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Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. Setting: Online Delphi survey and consensus conference. Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), 7–9 (agree). A priori (level 1) consensus was defined as 70% agreement and 15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). Results and limitations: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach, The authors would like to thank Peter E. Clark from Atrium Health, Levine Cancer Institute, Charlotte, NC, USA, for his contribution to the Delphi survey. Angela Corstorphine of Kstorfin Medical Communications Ltd provided medical writing support with the preparation of this manuscript; this support was funded jointly by EAU and ESMO.

Objectives: Investigating supportive care (SC) needs and utilization/willingness to use SC services from diagnosis to one year after radical cystectomy in bladder cancer (BC) patients. Materials & Methods: A longitudinal cohort study was conducted in 90 BC patients at Ghent/Leuven University Hospitals between April 2017 and December 2020. The Supportive Care Needs Survey-short form (SCNS-SF34) was used before radical cystectomy, one, three, six and 12 months after radical cystectomy. Additional questions assessed utilization/willingness to use SC services. Linear mixed models were performed. Results: The majority of BC patients report at least one moderate or high SC need at diagnosis (82%), month 1 (84%), month 3 (86%), month 6 (64%), and month 12 (60%). Significant decreases over time were seen for all domains (p

Contains fulltext : 238898.pdf (Publisher’s version ) (Closed access) BACKGROUND: Implant-supported overdentures (IOD) are becoming a more commonly used treatment in the dental practice and it risks causing speech problems. PURPOSE: The aim of this study was investigating the changes in speech, satisfaction with speech, and overall oral health-related quality of life (OHRQoL) in edentulous patients during and after treatment with maxillary IODs. MATERIALS AND METHODS: Twenty-one patients receiving an IOD participated in speech assessment. They were examined preoperatively with their conventional denture (CD) with full palatal coverage, after connection of the implant-bar connected denture, without palatal coverage, and 3 years thereafter. The examination included assessment of articulation in speech, OHRQoL based on total OHIP-14, and satisfaction with overall oral health and speech (visual analogue scale). RESULTS: There was a reduction in mean number of articulation disorders from 1.00 at baseline to 0.55 at connection, although statistically insignificant (p = 0.059). Especially the /s/ sound is vulnerable. At 3 years follow-up, still 6/16 (37.5%) of the patients suffered from this speech problem. Overall satisfaction improved from 64.05/100 at baseline to 82.95/100 at connection (p = 0.008) and remained unchanged with 81.69/100 after 3 years follow-up. Patients' satisfaction with speech increased from 70.62/100 with CD to 82.63/100, 3 years follow-up (p = 0.009). Total OHIP-14 decreased from 21.45/56 with CD to 8.00/56 (p

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT. ispartof: JOURNAL OF CLINICAL ONCOLOGY vol:40 issue:29 pages:3377-+ ispartof: location:United States status: published

Objective: To assess the face and content validity, acceptability and feasibility of a French version of the Children’s Palliative Outcome Scale (CPOS). Background: Instruments in French used to measure outcomes in pediatric palliative care are lacking. Methods: After forward-backward translation of the 12-item English CPOS to French, we conducted a qualitative pilot study. During semi structured interviews among children and parents, we used the CPOS, the Schedule for the Evaluation of Individual Quality of Life interview guide (SEIQoL) and the Quality of Life in Life-threatening Illness-Family Carer questionnaire (QOLLTI-F), in addition to three expert meetings with PLTs. Results: Fourteen children and adolescents (8-18 years) with life-limiting or life-threatening conditions cared for at home, in hospital or in respite care services, 19 parents, and 9 members of 4 pediatric liaison teams (PLTs) providing palliative care in a Belgian francophone region were included in the study. No families refused to participate. All children with verbal capacities chose to be interviewed in the presence of their parents and a PLT member. The children valued being given the opportunity to share their experiences. New QOL dimensions pertaining to social, emotional, and administrative health-care related issues were added to the original version of the 12-item CPOS, leading to a 22-item CPOS-2. Discussion: The CPOS-2 was perceived as relevant and easy to use by the principal stakeholders. Our study paves the way for a large-scale field study assessing its psychometric characteristics and its implementation in routine clinical care.

Introduction: Previous studies showed that healthcare professionals and patients had only moderate to low agreement on their assessment of treatment-related symptoms. We aimed to determine the levels of agreement in a large cohort of prostate cancer patients. Methods: Analyses were made of data from 1,756 prostate cancer patients treated with external beam radiotherapy (RT) and/or brachytherapy in Europe and the USA and recruited into the prospective mul-ticentre observational REQUITE study. Eleven pelvic symptoms at the end of RT were compared after translating patient-reported outcomes (PROs) into CTCAE-based healthcare professional ratings. Gwet's AC2 agreement coefficient and 95% confidence intervals were calculated for each symptom. To compare severity of grading between patients and healthcare professionals, percent agreement and deviations for each symptom were graphically depicted. Stratified and sensitivity analyses were conducted to identify potential influencing factors and to assess heterogeneity and robustness of results.Results: The agreement for the 11 pelvic symptoms varied from very good (AC2 > 0.8: haematuria, rectal bleeding, management of sphincter control) to poor agreement (AC2

This umbrella review aims to evaluate the quality, summarize and compare the conclusions of systematic reviews investigating the impact of curative treatment options on health-related quality of life (HRQoL) in muscle-invasive bladder cancer (MIBC). The Cochrane Library, MEDLINE, Embase and Web of Science were searched independently by two authors from inception until 06 January 2020. Systematic reviews and meta-analyses assessing the impact of any curative treatment option on HRQol in MIBC patients were eligible. Risk of bias was assessed using the AMSTAR 2 tool. Thirty-two reviews were included. Robot-assisted RC with extracorporeal urinary diversion and open RC have similar HRQoL (n = 10). Evidence for pelvic organ-sparing RC was too limited (n = 2). Patients with a neobladder showed better overall and physical HRQoL outcomes, but worse urinary function in comparison with ileal conduit (n = 17). Bladder-preserving radiochemotherapy showed slightly better urinary and sexual but worse gastro-intestinal HRQoL outcomes in comparison with RC patients (n = 6). Quality of the reviews was low in more than 50% of the available reviews and most of the studies included in the reviews were nonrandomized studies. This umbrella review gives a comprehensive overview of the available evidence to date.

PURPOSE: To determine the start exercise prescription dose in metastatic castrate-resistant prostate cancer (mCRPC) patients receiving second-line hormone treatment and recommended phase II exercise prescription. METHODS: Patients were enrolled in a 3 + 3 dose escalation phase I trial of aerobic, resistance, and flexibility exercises to evaluate dose-limiting tolerance and safety. Tolerance was defined as Borg score ≤ 16 and safety (pain) as a visual analogue scale score (VAS) ≤ 3 and CTCAE grade 3 during resistance training and/or flexibility training. No tolerance issues were observed in the two dosing cohorts. The optimal start exercise prescription dose was set at dose level 1 due to safety issues at dose level 2. CONCLUSION: Our findings suggest that exercise is perceived tolerable in mCRPC patients receiving second-line hormone therapy. Caution is indicated on safety during performance of the exercises.

BACKGROUND AND PURPOSE: Genome-wide association studies (GWAS) of late hematuria following prostate cancer radiotherapy identified single nucleotide polymorphisms (SNPs) near AGT, encoding angiotensinogen. We tested the hypothesis that patients taking angiotensin converting enzyme inhibitors (ACEi) have a reduced risk of late hematuria. We additionally tested genetically-defined hypertension.MATERIALS AND METHODS: Prostate cancer patients undergoing potentially-curative radiotherapy were enrolled onto two multi-center observational studies, URWCI (N = 256) and REQUITE (N = 1,437). Patients were assessed pre-radiotherapy and followed prospectively for development of toxicity for up to four years. The cumulative probability of hematuria was estimated by the Kaplan-Meier method. Multivariable grouped relative risk models assessed the effect of ACEi on time to hematuria adjusting for clinical factors and stratified by enrollment site. A polygenic risk score (PRS) for blood pressure was tested for association with hematuria in REQUITE and our Radiogenomics Consortium GWAS.RESULTS: Patients taking ACEi during radiotherapy had a reduced risk of hematuria (HR 0.51, 95%CI 0.28 to 0.94, p = 0.030) after adjusting for prior transurethral prostate and/or bladder resection, heart disease, pelvic node radiotherapy, and bladder volume receiving 70 Gy, which are associated with hematuria. A blood pressure PRS was associated with hypertension (odds ratio per standard deviation 1.38, 95%CI 1.31 to 1.46, n = 5,288, p < 0.001) but not hematuria (HR per standard deviation 0.96, 95%CI 0.87 to 1.06, n = 5,126, p = 0.41).CONCLUSIONS: Our study is the first to show a radioprotective effect of ACEi on bladder in an international, multi-site study of patients receiving pelvic radiotherapy. Mechanistic studies are needed to understand how targeting the angiotensin pathway protects the bladder.

In this study, we evaluated the impact ofIn this prospective observational study, 60 prostate cancer patients (9 primary staging, 51 biochemical recurrence) were imaged withThe patient-based detection rate was 82% and a management change was seen in 52% of the cases. The heterogeneous characteristics of the included patients resulted in a widely varying treatment change, mostly originating from an increase of disease extent on

PURPOSE: In 2016, international consensus clinical target volume (CTV) guidelines for adjuvant radiation treatment after radical cystectomy in patients with muscle-invasive bladder cancer with high risk for locoregional failure (LRF) were published. A subsequent external validation study recommended several CTV optimizations (CTV-OPT). This study aimed to update international consensus guidelines based on new clinical experiences. METHODS AND MATERIALS: Phase 1 (delineation interobserver variability): Four observers delineated the CTV of 9 patients post radical cystectomy, as in clinical practice. Interobserver agreement in contouring was evaluated using volume- and κ-statistics. Phase 2 (pattern of failure analysis): Among a prospective cohort of 72 patients treated with adjuvant radiation treatment, 11 developed LRF (10 available for review). LRFs were mapped in predefined pelvic subsites (ie, common, external and internal iliac, obturator and presacral node regions, and cystectomy bed), and their distance to CTV-OPT was measured. The actual delivered dose at each relapse site was calculated. Phase 3 (review CTV): Based on the results of phase 1 and 2, 5 senior radiation-oncologists (International Bladder Investigator Society) reviewed the published CTV borders and provided an update when indicated. RESULTS: Phase 1: The mean overall κ-value was 0.66 (range, 0.60-0.70), indicating substantial overall agreement per Landis-Koch criteria. Specific κ-values per area indicated for the common iliac and obturator node regions only slight and moderate variability, respectively. Phase 2: Thirteen out of 16 LRFs centers were not included in the CTV-OPT. Ten LRF sites received a median dose

Background: High-risk muscle-invasive bladder cancer (MIBC) has a poor prognosis. Old trials showed that external beam radiotherapy (EBRT) after radical cystectomy (RC) decreases the incidence of local recurrences but induces severe toxicity.Objective: To evaluate the toxicity and local control rate after adjuvant EBRT after RC delivered with volumetric arc radiotherapy. Design, setting, and participants: This is a multicentric phase 2 trial. From August 2014 till October 2020, we treated 72 high-risk MIBC patients with adjuvant EBRT after RC. High-risk MIBC is defined as >= pT3-MIBC +/- lymphovascular invasion, fewer than ten lymph nodes removed, pathological positive lymph nodes, or positive surgical margins.Intervention: Patients received 50 Gy in 25 fractions with intensity-modulated radio-therapy to the pelvic lymph nodes +/- cystectomy bed.Outcome measurements and statistical analysis: The primary outcome is acute toxicity. We report on local relapse-free rate (LRFR), clinical relapse-free survival (CRFS), overall survival (OS), and bladder cancer-specific survival (BCSS).Results and limitations: The median follow-up is 18 mo. Forty-two patients (61%) devel-oped acute grade 2 gastrointestinal (GI) toxicity. Four patients (6%) had acute grade 3 GI toxicity. One patient had grade 5 diarrhea and vomiting due to obstruction at 1 mo. Two-year probabilities of developing grade >= 3 and >= 2 GI toxicity were 17% and 76%, respec-tively. Urinary toxicity, assessed in 17 patients with a neobladder, was acceptable with acute grade 2 and 3 urinary toxicity reported in 53% (N = 9) and 18% (N = 3) of the patients, respectively. The 2-yr LRFR is 83% +/- 5% and the 2-yr CRFS rate is 43% with a median CRFS time of 12 mo (95% confidence interval: 3-21 mo). Two-year OS and BCSS are 52% +/- 7% and 62% +/- 7%, respectively. Shortcomings are the nonrandomized study design and limited follow-up.Conclusions: Adjuvant EBRT after RC can be administered without excessive severe toxicity.Patient summary: In this report, we looked at the incidence of toxicity and local control after adjuvant external beam radiotherapy (EBRT) following radical cystectomy (RC) in high-risk muscle-invasive bladder cancer patients. We found that adjuvant EBRT was feasible and resulted in good local control. We conclude that these data support further enrollment of patients in ongoing trials to evaluate the place of adjuvant EBRT after RC.(c) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY-NC-ND license (http://creative-commons.org/licenses/by-nc-nd/4.0/).

Large-animal models for Duchenne muscular dystrophy (DMD) are crucial for the evaluation of diagnostic procedures and treatment strategies. Pigs cloned from male cells lacking DMD exon 52 (DMDΔ52) exhibit molecular, clinical and pathological hallmarks of DMD, but die before sexual maturity and cannot be propagated by breeding. Therefore, we generated female DMD+/− carriers. A single founder animal had 11 litters with 29 DMDY/−, 34 DMD+/− as well as 36 male and 29 female wild-type offspring. Breeding with F1 and F2 DMD+/− carriers resulted in an additional 114 DMDY/− piglets. With intensive neonatal management, the majority survived for 3-4 months, providing statistically relevant cohorts for experimental studies. Pathological investigations and proteome studies of skeletal muscles and myocardium confirmed the resemblance to human disease mechanisms. Importantly, DMDY/− pigs displayed progressive myocardial fibrosis and increased expression of connexin-43, associated with significantly reduced left ventricular ejection fraction, at 3 months. Furthermore, behavioral tests provided evidence for impaired cognitive ability. Our breeding cohort of DMDΔ52 pigs and standardized tissue repositories provide important resources for studying DMD disease mechanisms and for testing novel treatment strategies., Editor's choice: A genetically tailored pig model that develops the hallmarks of Duchenne muscular dystrophy in an accelerated mode provides a new resource for testing targeted therapies.

Background The outcome of patients with muscle-invasive bladder cancer (MIBC) remains poor, despite aggressive treatments. Inadequate primary staging, classically performed by computed tomography (CT)-imaging, could lead to inappropriate treatment and might contribute to these poor results. Although not (yet) adapted by international guidelines, several reports have indicated the superiority of 18F-fluorodeoxyglucose-positron emission tomography-CT (18F-FDG-PET-CT) compared to CT in the detection of lymph node and distant metastases. Thereby the presence of extra-vesical disease on 18F-FDG-PET-CT has been correlated with a worse overall survival. This supports the hypothesis that 18F-FDG-PET-CT is useful in stratifying MIBC patients and that adapting the treatment plan accordingly might result in improved outcome. Methods EFFORT-MIBC is a multicentric prospective phase II trial aiming to include 156 patients. Eligible patients are patients with histopathology-proven MIBC or ≥ T3 on conventional imaging treated with MIBC radical treatment, without extra-pelvic metastases on conventional imaging (thoracic CT and abdominopelvic CT/ magnetic resonance imaging (MRI)). All patients will undergo radical local therapy and if eligible neo-adjuvant chemotherapy. An 18F-FDG-PET-CT will be performed in addition to and at the timing of the conventional imaging. In case of presence of extra-pelvic metastasis on 18F-FDG-PET-CT, appropriate intensification of treatment with metastasis-directed therapy (MDT) (in case of ≤3 metastases) or systemic immunotherapy (> 3 metastases) will be provided. The primary outcome is the 2-year overall survival rate. Secondary endpoints are progression-free survival, distant metastasis-free survival, disease-specific survival and quality of life. Furthermore, the added diagnostic value of 18F-FDG-PET-CT compared to conventional imaging will be evaluated and biomarkers in tumor specimen, urine and blood will be correlated with primary and secondary endpoints. Discussion This is a prospective phase II trial evaluating the impact of 18F-FDG-PET-CT in stratifying patients with primary MIBC and tailoring the treatment accordingly. We hypothesize that the information on the pelvic nodes can be used to guide local treatment and that the presence of extra-pelvic metastases enables MDT or necessitates the early initiation of immunotherapy leading to an improved outcome. Trial registration The Ethics Committee of the Ghent University Hospital (BC-07456) approved this study on 11/5/2020. The trial was registered on ClinicalTrials.gov (NCT04724928) on 21/1/2021.

This paper documents Scottish adolescents’ vocational interest types. Our research is based on the responses of 1,306 pupils from 18 secondary schools to an empirically verified online interest inventory test. Our results are threefold. First, the structural validity of the test with the Scottish sample is confirmed by evaluating the underlying circumplex structure of Holland’s RIASEC vocational interests. Second, gender distribution along the six primary vocational interest dimensions is consistent with the research literature: young men scoring higher on the Realistic vocational interest and young women scoring higher on the Social dimension. Finally, we observe that across dimensions, vocational interests of young women are less diverse than those of young men. We discuss how these dissimilarities could lead to differences in education choice and career decision-making. Publisher PDF

Context Multiple studies have reported on the genomic characteristics of metastatic hormone-sensitive prostate cancer (mHSPC). The impact of these findings on prognostication, treatment selection, and clinical trial design remains unclear. Objective To summarise genomic alteration prevalences in liquid and/or tissue biopsies, infer their clinical implications, and compare genomic alteration frequencies across different disease states and clinical phenotypes. Evidence acquisition The PubMed and Web of Knowledge databases were systematically searched up to January 2021. Quality assessment was performed using the Joanna Briggs Institute Critical Appraisal tools. Evidence synthesis In total, 11 studies encompassing 1682 mHSPC patients were included. High-volume disease was associated with more frequent alterations in TP53, DNA damage repair, and Wnt pathways. Tumours from patients with de novo mHSPC were enriched for alterations in TP53 and CDK12 compared with recurrent disease. Alterations in AR, TP53, cell cycle signalling, and MYC were associated with a poorer clinical outcome. A comparative analysis of gene alteration frequencies across disease states revealed a relative increase from localised to castration-resistant tumours, with noteworthy enrichment of CTNNB1 alterations in mHSPC (5%), which warrants further investigation. This study was limited by variability in methodology and definitions used among the eligible studies, including differences in sequencing methods, analytes (being either tissue or liquid), alteration calling thresholds, and target patient populations with a relative under-representation of recurrent metastatic disease. Conclusions Several genomic alterations are associated with differential prognosis and clinical phenotypes in mHSPC. We urge that emerging data on these potential predictive biomarkers must be validated in biomarker-driven randomised controlled trials before any clinical implementation. Alignment of the assay methodology and reporting will be critical for ensuring rapid scalability. Patient summary We reviewed current data on genomic alterations of metastatic hormone-sensitive prostate cancer, and summarised key genomic subtypes that associate with specific clinical phenotypes and treatment outcomes.

AIM: To identify the effect of single nucleotide polymorphism (SNP) interactions on the risk of toxicity following radiotherapy (RT) for prostate cancer (PCa) and propose a new method for polygenic risk score incorporating SNP-SNP interactions (PRSi). MATERIALS AND METHODS: Analysis included the REQUITE PCa cohort that received external beam RT and was followed for 2 years. Late toxicity endpoints were: rectal bleeding, urinary frequency, haematuria, nocturia, decreased urinary stream. Among 43 literature-identified SNPs, the 30% most strongly associated with each toxicity were tested. SNP-SNP combinations (named SNP-allele sets) seen in ≥10% of the cohort were condensed into risk (RS) and protection (PS) scores, respectively indicating increased or decreased toxicity risk. Performance of RS and PS was evaluated by logistic regression. RS and PS were then combined into a single PRSi evaluated by area under the receiver operating characteristic curve (AUC). RESULTS: Among 1,387 analysed patients, toxicity rates were 11.7% (rectal bleeding), 4.0% (urinary frequency), 5.5% (haematuria), 7.8% (nocturia) and 17.1% (decreased urinary stream). RS and PS combined 8 to 15 different SNP-allele sets, depending on the toxicity endpoint. Distributions of PRSi differed significantly in patients with/without toxicity with AUCs ranging from 0.61 to 0.78. PRSi was better than the classical summed PRS, particularly for the urinary frequency, haematuria and decreased urinary stream endpoints. CONCLUSIONS: Our method incorporates SNP-SNP interactions when calculating PRS for radiotherapy toxicity. Our approach is better than classical summation in discriminating patients with toxicity and should enable incorporating genetic information to improve normal tissue complication probability models. ispartof: RADIOTHERAPY AND ONCOLOGY vol:159 pages:241-248 ispartof: location:Ireland status: published

Severe ocular surface diseases can lead to limbal stem cell deficiency (LSCD), which is accompanied by defective healing. We aimed to evaluate the role of the substance P (SP)/neurokinin-1 receptor (NK1R) pathway in corneal epithelium wound healing in a pre-clinical model of LSCD. SP ablation or NK1R blockade significantly increased epithelial wound healing (p 0.001) and corneal transparency (p 0.001), compared with wild type (WT). In addition, a reduced number of infiltrating goblet and conjunctival cells (p 0.05) and increased number of epithelial stem cells (p 0.01), which also expressed NK1R, was observed. The mammalian target of rapamycin (mTOR) pathway was significantly inhibited (p 0.05) and expression of γH2AX was significantly reduced (p 0.05) after SP ablation. These results suggest that excessive expression of SP is associated with LSCD and results in accelerated senescence and exhaustion of residual stem cells. Topical treatment with NK1R antagonist ameliorates clinical signs associated with LSCD and could be used as an adjuvant treatment in LSCD.

In patients with prostate cancer who have a high risk of pelvic nodal disease, the use of elective whole pelvis radiotherapy is still controversial. Two large, randomised, controlled trials (RTOG 9413 and GETUG-01) did not show a benefit of elective whole pelvis radiotherapy over prostate-only radiotherapy. In 2020, the POP-RT trial established the role of elective whole pelvis radiotherapy in patients who have more than a 35% risk of lymph node invasion (known as the Roach formula). POP-RT stressed the importance of patient selection. In patients with cN1 (clinically node positive) disease or pN1 (pathologically node positive) disease, the addition of whole pelvis radiotherapy to androgen deprivation therapy significantly improved survival compared with androgen deprivation therapy alone, as shown in large, retrospective studies. This patient population might increase in the future because use of the more sensitive prostate-specific membrane antigen PET-CT will become the standard staging procedure. Additionally, the SPORTT trial suggested a benefit of whole pelvis radiotherapy in biochemical recurrence-free survival in the salvage setting. A correct definition of the upper field border, which should include the bifurcation of the abdominal aorta, is key in the use of pelvic radiotherapy. As a result of using modern radiotherapy technology, severe late urinary and intestinal toxic effects are rare and do not seem to increase compared with prostate-only radiotherapy.

Germ cell tumors (GCT), accounting for 95% of malignant testicular tumors, can be divided into two groups: seminoma (SGCT) and non-seminoma (NSGCT). Seminomas typically arise in men in the fourth decade of life, compromising 60% of the GCT. At diagnosis, approximately 75% present with local disease (Stage I); 15% is detected with metastatic regional lymph nodes (Stage II) and 5-10% present with juxtaregional or visceral metastasis (Stage III) . This article is protected by copyright. All rights reserved. ispartof: BJU INTERNATIONAL vol:124 issue:1 pages:35-39 ispartof: location:England status: published

External beam radiotherapy (EBRT), as part of a trimodality approach, is an attractive bladder-preserving alternative to radical cystectomy. Several EBRT regimens with different treatment volumes have been described with similar tumour control and, so far, clear recommendations on the optimal radiotherapy regimen and treatment volume are lacking. The current review summarises EBRT literature on dose prescription, fractionation as well as treatment volume in order to guide clinicians in their daily practice when treating patients with muscle-invasive bladder cancer. Taking into account literature on repopulation, continuous-course radiotherapy can be used safely in daily practice where a split-course should only be reserved for those patients who are fit enough to undergo a radical cystectomy in case of a poor early response. A recent meta-analysis has proven that hypofractionated radiotherapy is superior to conventional radiotherapy with regards to invasive locoregional control with similar toxicity profiles. In the absence of node-positive disease, the target volume can be restricted to the bladder. In order to compensate for organ motion, very large margins need to be applied in the absence of image-guided radiotherapy (IGRT). Therefore, the use of IGRT or an adaptive approach is recommended. Based on the available literature, one can conclude that moderate hypofractionated radiotherapy to a dose of 55 Gy in 20 fractions to the bladder only, delivered with IGRT, can be considered standard of care for patients with node-negative invasive bladder cancer.

Contains fulltext : 238870.pdf (Publisher’s version ) (Closed access) BACKGROUND: Modifications of facial and oral structures affect aesthetic appearance, orofacial functions, and have impact on quality of life. PURPOSE: This study determined alterations of articulation, oromyofunctional behavior, and Oral Health Related Quality of Life (OHRQoL) in patients replacing complete removable dentures by implant retained overdentures in the mandible. MATERIALS AND METHODS: Twenty-one fully edentulous patients received mandibular overdenture retained on a bar connecting two titanium dental implants. Patients were evaluated after receiving a new set of fully removable dentures (stage 1), after surgery during provisionalization on healing abutments (stage 2), and after final connection to the bar (stage 3). Assessments were taken by speech therapists and included evaluation of: articulation (picture naming and reading); oromyofunctional behavior; OHRQoL (OHIP-14 questionnaire), and overall satisfaction and speech (VAS). To measure changes over time, Wilcoxon matched-pairs signed-rank-test and McNemar test was used. RESULTS: There was no significant impact of the treatment on speech nor on the results of oromyofunction. In stage 1, patients had different kinds of articulation errors (mean:1.21) which evolved to 0.71 and 0.67. In stage 3, especially problems with the /s/ sound are seen in 37% (7/19) of the participants. Results of OHRQoL and satisfaction reveal that the average of satisfaction with oral health evolved from 67% to 63% and finally 78%. OHIP-14 total score was 17.4/56 in stage 1, remained unchanged in stage 2 and evolved in stage 3 to 9.8/56 (P: .010). This indicates improvement. Satisfaction with speech evolved significantly from 68% pretreatment to 82% in stage 3 (P: .013). CONCLUSION: Despite existing articulation and oromyofunctional disorders after treatment, people are very satisfied with their OHRQoL and their speech. Impact of mandibular denture wearing on OHRQoL declines once connected. It's important to inform patients that speech and oromyofunctional disorders may occur during treatment where especially the /s/ sound is vulnerable.

Contains fulltext : 229066.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Longitudinal evaluation of Oral Health-Related Quality of Life (OHRQoL) during treatment of flaplessly placed, one-piece mini-dental-implants (MDIs) for maxillary overdentures is rarely investigated, nor is the impact of MDI failures. MATERIAL AND METHODS: This multicenter prospective cohort study evaluated the 3-year outcome of 5-6 MDIs in the edentulous maxilla in patients above 50 years with dentate mandible. Provisional dentures were provided before final prosthetic connection was established at 6 months. Postoperative discomfort was assessed using a visual analogue score (VAS). OHRQoL was investigated using the Oral Health Impact Profile (OHIP)-14 at baseline (preoperatively), postoperatively, post-prosthetic connection and after 3 years in function. RESULTS: 164 (78.4%) of the 204 placed MDIs were still in situ after 3 years, in 29/31 patients. Two patients lost 5/6 MDIs resulting in two prosthetic failures (6.45%). With regard to pain, a score of 4.1/10 (SD 2.8) was recorded on day 1, and 1.1/10 (SD 1.7) on day 7. A decrease in total OHIP-14 scores was observed postoperatively (15.6; SD 12.8) as compared to baseline (21.3; SD 13.1), with improvement of OHRQoL. Furthermore, this was statistically significant at connection of the final prosthesis (7.3; SD 6.7) (p = .006). The OHIP-14 improved less (p = .011) when experiencing one or more implant losses (9.5; SD: 9.85), in comparison with no implant loss (20.7; SD: 13.97). A failure of one MDI did not affect OHIP-14 score (p = .658); however, multiple failures did (p = .007). CONCLUSION: Maxillary MDI overdenture treatment yields significant OHRQoL improvement when at least 5 MDIs survive, preserving functional comfort.

Background Radiotherapy to the prostate (RTp) prolongs survival for patients with low-volume, newly diagnosed metastatic prostate cancer (ndmPC). Objective to evaluate whether cytoreductive radical prostatectomy (cRP) is equally beneficial as RTp in low-volume ndmPC. Design, setting, and participants A multicenter prospective registry was established in 2014 to observe patients with ndmPC. Eligible patients were offered cRP or RTp. For this study we selected only patients with low-volume ndmPC (n = 109). Of these, 48, 26, and 35 patients underwent cRP, RTp, and no local therapy (NLT), respectively. Median follow-up was 32 mo (interquartile range 16–49). Intervention cRP was compared with RTp and NLT. Outcome measurements and statistical analysis Overall survival (OS), cancer-specific survival (CSS), and local event–free survival (LEFS) were calculated using the Kaplan-Meier method. Factors prognostic for OS were identified using univariate and multivariate Cox regression analysis. Results and limitations The 2-yr OS was 93%, 100%, and 69%, and 2-yr CSS was 93%, 100%, and 75% for cRP, RTp, and NLT, respectively. The cRP and RTp groups had better OS compared to NLT and there was no significant difference between cRP and RTp. The 2-yr LEFS was 92%, 77%, and 60% for cRP, RTp, and NLT, respectively. The cRP group had better LEFS compared to RTp and NLT, and there was no significant difference between RTp and NLT. Advanced tumor stage, Eastern Cooperative Oncology Group performance status ≥2, and NLT were negative prognostic factors for OS. The main limitation is selection of fitter patients with less advanced tumors for cRP and the small sample size. Conclusions For selected patients with low-volume ndmPC, cRP is able to achieve similar OS and CSS to RTp. cRP is effective in preventing local events due to disease progression. Patient summary Patients with a low volume of newly diagnosed prostate cancer that has spread beyond the prostate gland might benefit from removal of the prostate, which we found was as effective as radiotherapy to the prostate in prolonging survival. Removal of the prostate is effective in preventing urinary problems caused by cancer progression., Take Home Message In selected patients, cytoreductive radical prostatectomy is able to achieve similar overall survival and cancer-specific survival to radiotherapy.

Introduction Uptake of sufficient physical activity before and after radical cystectomy is important to improve physical and psychosocial outcomes in bladder cancer (BC) patients. Methods In this paper, we describe the development of an evidence-based and theory-informed intervention, guided by the steps of the Intervention Mapping approach, to promote physical activity before and after radical cystectomy in patients with BC. Results The intervention is a home-based physical activity program. The preoperative timeframe of the intervention is 4 or 12 weeks, depending on administration of neoadjuvant chemotherapy. Postoperatively, the intervention will last for 12 weeks. The intervention consists of a digital oncological platform (DOP), several consultations with healthcare professionals, personal booklet and follow-up phone calls. DOP includes information, diaries, visual representation of progress, mailbox, videos of peers and treating physician explaining the benefits of physical activity, photo material of exercises and a walking program with an activity tracker. Individual goals will be set and will be self-monitored by the patient through DOP. Patients will receive alerts and regular feedback. Conclusions Intervention Mapping ensures transparency of all intervention components and offers a useful approach for the development of behaviour change interventions for cancer patients and for translation of theories into practice.

Apalutamide, a competent inhibitor of the androgen receptor, has shown promising clinical efficacy results for patients with advanced prostate cancer. Here, we describe the rationale and design for the SAVE trial, a multi-center, Phase II study, wherein 202 men with biochemical progression after radical prostatectomy are randomly assigned 1:1 to apalutamide plus salvage radiotherapy (SRT) or androgen-deprivation therapy with an luteinizing hormone-releasing hormone agonist or antagonist plus SRT. The primary objective is to compare sexual function between the two treatment arms based on the expanded prostate cancer index-26 sexual domain score at nine months after start of hormonal treatment. The key secondary objectives are to assess quality of life, to evaluate the safety profile and the short-term efficacy of apalutamide in combination with SRT. ClinicalTrials.gov identifier: NCT03899077.

After breast conserving surgery (BCS) for breast cancer, radiotherapy (RT) reduces the risk of locoregional recurrences and improves overall survival [1,2]. Despite the benefits, late toxicity may ...

Objectives Contemporary research on the impact of dental rehabilitation scarcely focuses on the role of personality and social relationships in QoL related to dental implant treatment. To overcome biases related to evaluation with self-reports, descriptions provided by informed external observers are recommended. Aims To investigate the impact of implant-supported rehabilitation on quality of life and social participation taking into account patient’s personality. Materials and methods Fifty-four patients were included in this study and assigned to either a single unit group (n = 15) or a complete jaw restoration group (n = 39). Of the 54 participants, 49 nominated an external observer who can evaluate the daily behavior of the patient. Before and after treatment patients and their external observer completed the OHIP-14, the NEO-FFI and the MSPP questionnaires respectively focusing on Oral Health related Quality of Life, Personality and Social participation. Results and conclusion The correlations between self- and observer ratings on pre and post treatment outcomes on were insignificant (QoL pre: p = 0.086, post: p = 0.115, freq. soc. part pre: p = 0.944, post: p = 0.876, div. soc. part pre: p = 0.798, post: p = 0.167), suggesting considerable differences in observer perspectives. The traits Neuroticism, Extraversion and Agreeableness were associated with QoL. Openness, Conscientiousness and Agreeableness were associated with social participation. Patients in the complete jaw restoration group reported more impact of the implant treatment on quality of life as compared to the single unit group (p = 0.007). The complete jaw restoration group reported an improved quality of life after treatment and significant increases of both frequency (p = 0.001) and diversity of social participation (p = 0.036). In conclusion there was a minor impact of treatment with single crowns on quality of life and social participation compared to the full denture group. The role of personality and the use of multi-informants in evaluating dental treatment was found important.

Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference. Setting: Online Delphi survey and consensus conference. Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), and 7–9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). Results and limitations: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease. Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach. Patient summary: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.

Patients with oligometastatic prostate cancer (PC) may benefit from metastasis-directed therapy (MDT), delaying disease progression and the start of palliative systemic treatment. However, a significant proportion of oligometastatic PC patients progress to polymetastatic PC within a year following MDT, suggesting an underestimation of the metastatic load by current staging modalities. Molecular markers could help to identify true oligometastatic patients eligible for MDT. Patients with asymptomatic biochemical recurrence following primary PC treatment were classified as oligo- or polymetastatic based on 18F-choline PET/CT imaging. Oligometastatic patients had up to three metastases at baseline and did not progress to more than three lesions following MDT or surveillance within 1 year of diagnosis of metastases. Polymetastatic patients had > 3 metastases at baseline or developed > 3 metastases within 1 year following imaging. A model aiming to prospectively distinguish oligo- and polymetastatic PC patients was trained using clinicopathological parameters and serum-derived microRNA expression profiles from a discovery cohort of 20 oligometastatic and 20 polymetastatic PC patients. To confirm the models predictive performance, it was applied on biomarker data obtained from an independent validation cohort of 44 patients with oligometastatic and 39 patients with polymetastatic disease. Oligometastatic PC patients had a more favorable prognosis compared to polymetastatic ones, as defined by a significantly longer median CRPC-free survival (not reached versus 38 months; 95% confidence interval 31–45 months with P

To evaluate the morbidity of different surgical approaches for pelvic lymph node dissection (PLND), to evaluate the influence of morbidity on radiotherapy (RT) planning and to evaluate a possible therapeutic effect of a more extensive yield of PLND.From 2000-2016, 228 patients received staging PLND before primary RT in a single tertiary care center. Nine patients were excluded for the evaluation of morbidity. Fifty patients were operated in an open approach, 96 laparoscopic and 73 robot-assisted (RA). Clavien-Dindo classification was used for evaluating complications. Predictors of biochemical recurrence (BCR), clinical relapse (CR), cancer-specific survival (CSS) and overall survival (OS) were evaluated by regression analyses to determine a possible therapeutic effect.Minimal invasive surgery (laparoscopic or RA) caused five times less major complications (22% vs. 4.3%, p = .001) and a median 3 days shorter hospital stay (5 days versus 2 days, p .001). Major complications resulted in a delayed (23 days, p .001) RT start but no oncological effect was seen. Independent oncological predictors were the number of positive nodes (BCR, CR, CSS, OS), a lower age (CR), a higher level of initial prostate-specific antigen (PSA) (BCR) and post-RT PSA (BCR).Minimal invasive surgery can diminish major complications which delay RT start. Nodal staging proved to be of importance for prognosis but no therapeutic effect was seen of performing PLND as such.

Purpose Hypofractionated radiation therapy (HFRT) for localized prostate cancer is safe and effective. The question that remains is which hypofractionation schedule to implement. We compared 2 different HFRT regimens in the present study. Methods and Materials From June 2013 to July 2016, 160 patients with prostate cancer were randomly assigned (1:1), within this single-center phase III trial, to 56 Gy (16 fractions of 3.5 Gy; arm A) or 67 Gy (25 fractions of 2.68 Gy; arm B). Randomization was performed using computer-generated permuted blocks, stratified by previous transurethral resection of the prostate and the presence of a dominant intraprostatic lesion. Treatment allocation was not masked, and the clinicians were not blinded. The primary endpoint was acute gastrointestinal (GI) toxicity, assessed using the Common Terminology Criteria for Adverse Events, version 4.0, and Radiation Therapy Oncology Group toxicity scale. An interim analysis of acute toxicity was planned at 160 patients to prove the safety of both treatment regimens. If ≥22 of 72 patients had grade ≥2 GI toxicity, the study arm would be rejected. The study is registered at ClinicalTrials.gov ( NCT01921803 ). Results In arm A, 20 patients (26%) and 1 patient (1%) developed acute grade 2 and grade 3 GI toxicity. In arm B, 16 patients (20%) reported acute grade 2 GI toxicity. In arm A, 42 (55%) and 5 (6%) patients developed acute grade 2 and grade 3 urinary toxicity. In arm B, 40 (49%) and 7 (9%) patients reported acute grade 2 and grade 3 urinary toxicity. Toxicity peaked during radiation therapy and resolved in the months after radiation therapy. Conclusions With acute grade ≥2 GI toxicity reported in 21 of 77 patients in arm A and 16 of 82 patients in arm B, both treatment arms can be considered safe.

Objectives To explore patient perspectives of muscle-invasive bladder cancer (MIBC) on how the health care team and their social network can support them during their cancer trajectory. Data sources Sixteen semi-structured interviews were conducted with MIBC survivors who underwent radical cystectomies at Ghent University Hospital. The interviews were audiotaped, transcribed verbatim, and analyzed with an iterative content analysis approach. Conclusion Information to support people affected by bladder cancer (BC) in several aspects of their disease trajectory (eg, shared decision-making and self-management of their urinary diversion) was most important throughout the interviews (although type and source of required information varied). The clinical nurse specialist was important for informational and emotional support because receiving sufficient information might help patients reduce emotional stress. People affected by BC are still reluctant to consult a psychologist, and several barriers were indicated for this. Also physical needs in the early postoperative phase could be reduced with appropriate information. Communication skills of clinicians in the hospital and knowledge of general practitioners about the important aspects of BC care are also important aspects that should be further optimized. Furthermore, peer support groups and family members can offer important support throughout the BC pathway. Implications for nursing practice This study provides an overview of how people affected by BC want to be supported by their health care team and their social network. This overview can serve as a basis to develop educational interventions for both patients and health care professionals to guide restructuring of BC pathways and can also be used to develop future intervention studies to improve BC outcomes.

Context: There is uncertainty regarding the oncologic effectiveness and the survival advantage of local treatment (LT) in men with clinically lymph node-positive (cN+) prostate cancer (PCa). Objective: To systematically review the current literature comparing oncologic outcomes associated with the use of any form of LT for PCa patients with cN+ disease. Evidence acquisition: A computerized bibliographic search of the Medline, Embase, and Cochrane databases was performed for all studies reporting comparative oncologic outcomes of LT ± androgen deprivation therapy (ADT) versus ADT alone. LT included both radical prostatectomy (RP) and radiotherapy (RT). Using the methodology recommended by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, we identified five nonrandomized comparative retrospective studies published between 1999 and 2018, which were eligible for inclusion in this systematic review. A narrative review and risk-of-bias assessment were performed to determine the impact of LT on recurrence-free survival, cancer-specific survival (CSS), and overall survival (OS). Evidence synthesis: Four studies compared the use of RT ± ADT versus ADT alone, whereas one study compared any form of LT ± ADT versus ADT alone. Different statistical strategies were used in the included studies to account for baseline measured and unmeasured confounders. Overall, the use of RT and, generally speaking, any form of LT was associated with an OS as well as a CSS benefit over ADT alone, without any clear superiority shown either by RP ± ADT or by RT ± ADT. Conclusions: Our systematic review suggests an advantage in terms of both OS and CSS for men with cN+ PCa receiving LT. However, these results should be interpreted with caution due to the low level of evidence of available reports. Patient summary: We reviewed the studies that assessed the role of local treatment in men with prostate cancer and with clinical evidence of lymph node involvement at diagnosis. We found that local treatment was constantly associated with recurrence-free, cancer-specific, and overall survival benefits throughout the included studies. Local treatment for clinically lymph node-positive prostate cancer is constantly associated with recurrence-free, cancer-specific, and overall survival benefits throughout the studies included in this systematic review.

Background: The optimal duration of hormonal therapy (HT) when associated with postprostatectomy radiation therapy (RT) remains controversial. Objective: To test the impact of HT duration among patients treated with postprostatectomy RT, stratified by clinical and pathologic characteristics. Design, setting, and participants: The study included 1264 patients who received salvage RT (SRT) to the prostatic and seminal vesicle bed at eight referral centers after radical prostatectomy (RP). Patients received SRT for either rising prostate-specific antigen (PSA) or PSA persistence after RP, defined as PSA ≥0.1 ng/ml at 1 mo after surgery. Administration of concomitant HT was at the discretion of the treating physician. Outcome measurements and statistical analysis: The outcome of interest was clinical recurrence (CR) after SRT, as identified by imaging. Multivariable Cox regression analysis was used to test the association between CR and HT duration. We applied an interaction test between HT duration and baseline risk factors to assess the hypothesis that CR-free survival differed by HT duration according to patient profile. Three risk factors were prespecified for evaluation: pT stage ≥pT3b, pathologic Gleason ≥8, and PSA level at SRT >0.5 ng/ml. The relationship between HT duration and CR-free survival rate at 8 yr was graphically explored according to the number of risk factors (0 vs 1 vs ≥2). Results and limitations: Overall, 1125 men (89%) received SRT for rising PSA and 139 (11%) were treated for PSA persistence. Concomitant HT was administered to 363 patients (29%), with a median HT duration of 9 mo. At median follow-up of 93 mo after surgery, 182 patients developed CR. The 8-yr CR-free survival was 92%. On multivariable analysis, HT duration was inversely associated with the risk of CR (hazard ratio 0.95; p = 0.022). A total of 531 (42%) patients had none of the prespecified risk factors, while 507 (40%) had one and 226 (18%) had two or more risk factors. The association between HT duration and CR was significantly different by risk factors (0 vs 1, p = 0.001; 0 vs ≥2, p < 0.0001). We observed a significant effect of HT duration for patients with two or more risk factors, for whom HT administration was beneficial when given for up to 36 mo. This effect was attenuated among patients with one risk factor, with concomitant HT slightly beneficial when administered for a shorter time (

Objectives To describe the anatomical patterns of PCa recurrence following primary therapy and investigate if patients with low-volume disease have a better prognosis as compared to their counterparts. Material and methods Patients eligible for a F18-choline PET-CT were entered in a prospective cohort study. Eligible patients had an asymptomatic biochemical recurrence following primary PCa treatment and testosterone levels >50 ng/ml. The number of lesions were counted per scan. Patients with an isolated local recurrence or with up to 3 metastases (+/- local recurrence) were considered “low-volume” and patients with >3 metastases as high-volume. Descriptive statistics were used to report recurrences. Cox-regression analysis investigated the influence of prognostic variables on the time to developing castration resistant PCa (CRPC). Results In 208 patients, 625 sites of recurrence were detected in the lymph nodes (N1/M1a: 30%), the bone (18%), the prostate (bed) (11%), viscera (4%) or a combination of any of the previous (37%). In total, 153 patients (74%) had a low-volume recurrence and 55 patients (26%) had a high-volume recurrence. The 3-year CRPC-free survival for the whole cohort was 79% (95% CI: 43 – 55%) and 88% for low-volume recurrences and 50% for high-volume recurrences, respectively (p

Background Current first-line standard of therapy for metastatic urothelial carcinoma is platinum-based combination chemotherapy. Pembrolizumab in phase III has demonstrated a promising overall response rate of 21.1% in patients with progression or recurrence after platinum-based chemotherapy. Preclinical and clinical evidence suggests that radiotherapy has a systemic anti-cancer immune effect and can increase the level of PD-L1 and tumor infiltrating lymphocytes in the tumor microenvironment. These findings gave rise to the hypothesis that the combination of radiotherapy with anti-PD1 treatment could lead to a synergistic effect, hereby enhancing response rates. Methods The phase I part will assess the dose limiting toxicity of the combination treatment of stereotactic body radiotherapy (SBRT) with four cycles of pembrolizumab (200 mg intravenously, every 3 weeks) in patients with metastatic urothelial carcinoma. The dose of both pembrolizumab and SBRT will be fixed, yet the patients will be randomized to receive SBRT either before the first cycle of pembrolizumab or before the third cycle of pembrolizumab. SBRT will be delivered (24 Gy in 3 fractions every other day) to the largest metastatic lesion. Secondary objectives include response rate according to RECIST v1.1 and immune related response criteria, progression-free survival and overall survival. The systemic immune effect triggered by the combination therapy will be monitored on various time points during the trial. The PD-L1/TIL status of the tumors will be analyzed via immunohistochemistry and response rates in the subgroups will be analyzed separately. A Simon’s two-stage optimum design is used to select the treatment arm associated with the best response rate and with acceptable toxicity to proceed to the phase II trial. In this phase, 13 additional patients will be accrued to receive study treatment. Discussion The progress made in the field of immunotherapy has lead to promising breakthroughs in various solid malignancies. Unfortunately, the majority of patients do not respond. The current trial will shed light on the toxicity and potential anti-tumor activity of the combination of radiotherapy with anti-PD1 treatment and may identify potential new markers for response and resistance to therapy. Trial registration this trial is registered on clinicaltrials.gov (NCT02826564). Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1251-3) contains supplementary material, which is available to authorized users.

• The most common treatment for non-metastatic muscle invasive bladder cancer (MIBC) is radical cystectomy with pelvic lymph node dissection. For selected patients, trimodal therapy (TMT) consisting in a maximal transurethral resection of the bladder, followed by a concurrent chemotherapy and radiotherapy, spread over 5 to 7 weeks, is considered as an acceptable option. We aimed to perform a systematic review to report the current results of curative hypo-fractionated radiotherapy in terms of oncological outcomes and toxicity. In total, 5 phase III and 13 phase II trials were retained. Our review shows that TMT using hypo-fractionated radiotherapy allows a 2-year recurrence free survival rate between 43% and 83%, a 5-year OS rate going from 36% to 58%. Less than 12% of late grade ≥3 gastro-intestinal toxicities and between 4 to 46% grade ≥3 genito-urinary late toxicities were observed. This approach must be evaluated with prospective trials including quality of life scales.

PURPOSE: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. METHODS: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. RESULTS: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician- (47,025 forms) and patient- (54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade ≥2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). CONCLUSION: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. PATIENT SUMMARY: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short- and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity. ispartof: RADIOTHERAPY AND ONCOLOGY vol:138 pages:59-67 ispartof: location:Ireland status: published

BackgroundAlthough guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.ObjectiveTo bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.DesignA steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.SettingOnline Delphi survey and consensus conference.ParticipantsThe European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.Outcome measurements and statistical analysisStatements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), and 7–9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).Results and limitationsOverall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.ConclusionsThese consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.Patient summaryThis report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.

To determine the start exercise prescription dose in metastatic castrate-resistant prostate cancer (mCRPC) patients receiving second-line hormone treatment and recommended phase II exercise prescription.Patients were enrolled in a 3 + 3 dose escalation phase I trial of aerobic, resistance, and flexibility exercises to evaluate dose-limiting tolerance and safety. Tolerance was defined as Borg score ≤ 16 and safety (pain) as a visual analogue scale score (VAS) ≤ 3 and CTCAE grade 2. Dose level 1 (escalation start dose) was set at 15 min. Aerobic training (50-80% HRmax warm-up and cooling-down; and 65-80% HRmax. core), 1 set with 8-10 repetitions (reps.) resistance training (50-60% 1-RM, 8 exercises), and 1 set (30s) with 2 reps flexibility training (5 exercises). The prescription dose escalation was designed in four levels (from dose -1 to 3), with a dose escalation in volume and intensity of the exercises.Nine patients were included in two dosing cohorts and were under active treatment (n = 4 abiraterone acetate and n = 5 enzalutamide). Dose limiting safety concerns were observed in 2 out of 3 patients in dose level 2 and 1 patient out of 6 in dose level 1 due to VAS 3 during resistance training and/or flexibility training. No tolerance issues were observed in the two dosing cohorts. The optimal start exercise prescription dose was set at dose level 1 due to safety issues at dose level 2.Our findings suggest that exercise is perceived tolerable in mCRPC patients receiving second-line hormone therapy. Caution is indicated on safety during performance of the exercises.

The extent to which a good person-environment (PE) interest fit between student and study program leads to better study results in higher education is an ongoing debate wherein the role of the study program environment has remained inadequately studied. Unanswered questions include: how diverse study programs are in the interests of their student populations, and how this program interest diversity influences study results, in comparison to individual PE fit? The present study addressed these questions in students (N = 4,635) enrolled in open-access university education. In such an open access system, students are allowed to make study choices without prior limitations based on previous achievement or high stakes testing. Starting from the homogeneity assumption applied to this open access setting, we propose several hypotheses regarding program interest diversity, motivation, student-program interest fit, and study results. Furthermore, we applied a method of measuring interest diversity based on an existing measure of correlational person-environment fit. Results indicated that interest diversity in an open access study environment was low across study programs. Results also showed the variance present in program interest diversity was linked to autonomous and controlled motivation in the programs' student populations. Finally, program interest diversity better explained study results than individual student fit with their program of choice. Indeed, program interest diversity explained up to 44% of the variance in the average program's study results while individual student-program fit hardly predicted study success at all. Educational policy makers should therefore be aware of the importance of both interest fit and interest diversity during the process of study orientation.

The present study assessed the efficacy of hyperbaric oxygen therapy in reducing symptoms of radiation cystitis, a specific type of iatrogenic injury to the bladder, by systematic review of recent literature. The MEDLINE, Embase and Web of Science databases were searched using combinations of the terms "radiation," "cystitis" and "hyperbaric oxygen" to identify articles evaluating patients with radiation cystitis, treated with hyperbaric oxygen therapy. Only recent (

Up to 50% of patients recur after salvage radiation therapy (sRT) for prostate-specific antigen (PSA) rise following radical prostatectomy (RP). Notably, the importance of lymph node dissection (LND) at the time of RP with regard to recurrence risk following sRT has not been previously determined. Therefore, we evaluated the association between nodal yield at RP and recurrence after sRT. We performed a multi-institutional review of men with a rising PSA after RP treated with sRT. Clinicopathologic variables were abstracted, and the associations between lymph node yield and biochemical (BCR) as well as clinical recurrence (CR) after sRT were assessed using multivariable Cox proportional hazards regression models. In total, 728 patients were identified; of these, 221 and 116 were diagnosed with BCR and CR, respectively, during a median follow-up of 8.4 (interquartile range: 4.2–11.2) yr. On multivariable analysis, the risk of BCR after sRT was inversely associated with the number of nodes resected at RP (hazards ratio [HR]: 0.98; 95% confidence interval [CI]: 0.96–0.99; p =0.049). Increased extent of dissection was also independently associated with a decreased risk of CR after sRT (HR: 0.97; 95%CI: 0.94–0.99; p =0.042). These data support the importance of an extensive LND at surgery and may be used in prognosis assessment when sRT is being considered. Patient summary We found that patients who had increased number of lymph nodes resected at surgery had improved outcomes after the receipt of salvage radiation therapy. These findings support the use of the extended lymph node dissection at initial surgery and should serve to improve counseling among patients who require salvage radiation therapy.

The goal of this work was to investigate the oncological outcome of whole pelvis radiotherapy (wpRT) in pathologic pelvic lymph node-positive (pN1) prostate cancer (PCa), evaluate the location of relapse, and identify potential prognostic factors. All patients undergoing pelvic lymph node dissection (PLND) since the year 2000 at a single tertiary care center were evaluated. A total of 154 patients with pN1 PCa were treated with wpRT (39 in an adjuvant setting) and 2–3 years of androgen deprivation therapy (ADT). Kaplan–Meier analysis was performed to estimate biochemical recurrence-free survival (bRFS), clinical progression-free survival (cPFS), and prostate cancer-specific survival (CSS). Uni- and multivariate regression analyses were performed to identify prognostic factors. Estimated bRFS was 67%, cPFS was 71%, and CSS was 96% at 5 years. Median follow-up was 55 months (interquartile range 25–87). Multivariate analysis identified having only 1 positive lymph node, a shorter time between diagnosis and PLND, and older age as independent favorable prognostic factors for biochemical and clinical recurrence. The number of positive lymph nodes was prognostic for CSS (hazard ratio [HR] 1.34, 95% confidence interval 1.17–1.54) and OS (HR 1.22, 95% confidence interval 1.10–1.36). Bone metastases were the most frequent location of PCa relapse (n = 32, 64%). Patients with pN1 PCa treated with wpRT and 2–3 years ADT have an encouraging 5‑year CSS. Understaging of the disease extent may be the most important enemy in definitive pN1 PCa treatment.

Background Hormonal manipulation concomitant to salvage radiotherapy (SRT) given for biochemical recurrence (BCR) after radical prostatectomy (RP) improved outcomes in two randomized trials. However, neither of these studies focused on men treated at low prostate-specific antigen (PSA) levels. Objective To test if the impact of androgen deprivation therapy (ADT) on metastasis in patients undergoing early SRT varies according to prostate cancer (PCa) features. Design, setting, and participants A total of 525 patients received SRT at PSA levels ≤2ng/ml. Outcome measurements and statistical analyses Multivariable Cox regression analyses assessed factors associated with metastasis. We tested the hypothesis that the impact of ADT varied according to the risk of metastasis. An interaction with groups (concomitant ADT vs no ADT) and the probability of distant metastasis according to a newly developed model was tested. A nonparametric curve explored the relationship between the risk of metastasis and 10-yr metastasis rates according to ADT. Results and limitations Median PSA and radiotherapy dose were 0.42ng/ml and 66Gy, respectively. Overall, 178 (34%) patients received ADT. At a median follow-up of 104 mo, 71 patients experienced metastasis. Grade group ≥4 (hazard ratio [HR]: 1.66; 95% confidence interval [CI]: 1.01–3.30), pT3b/4 (HR: 2.61; 95% CI: 1.51–4.52), and dose (HR: 0.82; 95% CI: 0.76–0.89) were associated with metastasis. The impact of ADT differed according to the risk of metastasis calculated using a multivariable model (p=0.01). This was confirmed when considering patients treated with early SRT (p=0.046), where ADT was associated with a reduction in the rate of metastasis only in eSRT; patients with more aggressive characteristics (ie, pT3b/4 and grade group ≥4, or pT3b/4 and PSA at eSRT ≥0.4ng/ml). Conclusions The beneficial effect of ADT concomitant to eSRT varied significantly according to disease characteristics, such that only men with more aggressive PCa features benefit from ADT in the eSRT setting for BCR after RP. Patient summary The oncological benefits of concomitant androgen deprivation therapy (ADT) in patients undergoing salvage radiotherapy (SRT) vary according to pathological characteristics. Only patients with more aggressive disease characteristics seemed to benefit from the use of hormonal manipulation at the time of early SRT. Conversely, the potential side effects of ADT could be spared in patients with low prostate-specific antigen levels and favorable pathological features.

Renal-cell carcinoma is considered to be a radioresistant tumour, but this notion might be wrong. If given in a few (even single) fractions, but at a high fraction dose, stereotactic body radiotherapy becomes increasingly important in the management of renal-cell carcinoma, both in primary settings and in treatment of oligometastatic disease. There is an established biological rationale for the radiosensitivity of renal-cell carcinoma to stereotactic body radiotherapy based on the ceramide pathway, which is activated only when a high dose per fraction is given. Apart from the direct effect of stereotactic body radiotherapy on renal-cell carcinoma, stereotactic body radiotherapy can also induce an abscopal effect. This effect, caused by immunological processes, might be enhanced when targeted drugs and stereotactic body radiotherapy are combined. Therefore, rigorous, prospective randomised trials involving a multidisciplinary scientific panel are needed urgently. © 2014 Elsevier Ltd.

Background and purpose Local recurrences after radiotherapy are dose-dependent and occur in the dominant intraprostatic lesion (DIL). The purpose of this study was to evaluate the impact of a simultaneous integrated boost (SIB) to the magnetic resonance imaging (MRI)-defined DIL on toxicity. Materials and methods Four-hundred and ten patients were treated with intensity-modulated radiotherapy. A median dose of 78Gy was prescribed to the prostate. A SIB of 82Gy to the DIL was performed in 225 patients (SIB+). Genitourinary and rectal toxicity on fixed time points up to 8years were compared between SIB− (185 patients) and SIB+ patients. Chi-square, Fisher's exact and Kaplan–Meier statistics were applied. With a median follow up of 72months, the six-year actuarial risk of genitourinary and rectal toxicity grade⩾2 was 31% and 12% respectively. The actuarial risk of developing toxicity and incidence of symptoms at fixed time points were not increased with a SIB. Conclusion Performing a SIB did not increase genitourinary or rectal toxicity up to 8years' follow-up.

Ample empirical evidence endorses the role of associative learning in pain-related fear acquisition. Nevertheless, research typically focused on self-reported and psychophysiological measures of fear. Avoidance, which is overt behavior preventing the occurrence of an aversive (painful) stimulus, has been largely neglected so far. Therefore, we aimed to fill this gap and developed an operant conditioning procedure for pain-related avoidance behavior. Participants moved their arm to a target location using the HapticMaster (FCS Robotics; Moog Inc, East Aurora, New York), a 3 degrees-of-freedom, force-controlled robotic arm. Three movement trajectories led to the target location. If participants in the Experimental Group took the shortest/easiest trajectory, they always received a painful stimulus (T1 = 100% reinforcement; no resistance). If they deviated from this trajectory, the painful stimulus could be partly or totally prevented (T2 = 50% reinforcement; T3 = 0% reinforcement), but more effort was needed (T2 = moderate resistance and deviation; T3 = strongest resistance and largest deviation). The Yoked Group received the same reinforcement schedule irrespective of their own behavior. During the subsequent extinction phase, no painful stimuli were delivered. Self-reported pain-expectancy and pain-related fear were assessed, and avoidance behavior was operationalized as the maximal distance from the shortest trajectory. During acquisition, the Experimental Group reported more pain-related fear and pain-expectancy to T1 vs T2 vs T3 and deviated more from the shortest trajectory than the Yoked Group. During subsequent extinction, avoidance behavior, self-reported fear, and pain-expectancy decreased significantly, but conditioned differences persisted despite the absence of painful stimuli. To conclude, this operant learning task might provide a valid paradigm to study pain-related avoidance behavior in future studies.