Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Predicting Response to Intravesical Bacillus Calmette-Guérin Immunotherapy: Are We There Yet? A Systematic Review.

International audienceBacillus Calmette-Guérin (BCG) is currently the most effective intravesical therapy for nonmuscle invasive bladder cancer, reducing not only recurrence rates but also preventing progression and reducing deaths. However, response rates to BCG vary widely and are dependent on a multitude of factors

Perioperative Chemotherapy in Muscle-invasive Bladder Cancer : Overview and the Unmet Clinical Need for Alternative Adjuvant Therapy as Studied in the MAGNOLIA Trial

Contains fulltext : 136501.pdf (publisher's version ) (Closed access)The European Association of Urology Research Foundation has proposed that alternatives to perioperative chemotherapy should be evaluated. The MAGNOLIA study represents a unique opportunity to investigate the concept of immunotherapy in muscle-invasive bladder cancer

Local therapy in primary metastatic prostate cancer Lokale behandeling bij het primair gemetastaseerd prostaatcarcinoom

A substantial proportion of patients with prostate cancer have metastases at the time of diagnosis. Recent literature suggests that local radiotherapy to the prostate should be advised in these patients, provided they have a low metastasic burden (as defined by the CHAARTED criteria). This article discusses the available literature

Computerised assessment of maximum urinary flow: An efficient, consistent and valid approach

Objectives: To evaluate the relative accuracy of a computerised method to quantitatively assess maximum urinary flow. Methods: A total of 1147 uroflows were evaluated by the computerised method and by three experts from different European countries. The sample consisted of uroflows from the respective visits by a 20% sample of randomly chosen patients (n = 223) with lower urinary tract symptoms with participation in two clinical trials in which the efficacy and safety of Permixon was evaluated. The proportions of automated maximum flow values included in the 10% extended range of experts (and their 95% confidence intervals) were assessed, as well as the concordance coefficients between experts and the computerised method and the paired Student's t-test for the average differences between experts and computer. Results: The rate of agreement between experts and computer varied between about 95 and 100% over factor levels for visit, type of machine and country. Concordance coefficients indicated good agreement between experts and the automated method. When looking at average differences between experts and the computer, the smallest differences were observed between experts 2, 3 and the computer (differences not statistically significant). Statistically significant average differences were observed between expert 1 and the other experts as well as between expert 1 and the computer. Conclusions: The computerised assessment decreases the fraction of variability of maximum urinary flow caused by artifacts as well as intra- and inter-expert variation. The computerised assessment of maximum urinary flow is an efficient, consistent and valid approach to quantitatively assess maximum urinary flow in clinical trials. © 2002 Elsevier Science B.V. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial

Background: The cornerstone of standard treatment for patients with primary bone metastatic prostate cancer (mPCa) is androgen deprivation therapy (ADT). Retrospective studies suggest a survival benefit for treatment of the primary prostatic tumour in mPCa, but to date, no randomised-controlled-trials (RCTs) have been published addressing this issue. Objective: To determine whether overall survival is prolonged by adding local treatment of the primary prostatic tumour with external beam radiation therapy (EBRT) to ADT. Design, setting, and participants: The HORRAD trial is a multicentre RCT recruiting 432 patients with prostate-specific antigen (PSA) >20 ng/ml and primary bone mPCa on bone scan between 2004 and 2014. Intervention: Patients were randomised to either ADT with EBRT (radiotherapy group) or ADT alone (control group). Outcome measurements and statistical analysis: Primary endpoint was overall survival. Secondary endpoint was time to PSA progression. Crude and adjusted analyses were applied to evaluate treatment effect. Results and limitations: Median PSA level was 142 ng/ml and 67% of patients had more than five osseous metastases. Median follow up was 47 mo. Median overall survival was 45 mo (95% confidence interval [CI], 40.4–49.6) in the radiotherapy group and 43 mo (95% CI: 32.6–53.4) in the control group (p = 0.4). No significant difference was found in overall survival (hazard ratio [HR]: 0.90; 95% CI: 0.70–1.14; p = 0.4). Median time to PSA progression in the radiotherapy group was 15 mo (95% CI: 11.8–18.2), compared with 12 mo (95% CI: 10.6–13.4) in the control group. The crude HR (0.78; 95% CI: 0.63–0.97) was statistically significant (p = 0.02). Conclusions: The current RCT comparing ADT to ADT with EBRT to the prostate in patients with primary bone mPCa did not show a significant difference in overall survival, although the CI cannot exclude a substantial survival benefit. Further research is needed to confirm our findings. Patient summary: This study investigated the effect of adding radiation therapy to the prostate to hormonal therapy in prostate cancer patients with metastasis to the bone at diagnosis. In our patient group, additional radiotherapy did not improve overall survival. Further research is needed to confirm our findings. Twitter summary: Adding radiotherapy to the prostate in patients with bone metastatic prostate cancer does not improve overall survival. In the current randomised controlled trial, there is no improvement in overall survival when comparing androgen deprivation therapy alone to androgen deprivation therapy with concurrent radiotherapy to the prostate in patients with primary bone metastatic prostate cancer

Patient-reported Quality of Life in Patients with Primary Metastatic Prostate Cancer Treated with Androgen Deprivation Therapy with and Without Concurrent Radiation Therapy to the Prostate in a Prospective Randomised Clinical Trial; Data from the HORRAD Trial

Background: A survival benefit was demonstrated for patients with low-volume metastatic prostate cancer (mPCa) when local radiotherapy was added to androgen deprivation therapy (ADT). Objective: To determine the effect of ADT combined with external beam radiotherapy (EBRT) to the prostate on health-related quality of life (HRQoL) of patients with primary bone mPCa. Design, setting, and participants: The HORRAD trial is a multicentre randomised controlled trial recruiting 432patients with primary bone mPCa between 2004 and 2014. Intervention: Patients were randomised to ADT with EBRT or to ADT alone. Outcome measurements and statistical analysis: Patients completed two validated HRQoL questionnaires (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Core Module (QLQ-C30) and EORTC Quality of Life Questionnaire Prostate Module [QLQ-PR25]) at baseline and at 3, 6, 12, and24 mo after the initiation of treatment. The effect of both treatments was evaluated based on mixed-effect models. Results and limitations: Patient characteristics and HRQoL scores at baseline were similar in both arms. At baseline, 98% of patients completed the questionnaires, compared with 58% at 24 mo. Patients reported significantly more diarrhoea (difference between the groups 10.8; 95% confidence interval [CI] 7.3–14.2), bowel symptoms (4.5; 95% CI 2.1–6.8), and urinary symptoms (11.9; 95% CI 8.9–14.8) after EBRT and ADT compared with ADT alone (all between-arm difference p < 0.001). Urinary complaints levelled at 6 mo. At 2 yr, only bowel symptom scores were significantly different (8.0; 95% CI 4.8–11.1, p ≤ 0.001), but 68% of patients in the radiotherapy group did not report clinically relevant worsening of their bowel symptom scores. Conclusions: Patients with bone mPCa reported temporary modest urinary and bowel symptoms after combined treatment with EBRT of the prostate and ADT compared with ADT alone. For some patients (22%), deterioration of bowel functions remains at 2 yr, whereas general HRQoL does not deteriorate. Patient summary: This study investigated the effect of radiotherapy to the prostate added to hormonal therapy on patient-reported health-related quality of life (HRQoL) in patients with primary bone metastatic prostate cancer. Most patients reported only temporary urinary and bowel symptoms. In 22% of patients, bowel symptoms remained at 2 yr, whereas general HRQoL did not deteriorate. Patients with bone metastatic prostate cancer reported temporary modest urinary and bowel symptoms after combined treatment with prostate radiotherapy and hormonal therapy compared with hormonal therapy alone. Both treatments did not affect global health-related quality of life

Patient-reported Quality of Life in Patients with Primary Metastatic Prostate Cancer Treated with Androgen Deprivation Therapy with and Without Concurrent Radiation Therapy to the Prostate in a Prospective Randomised Clinical Trial; Data from the HORRAD Trial

Background: A survival benefit was demonstrated for patients with low-volume metastatic prostate cancer (mPCa) when local radiotherapy was added to androgen deprivation therapy (ADT). Objective: To determine the effect of ADT combined with external beam radiotherapy (EBRT) to the prostate on health-related quality of life (HRQoL) of patients with primary bone mPCa. Design, setting, and participants: The HORRAD trial is a multicentre randomised controlled trial recruiting 432patients with primary bone mPCa between 2004 and 2014. Intervention: Patients were randomised to ADT with EBRT or to ADT alone. Outcome measurements and statistical analysis: Patients completed two validated HRQoL questionnaires (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Core Module (QLQ-C30) and EORTC Quality of Life Questionnaire Prostate Module [QLQ-PR25]) at baseline and at 3, 6, 12, and24 mo after the initiation of treatment. The effect of both treatments was evaluated based on mixed-effect models. Results and limitations: Patient characteristics and HRQoL scores at baseline were similar in both arms. At baseline, 98% of patients completed the questionnaires, compared with 58% at 24 mo. Patients reported significantly more diarrhoea (difference between the groups 10.8; 95% confidence interval [CI] 7.3–14.2), bowel symptoms (4.5; 95% CI 2.1–6.8), and urinary symptoms (11.9; 95% CI 8.9–14.8) after EBRT and ADT compared with ADT alone (all between-arm difference p < 0.001). Urinary complaints levelled at 6 mo. At 2 yr, only bowel symptom scores were significantly different (8.0; 95% CI 4.8–11.1, p ≤ 0.001), but 68% of patients in the radiotherapy group did not report clinically relevant worsening of their bowel symptom scores. Conclusions: Patients with bone mPCa reported temporary modest urinary and bowel symptoms after combined treatment with EBRT of the prostate and ADT compared with ADT alone. For some patients (22%), deterioration of bowel functions remains at 2 yr, whereas general HRQoL does not deteriorate. Patient summary: This study investigated the effect of radiotherapy to the prostate added to hormonal therapy on patient-reported health-related quality of life (HRQoL) in patients with primary bone metastatic prostate cancer. Most patients reported only temporary urinary and bowel symptoms. In 22% of patients, bowel symptoms remained at 2 yr, whereas general HRQoL did not deteriorate. Patients with bone metastatic prostate cancer reported temporary modest urinary and bowel symptoms after combined treatment with prostate radiotherapy and hormonal therapy compared with hormonal therapy alone. Both treatments did not affect global health-related quality of life