06/016) was supported by the Department of Health and Cancer Research UK (C8262/A7253); trial recruitment was facilitated within centers by the National Institute for Health Research Cancer Research Network.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Nature Publishing Group