Publications by authors named "Nicholas D James"

129 Publications

Genomic Profiles of De Novo High- and Low-Volume Metastatic Prostate Cancer: Results From a 2-Stage Feasibility and Prevalence Study in the STAMPEDE Trial.

JCO Precis Oncol 2020 Nov;4:882-897

Guys and St Thomas' Hospitals, London, United Kingdom.

Purpose: The STAMPEDE trial recruits men with newly diagnosed, high-risk, hormone-sensitive prostate cancer. To ascertain the feasibility of targeted next-generation sequencing (tNGS) and the prevalence of baseline genomic aberrations, we sequenced tumor and germline DNA from patients with metastatic prostate cancer (mPCa) starting long-term androgen-deprivation therapy (ADT).

Methods: In a 2-stage approach, archival, formalin-fixed, paraffin-embedded (FFPE) prostate tumor core biopsy samples were retrospectively subjected to 2 tNGS assays. Prospective enrollment enabled validation using tNGS in tumor and germline DNA.

Results: In stage 1, tNGS data were obtained from 185 tumors from 287 patients (65%); 98% had de novo mPCa. We observed PI3K pathway aberrations in 43%, due to copy-number loss (34%) and/or activating mutations in genes or (18%) and mutation or loss in 33%. No androgen receptor () aberrations were detected; loss was observed in < 1%. In stage 2, 93 (92%) of 101 FFPE tumors (biopsy obtained within 8 months) were successfully sequenced prospectively. The prevalence of DNA damage repair (DDR) deficiency was 14% (somatic) and 5% (germline). mutations and mismatch repair gene mutations were exclusive to high-volume disease. Aberrant DDR (22% 15%), Wnt pathway (16% 4%), and chromatin remodeling (16% 8%) were all more common in high-volume compared with low-volume disease, but the small numbers limited statistical comparisons.

Conclusion: Prospective genomic characterization is feasible using residual diagnostic tumor samples and reveals that the genomic landscapes of de novo high-volume mPCa and advanced metastatic prostate cancer have notable similarities (PI3K pathway, DDR, Wnt, chromatin remodeling) and differences (, ). These results will inform the design and conduct of biomarker-directed trials in men with metastatic hormone-sensitive prostate cancer.
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http://dx.doi.org/10.1200/PO.19.00388DOI Listing
November 2020

Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol.

Lancet 2021 Dec 23. Epub 2021 Dec 23.

Yeovil District Hospital NHS Foundation Trust, Yeovil, UK; Musgrove Park Hospital, Taunton, UK.

Background: Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population.

Methods: These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0-2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544.

Findings: Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63-73) and median PSA 34 ng/ml (14·7-47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60-84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]-NE) than in the control groups (not reached, 97-NE; hazard ratio [HR] 0·53, 95% CI 0·44-0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79-85) in the combination-therapy group and 69% (66-72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70-1·50, p=0·91) and no evidence of between-trial heterogeneity (I p=0·90). Overall survival (median not reached [IQR NE-NE] in the combination-therapy groups vs not reached [103-NE] in the control groups; HR 0·60, 95% CI 0·48-0·73, p<0·0001), prostate cancer-specific survival (not reached [NE-NE] vs not reached [NE-NE]; 0·49, 0·37-0·65, p<0·0001), biochemical failure-free-survival (not reached [NE-NE] vs 86 months [83-NE]; 0·39, 0·33-0·47, p<0·0001), and progression-free-survival (not reached [NE-NE] vs not reached [103-NE]; 0·44, 0·36-0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death).

Interpretation: Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population.

Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.
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http://dx.doi.org/10.1016/S0140-6736(21)02437-5DOI Listing
December 2021

Quality of Life in Men With Prostate Cancer Randomly Allocated to Receive Docetaxel or Abiraterone in the STAMPEDE Trial.

J Clin Oncol 2021 Nov 10:JCO2100728. Epub 2021 Nov 10.

University Hospital Birmingham, Birmingham, United Kingdom.

Purpose: Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices.

Methods: A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints.

Results: Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; < .001).

Conclusion: Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.
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http://dx.doi.org/10.1200/JCO.21.00728DOI Listing
November 2021

Confronting false discoveries in single-cell differential expression.

Nat Commun 2021 09 28;12(1):5692. Epub 2021 Sep 28.

Center for Neuroprosthetics and Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

Differential expression analysis in single-cell transcriptomics enables the dissection of cell-type-specific responses to perturbations such as disease, trauma, or experimental manipulations. While many statistical methods are available to identify differentially expressed genes, the principles that distinguish these methods and their performance remain unclear. Here, we show that the relative performance of these methods is contingent on their ability to account for variation between biological replicates. Methods that ignore this inevitable variation are biased and prone to false discoveries. Indeed, the most widely used methods can discover hundreds of differentially expressed genes in the absence of biological differences. To exemplify these principles, we exposed true and false discoveries of differentially expressed genes in the injured mouse spinal cord.
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http://dx.doi.org/10.1038/s41467-021-25960-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479118PMC
September 2021

Genome-wide Meta-analysis Identifies Novel Genes Associated with Recurrence and Progression in Non-muscle-invasive Bladder Cancer.

Eur Urol Oncol 2021 Aug 2. Epub 2021 Aug 2.

Department for Health Evidence, Radboud university medical center, Nijmegen, The Netherlands.

Background: Non-muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrences and a risk of progression in stage and grade. Increased knowledge of underlying biological mechanisms is needed.

Objective: To identify single nucleotide polymorphisms (SNPs) associated with recurrence-free (RFS) and progression-free (PFS) survival in NMIBC.

Design, Setting, And Participants: We analyzed outcome data from 3400 newly diagnosed NMIBC patients from the Netherlands, the UK, Canada, and Spain. We generated genome-wide germline SNP data using Illumina OmniExpress and Infinium Global Screening Array in combination with genotype imputation.

Outcome Measurements And Statistical Analysis: Cohort-specific genome-wide association studies (GWASs) for RFS and PFS were performed using a Cox proportional hazard model. Results were combined in a fixed-effect inverse-variance weighted meta-analysis. Candidate genes for the identified SNP associations were prioritized using functional annotation, gene-based analysis, expression quantitative trait locus analysis, and transcription factor binding site databases. Tumor expression levels of prioritized genes were tested for association with RFS and PFS in an independent NMIBC cohort.

Results And Limitations: This meta-analysis revealed a genome-wide significant locus for RFS on chromosome 14 (lead SNP rs12885353, hazard ratio [HR] C vs T allele 1.55, 95% confidence interval [CI] 1.33-1.82, p = 4.0 × 10), containing genes G2E3 and SCFD1. Higher expression of SCFD1 was associated with increased RFS (HR 0.70, 95% CI 0.59-0.84, p = 0.003). Twelve other loci were suggestively associated with RFS (p < 10), pointing toward 18 additional candidate genes. For PFS, ten loci showed suggestive evidence of association, indicating 36 candidate genes. Expression levels of ten of these genes were statistically significantly associated with PFS, of which four (IFT140, UBE2I, FAHD1, and NME3) showed directional consistency with our meta-analysis results and published literature.

Conclusions: In this first prognostic GWAS in NMIBC, we identified several novel candidate loci and five genes that showed convincing associations with recurrence or progression.

Patient Summary: In this study, we searched for inherited DNA changes that affect the outcome of non-muscle-invasive bladder cancer (NMIBC). We identified several genes that are associated with disease recurrence and progression. The roles and mechanisms of these genes in NMIBC prognosis should be investigated in future studies.
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http://dx.doi.org/10.1016/j.euo.2021.07.001DOI Listing
August 2021

Reply to Trey Durdin, Alvin Goh, and Eugene Pietzak. Can an Imaging-guided Pathway Replace the Current Paradigm for Muscle-invasive Bladder Cancer?

Eur Urol 2021 07 8;80(1):18-19. Epub 2021 May 8.

Cancer Research UK Clinical Trials Unit, Institute of Cancer & Genomic Sciences, University of Birmingham, Birmingham, UK.

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http://dx.doi.org/10.1016/j.eururo.2021.04.034DOI Listing
July 2021

Multi-pronged neuromodulation intervention engages the residual motor circuitry to facilitate walking in a rat model of spinal cord injury.

Nat Commun 2021 03 26;12(1):1925. Epub 2021 Mar 26.

Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Geneva, Switzerland.

A spinal cord injury usually spares some components of the locomotor circuitry. Deep brain stimulation (DBS) of the midbrain locomotor region and epidural electrical stimulation of the lumbar spinal cord (EES) are being used to tap into this spared circuitry to enable locomotion in humans with spinal cord injury. While appealing, the potential synergy between DBS and EES remains unknown. Here, we report the synergistic facilitation of locomotion when DBS is combined with EES in a rat model of severe contusion spinal cord injury leading to leg paralysis. However, this synergy requires high amplitudes of DBS, which triggers forced locomotion associated with stress responses. To suppress these undesired responses, we link DBS to the intention to walk, decoded from cortical activity using a robust, rapidly calibrated unsupervised learning algorithm. This contingency amplifies the supraspinal descending command while empowering the rats into volitional walking. However, the resulting improvements may not outweigh the complex technological framework necessary to establish viable therapeutic conditions.
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http://dx.doi.org/10.1038/s41467-021-22137-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997909PMC
March 2021

PD-L2 Is Constitutively Expressed in Normal and Malignant Urothelium.

Front Oncol 2021 25;11:626748. Epub 2021 Feb 25.

Bladder Cancer Research Centre, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.

The use of immune checkpoint blockade, in particular PD-1 and PD-L1 inhibitors, is now commonplace in many clinical settings including the treatment of muscle-invasive bladder cancer (MIBC). Notwithstanding, little information exists regarding the expression of the alternative PD-1 ligand, PD-L2 in urothelial bladder cancer (UBC). We therefore set out to characterise the expression of PD-L2 in comparison to PD-L1. Firstly, we assessed PD-L2 expression by immunohistochemistry and found widespread expression of PD-L2 in UBC, albeit with reduced expression in MIBC. We further investigated these findings using RNA-seq data from a cohort of 575 patients demonstrating that PDCD1LG2 (PD-L2) is widely expressed in UBC and correlated with CD274 (PD-L1). However, in contrast to our immunohistochemistry findings, expression was significantly increased in advanced disease. We have also provided detailed evidence of constitutive PD-L2 expression in normal urothelium and propose a mechanism by which PD-L2 is cleaved from the cell surface in MIBC. These data provide a comprehensive assessment of PD-L2 in UBC, showing PD-L2 is abundant in UBC and, importantly, constitutively present in normal urothelium. These data have implications for future development of immune checkpoint blockade, and also the understanding of the function of the immune system in the normal urinary bladder.
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http://dx.doi.org/10.3389/fonc.2021.626748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951139PMC
February 2021

Comparing an Imaging-guided Pathway with the Standard Pathway for Staging Muscle-invasive Bladder Cancer: Preliminary Data from the BladderPath Study.

Eur Urol 2021 07 27;80(1):12-15. Epub 2021 Feb 27.

Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK. Electronic address:

Transurethral resection of bladder tumour (TURBT) is central to the diagnosis of muscle-invasive bladder cancer (MIBC). With the oncological safety of TURBT unknown, staging inaccuracies commonplace, and correct treatment of MIBC potentially delayed, multiparametric magnetic resonance imaging (mpMRI) may offer rapid, accurate, and noninvasive diagnosis of MIBC. BladderPath is a randomised trial comparing risk-stratified (5-point Likert scale) image-directed care with TURBT for patients with newly diagnosed BC. To date, we have screened 279 patients and randomised 113. Here we report on the first 100 participants to complete staging: 48 in pathway 1 (TURBT) and 52 in pathway 2 (mpMRI for possible MIBC, Likert 3-5). Fifty of 52 participants designated Likert 1-2 (probable NMIBC) from both pathways were confirmed as having NMIBC (96%). Ten of 11 cases diagnosed as NMIBC by mpMRI have been pathologically confirmed as NMIBC, and 10/15 cases diagnosed as MIBC by mpMRI have been treated as MIBC (5 participants underwent TURBT). The specificity of mpMRI for identification of MIBC remains a limitation. These initial experiences indicate that it is feasible to direct possible MIBC patients to mpMRI for staging instead of TURBT. Furthermore, a 5-point Likert scale accurately identifies patients with low risk of MIBC (Likert 1-2), and flexible cystoscopy biopsies appear sufficient for diagnosing BC. PATIENT SUMMARY: We are conducting a clinical trial to assess whether some bladder tumour surgery can be replaced by magnetic resonance imaging scans to determine the stage of the cancer in patients whose tumours appear to be invasive. Our early data suggest that this approach is feasible. The data also show that using a visual score ('Likert scale') can help to identify bladder tumours that are very unlikely to be invasive, and that taking a biopsy in the outpatient clinic when first inspecting the bladder via a camera (diagnostic flexible cystoscopy) is useful for confirming bladder cancer.
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http://dx.doi.org/10.1016/j.eururo.2021.02.021DOI Listing
July 2021

Association of Bone Metastatic Burden With Survival Benefit From Prostate Radiotherapy in Patients With Newly Diagnosed Metastatic Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial.

JAMA Oncol 2021 Apr;7(4):555-563

Genito-Urinary Cancer Research Group, Division of Cancer Sciences, The University of Manchester, Manchester, United Kingdom.

Importance: Prostate radiotherapy (RT) improves survival in men with low-burden metastatic prostate cancer. However, owing to the dichotomized nature of metastatic burden criteria, it is not clear how this benefit varies with bone metastasis counts and metastatic site.

Objective: To evaluate the association of bone metastasis count and location with survival benefit from prostate RT.

Design, Setting, And Participants: This exploratory analysis of treatment outcomes based on metastatic site and extent as determined by conventional imaging (computed tomography/magnetic resonance imaging and bone scan) evaluated patients with newly diagnosed metastatic prostate cancer randomized within the STAMPEDE trial's metastasis M1 RT comparison. The association of baseline bone metastasis counts with overall survival (OS) and failure-free survival (FFS) was assessed using a multivariable fractional polynomial interaction procedure. Further analysis was conducted in subgroups.

Interventions: Patients were randomized to receive either standard of care (androgen deprivation therapy with or without docetaxel) or standard of care and prostate RT.

Main Outcomes And Measures: The primary outcomes were OS and FFS.

Results: A total of 1939 of 2061 men were included (median [interquartile range] age, 68 [63-73] years); 1732 (89%) had bone metastases. Bone metastasis counts were associated with OS and FFS benefit from prostate RT. Survival benefit decreased continuously as the number of bone metastases increased, with benefit most pronounced up to 3 bone metastases. A plot of estimated treatment effect indicated that the upper 95% CI crossed the line of equivalence (hazard ratio [HR], 1) above 3 bone metastases without a detectable change point. Further analysis based on subgroups showed that the magnitude of benefit from the addition of prostate RT was greater in patients with low metastatic burden with only nonregional lymph nodes (M1a) or 3 or fewer bone metastases without visceral metastasis (HR for OS, 0.62; 95% CI, 0.46-0.83; HR for FFS, 0.57; 95% CI, 0.47-0.70) than among patients with 4 or more bone metastases or any visceral/other metastasis (HR for OS, 1.08; 95% CI, 0.91-1.28; interaction P = .003; HR for FFS, 0.87; 95% CI, 0.76-0.99; interaction P = .002).

Conclusions And Relevance: In this exploratory analysis of a randomized clinical trial, bone metastasis count and metastasis location based on conventional imaging were associated with OS and FFS benefit from prostate RT in M1 disease.

Trial Registration: ClinicalTrials.gov Identifier: NCT00268476; ISRCTN.com Identifier: ISRCTN78818544.
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http://dx.doi.org/10.1001/jamaoncol.2020.7857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893550PMC
April 2021

Hypofractionated radiotherapy in locally advanced bladder cancer: an individual patient data meta-analysis of the BC2001 and BCON trials.

Lancet Oncol 2021 02;22(2):246-255

Division of Cancer Sciences, University of Manchester, Manchester, UK; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Mount Vernon Cancer Centre, Northwood, UK.

Background: Two radiotherapy fractionation schedules are used to treat locally advanced bladder cancer: 64 Gy in 32 fractions over 6·5 weeks and a hypofractionated schedule of 55 Gy in 20 fractions over 4 weeks. Long-term outcomes of these schedules in several cohort studies and case series suggest that response, survival, and toxicity are similar, but no direct comparison has been published. The present study aimed to assess the non-inferiority of 55 Gy in 20 fractions to 64 Gy in 32 fractions in terms of invasive locoregional control and late toxicity in patients with locally advanced bladder cancer.

Methods: We did a meta-analysis of individual patient data from patients (age ≥18 years) with locally advanced bladder cancer (T1G3 [high-grade non-muscle invasive] or T2-T4, N0M0) enrolled in two multicentre, randomised, controlled, phase 3 trials done in the UK: BC2001 (NCT00024349; assessing addition of chemotherapy to radiotherapy) and BCON (NCT00033436; assessing hypoxia-modifying therapy combined with radiotherapy). In each trial, the fractionation schedule was chosen according to local standard practice. Co-primary endpoints were invasive locoregional control (non-inferiority margin hazard ratio [HR]=1·25); and late bladder or rectum toxicity, assessed with the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic tool (non-inferiority margin for absolute risk difference [RD]=10%). If non-inferiority was met for invasive locoregional control, superiority could be considered if the 95% CI for the treatment effect excluded the null effect (HR=1). One-stage individual patient data meta-analysis models for the time-to-event and binary outcomes were used, accounting for trial differences, within-centre correlation, randomised treatment received, baseline variable imbalances, and potential confounding from relevant prognostic factors.

Findings: 782 patients with known fractionation schedules (456 from the BC2001 trial and 326 from the BCON trial; 376 (48%) received 64 Gy in 32 fractions and 406 (52%) received 55 Gy in 20 fractions) were included in our meta-analysis. Median follow-up was 120 months (IQR 99-159). Patients who received 55 Gy in 20 fractions had a lower risk of invasive locoregional recurrence than those who received 64 Gy in 32 fractions (adjusted HR 0·71 [95% CI 0·52-0·96]). Both schedules had similar toxicity profiles (adjusted RD -3·37% [95% CI -11·85 to 5·10]).

Interpretation: A hypofractionated schedule of 55 Gy in 20 fractions is non-inferior to 64 Gy in 32 fractions with regard to both invasive locoregional control and toxicity, and is superior with regard to invasive locoregional control. 55 Gy in 20 fractions should be adopted as a standard of care for bladder preservation in patients with locally advanced bladder cancer.

Funding: Cancer Research UK.
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http://dx.doi.org/10.1016/S1470-2045(20)30607-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851111PMC
February 2021

Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury.

Nature 2021 02 27;590(7845):308-314. Epub 2021 Jan 27.

Motac Neuroscience Ltd, Manchester, UK.

Spinal cord injury (SCI) induces haemodynamic instability that threatens survival, impairs neurological recovery, increases the risk of cardiovascular disease, and reduces quality of life. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury, and restored walking after paralysis. Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This 'neuroprosthetic baroreflex' controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.
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http://dx.doi.org/10.1038/s41586-020-03180-wDOI Listing
February 2021

Combined treatment with enteric neural stem cells and chondroitinase ABC reduces spinal cord lesion pathology.

Stem Cell Res Ther 2021 01 6;12(1):10. Epub 2021 Jan 6.

Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK.

Background: Spinal cord injury (SCI) presents a significant challenge for the field of neurotherapeutics. Stem cells have shown promise in replenishing the cells lost to the injury process, but the release of axon growth-inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) by activated cells within the injury site hinders the integration of transplanted cells. We hypothesised that simultaneous application of enteric neural stem cells (ENSCs) isolated from the gastrointestinal tract, with a lentivirus (LV) containing the enzyme chondroitinase ABC (ChABC), would enhance the regenerative potential of ENSCs after transplantation into the injured spinal cord.

Methods: ENSCs were harvested from the GI tract of p7 rats, expanded in vitro and characterised. Adult rats bearing a contusion injury were randomly assigned to one of four groups: no treatment, LV-ChABC injection only, ENSC transplantation only or ENSC transplantation+LV-ChABC injection. After 16 weeks, rats were sacrificed and the harvested spinal cords examined for evidence of repair.

Results: ENSC cultures contained a variety of neuronal subtypes suitable for replenishing cells lost through SCI. Following injury, transplanted ENSC-derived cells survived and ChABC successfully degraded CSPGs. We observed significant reductions in the injured tissue and cavity area, with the greatest improvements seen in the combined treatment group. ENSC-derived cells extended projections across the injury site into both the rostral and caudal host spinal cord, and ENSC transplantation significantly increased the number of cells extending axons across the injury site. Furthermore, the combined treatment resulted in a modest, but significant functional improvement by week 16, and we found no evidence of the spread of transplanted cells to ectopic locations or formation of tumours.

Conclusions: Regenerative effects of a combined treatment with ENSCs and ChABC surpassed either treatment alone, highlighting the importance of further research into combinatorial therapies for SCI. Our work provides evidence that stem cells taken from the adult gastrointestinal tract, an easily accessible source for autologous transplantation, could be strongly considered for the repair of central nervous system disorders.
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http://dx.doi.org/10.1186/s13287-020-02031-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789480PMC
January 2021

Outcomes in Patients with Muscle-invasive Bladder Cancer Treated with Neoadjuvant Chemotherapy Followed by (Chemo)radiotherapy in the BC2001 Trial.

Eur Urol 2021 02 6;79(2):307-315. Epub 2020 Dec 6.

The Institute of Cancer Research, London, UK.

Background: BC2001 demonstrated improved local control with the addition of chemotherapy to radiotherapy in 360 patients with muscle-invasive bladder cancer.

Objective: To establish whether such benefit remained in BC2001 patients who received prior neoadjuvant chemotherapy.

Design, Setting, And Participants: A total of 117 patients (33%) received neoadjuvant chemotherapy and were randomised to radiotherapy with (48%) or without (52%) concomitant chemotherapy. Patients were recruited between August 2001 and April 2008 from 28 UK centres.

Intervention: Platinum-based neoadjuvant chemotherapy, followed by radiotherapy with (cRT) or without (RT) synchronous 5-fluorouracil and mitomycin-C.

Outcome Measurements And Statistical Analysis: Toxicity, locoregional control (LRC), overall survival (OS), and quality of life (QoL) were measured.

Results And Limitations: Of the patients, 74% received gemcitabine plus cisplatin or carboplatin. Compliance rates with full-dose radiotherapy were cRT 93% and RT 92%. An excess of grade ≥3 toxicities while on (chemo)radiation occurred for cRT 33% versus RT 22%, although nonstatistically significant (p = 0.16). With 110 mo median follow-up for survival (interquartile range 96-123), cRT showed improved LRC though not statistically significant (adjusted hazard ratio [aHR] = 0.64, 95% confidence interval [CI] 0.33-1.23, p = 0.18). No differences in OS (aHR = 0.95, 95% CI 0.57-1.57, p = 0.8) were observed. No significant detriment in QoL was observed between cRT and RT in this subgroup of patients.

Conclusions: Neoadjuvant chemotherapy does not compromise the delivery of radical curative treatment. Although underpowered due to a small sample size, the benefit of chemoradiotherapy to improve local control in this group of patients receiving neoadjuvant chemotherapy is consistent with that observed in the main trial. Although a nonsignificant excess of toxicity was observed, there was no evidence of impaired QoL.

Patient Summary: Chemotherapy before radical chemo(radiotherapy) is feasible and well tolerated.
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http://dx.doi.org/10.1016/j.eururo.2020.11.036DOI Listing
February 2021

Development and validation of a follow-up methodology for a randomised controlled trial, utilising routine clinical data as an alternative to traditional designs: a pilot study to assess the feasibility of use for the BladderPath trial.

Pilot Feasibility Stud 2020 Oct 31;6(1):165. Epub 2020 Oct 31.

University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, B15 2GW, UK.

Background: Bladder cancer outcomes have not changed significantly in 30 years; the BladderPath trial (Image Directed Redesign of Bladder Cancer Treatment Pathway, ISRCTN35296862) proposes to evaluate a modified pathway for diagnosis and treatment ensuring appropriate pathways are undertaken earlier to improve outcomes. We are piloting a novel data collection technique based on routine National Health Service (NHS) data, with no traditional patient-Health Care Professional contact after recruitment, where trial data are traditionally collected on case report forms. Data will be collected from routine administrative sources and validated via data queries to sites. We report here the feasibility and pre-trial methodological development and validation of the schema proposed for BladderPath.

Methods: Locally treated patient cohorts were utilised for routine data validation (hospital interactions data (HID) and administrative radiotherapy department data (RTD)). Single site events of interest were algorithmically extracted from the 2008-2018 HID and validated against reference datasets to determine detection sensitivity. Survival analysis was performed using RTD and HID data. Hazard ratios and survival statistics were calculated estimating treatment effects and further validating and assessing the scope of routine data.

Results: Overall, 829/1042 (sensitivity 0.80) events of interest were identified in the HID, with varying levels of sensitivity; identifying, 202/206 (sensitivity 0.98; PPV 0.96) surgical events but only 391/568 (sensitivity 0.69; PPV 0.95) radiotherapy regimens. An overall temporal quality improvement trend was present: detecting 41/117 events (35%) in 2011 to 104/109 (95%) in 2017 (all event types). Using the RTD, 5-year survival rates were 43% (95% CI 25-59%) in the chemoradiotherapy group and 30% (95% CI 23-36%) in the radiotherapy group; using the HID, the 5-year radical cystectomy survival rate was 57% (95% CI 50-63%).

Conclusions: Routine data are a feasible method for trial data collection. As long as events of interest are pre-validated, very high sensitivities for trial conduct can be achieved and further improved with targeted data queries. Outcomes can also be produced comparable to clinical trial and national dataset results. Given the real-time, obligatory nature of the HID, which forms the Hospital Episode Statistics (HES) data, alongside other datasets, we believe routine data extraction and validation is a robust way of rapidly collecting datasets for trials.
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http://dx.doi.org/10.1186/s40814-020-00713-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599120PMC
October 2020

Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.

Lancet 2020 10 28;396(10260):1413-1421. Epub 2020 Sep 28.

Kent Oncology Centre, Maidstone Hospital, Kent, UK.

Background: The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression.

Methods: We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047.

Findings: Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020).

Interpretation: These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy.

Funding: Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.
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http://dx.doi.org/10.1016/S0140-6736(20)31553-1DOI Listing
October 2020

Structured nanoscale metallic glass fibres with extreme aspect ratios.

Nat Nanotechnol 2020 10 3;15(10):875-882. Epub 2020 Aug 3.

Laboratory of Photonic Materials and Fibre Devices (FIMAP), Institute of Materials, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

Micro- and nanoscale metallic glasses offer exciting opportunities for both fundamental research and applications in healthcare, micro-engineering, optics and electronics. The scientific and technological challenges associated with the fabrication and utilization of nanoscale metallic glasses, however, remain unresolved. Here, we present a simple and scalable approach for the fabrication of metallic glass fibres with nanoscale architectures based on their thermal co-drawing within a polymer matrix with matched rheological properties. Our method yields well-ordered and uniform metallic glasses with controllable feature sizes down to a few tens of nanometres, and aspect ratios greater than 10. We combine fluid dynamics and advanced in situ transmission electron microscopy analysis to elucidate the interplay between fluid instability and crystallization kinetics that determines the achievable feature sizes. Our approach yields complex fibre architectures that, combined with other functional materials, enable new advanced all-in-fibre devices. We demonstrate in particular an implantable metallic glass-based fibre probe tested in vivo for a stable brain-machine interface that paves the way towards innovative high-performance and multifunctional neuro-probes.
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http://dx.doi.org/10.1038/s41565-020-0747-9DOI Listing
October 2020

Back-Splicing Transcript Isoforms (Circular RNAs) Affect Biologically Relevant Pathways and Offer an Additional Layer of Information to Stratify NMIBC Patients.

Front Oncol 2020 22;10:812. Epub 2020 May 22.

Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Circularized transcript isoforms due to back-splicing are increasingly being reported in different tissues types and pathological states including cancer. Since these circular RNAs (circRNAs) are more stable than linear messenger RNA their identification and profiling in tumor tissue could aid in stratifying patients and may serve as biomarkers. In this study, we have investigated the relationship between circRNA expression and tumor grade in a cohort of 58, mostly non-muscle-invasive bladder cancer patients. From 4571 circRNAs detected, we identified 157 that were significantly differentially expressed between tumor grades relative to the linear transcript. We demonstrated that such grade-related differences can be identified in an independent cohort, and that a large fraction of circRNAs can be, in principle, detected in urine. The differentially expressed circRNAs cluster into subgroups according to their co-expression, subgroups which are enriched for DNA repair, cell cycle and intracellular signaling genes. Since one proposed function of circRNAs is to interfere with gene-regulation by acting as microRNA "sponges," candidates which were differentially expressed between tumor grades were investigated for potential miRNA target sites. By investigating the circRNAs from bladder cancer related pathways we demonstrated that the expression of these pathways, the circRNAs, and their parental genes are often decoupled and do not correlate, yet that some circRNAs do not follow this tendency. The present study provides the next step for the comprehensive evaluation of this novel class of RNAs in the context of non-muscle-invasive bladder cancer. Intriguingly, despite their possible function as microRNA sponges, they potentially affect host mRNA levels at the transcriptional stage, as compared to post-transcriptional control by miRNAs. Our analysis indicates differences of their activity between bladder cancer tumor stages, and their relative expression levels may provide an additional layer of information for patient stratification.
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http://dx.doi.org/10.3389/fonc.2020.00812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326039PMC
May 2020

The Automated Bone Scan Index as a Predictor of Response to Prostate Radiotherapy in Men with Newly Diagnosed Metastatic Prostate Cancer: An Exploratory Analysis of STAMPEDE's "M1|RT Comparison".

Eur Urol Oncol 2020 08 24;3(4):412-419. Epub 2020 Jun 24.

Genito-Urinary Cancer Research Group, Division of Cancer Sciences, The University of Manchester, Manchester, UK; FASTMAN Centre of Prostate Cancer Excellence, Manchester Cancer Research Centre, Manchester, UK; Department of Surgery, The Christie NHS Foundation Trust, Manchester, UK; Department of Urology, The Salford NHS Foundation Trust, Manchester, UK. Electronic address:

Background: Prostate radiotherapy (RT) is a first-line option for newly diagnosed men with low-burden metastatic prostate cancer. The current criterion to define this clinical state is based on manual bone metastasis counts, but enumeration of bone metastases is limited by interobserver variations, and it does not account for metastasis volume or lesional coalescence. The automated bone scan index (aBSI) is a quantitative method of evaluating bone metastatic burden in a standardised and reproducible manner.

Objective: To evaluate whether aBSI has utility as a predictive imaging biomarker to define a newly diagnosed metastatic prostate cancer population that might benefit from the addition of prostate RT to standard of care (SOC) systemic therapy.

Design, Setting, And Participants: This is an exploratory analysis of men with newly diagnosed metastatic prostate cancer randomised in a 1:1 ratio to either SOC or SOC + prostate RT within the STAMPEDE "M1|RT comparison".

Intervention: The SOC was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December 2015. Men allocated RT received either a daily or a weekly schedule that was nominated before randomisation.

Outcome Measurements And Statistical Analysis: Baseline bone scans were evaluated retrospectively to calculate aBSI. We used overall (OS) and failure-free (FFS) survival as the end points. Treatment-aBSI interaction was evaluated using the multivariable fractional polynomial interaction (MFPI) and subpopulation treatment effect pattern plot. Further analysis was done in aBSI quartiles using Cox regression models adjusted for stratification factors.

Results And Limitations: Baseline bone scans for 660 (SOC: 323 and SOC + RT: 337) of 2061 men randomised within the "M1|RT comparison" met the software requirements for aBSI calculation. The median age was 68 yr, median PSA was 100 ng/mL, median aBSI was 0.9, and median follow-up was 39 mo. Baseline patient characteristics including aBSI were balanced between the treatment groups. Using the MFPI procedure, there was evidence of aBSI-treatment interaction for OS (p = 0.04, MFPI procedure) and FFS (p <  0.01, MFPI procedure). Graphical evaluation of estimated treatment effect plots showed that the OS and FFS benefit from prostate RT was greatest in patients with a low aBSI. Further analysis in quartiles based on aBSI supported this finding.

Conclusions: A low automated bone scan index is predictive of survival benefit associated with prostate RT in men with newly diagnosed metastatic prostate cancer.

Patient Summary: The widely used bone scan can be evaluated using an automated technique to potentially select men with newly diagnosed metastatic prostate cancer who might benefit from prostate radiotherapy.
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http://dx.doi.org/10.1016/j.euo.2020.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443695PMC
August 2020

Fluid intake and clinicopathological characteristics of bladder cancer: the West Midlands Bladder Cancer Prognosis Programme.

Eur J Cancer Prev 2020 03;29(2):110-118

Departments of Complex Genetics, NUTRIM School for Nutrition and Translational Research in Metabolism.

Objective: Between 10 and 20% of bladder cancer patients who are diagnosed with nonmuscle-invasive bladder cancer will progress to muscle-invasive disease. Risk of progression depends on several factors at diagnosis including age, tumour stage, grade, size and number, and the presence or absence of carcinoma in situ. Fluid intake may be related to these factors.

Methods: Data of 1123 participants from the West Midlands Bladder Cancer Prognosis Programme were used. Data collection was via a semistructured questionnaire, and case report forms were used to collect clinicopathological data. Fluid intake was measured for six main categories: alcoholic fluids, hot fluids, fruit fluids, milk, fizzy drinks, and water, and converted into quintile variables. Multilevel mixed-effects linear regression was performed for every beverage category per clinicopathological variable and corrected for age, gender, and smoking status.

Results: Age at diagnosis was distributed differently amongst those in different total fluid intake quintiles (predicted means 71.5, 70.9, 71.5, 69.9, and 67.4, respectively) and showed a significant inverse linear trend in alcohol (P < 0.01), hot fluids (P < 0.01), and total fluids intake (P < 0.01), in nonmuscle-invasive bladder cancer patients.

Conclusion: Our results suggest an inverse association for alcohol intake and total fluid intake with age at diagnosis. These results should be confirmed by future studies, alongside a possible (biological) mechanism that could influence tumour growth, and the effect of micturition frequency.
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http://dx.doi.org/10.1097/CEJ.0000000000000525DOI Listing
March 2020

Isoform Expression Associated with Outcome Following Radiotherapy in Muscle-Invasive Bladder Cancer does not Alter Cell Survival and DNA Double-Strand Break Repair Following Ionising Radiation.

Bladder Cancer 2019 Aug 16;5(2):147-157. Epub 2019 Aug 16.

CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.

Background: DNA double strand breaks are the cytotoxic lesions produced by ionising radiation. Critical for the repair of these lesions is the DNA damage response protein MRE11 which, in a complex with RAD50 and NBS1, mediates DNA damage signalling and double-strand break repair. We previously found the presence of an germline single nucleotide polymorphism (SNP), rs1805363 ( > A), to be associated with poor outcome following radiotherapy (RT) and increased expression of isoform 2 in a limited panel of bladder cancer cell lines and tumours.

Objectives: To look for further evidence in support of the SNP/isoform association in a larger panel of germline and tumour samples donated by patients diagnosed with invasive bladder cancer, and to test the hypothesis that bladder cancer cells expressing isoform 2 would be more radio resistant than cells expressing isoform 1.

Methods: Germline DNA from 189 patients with invasive bladder cancer (141 T2, 48 T1) was genotyped for the rs1805363  > A SNP. Loss of heterozygosity was determined by genotyping tumour DNA in 17GA germline patients. The Cancer Genome Atlas was mined to correlate presence of the GA germline genotype with MRE11 isoform expression. We used colony formation assays and H2AX foci kinetics after ionising radiation in RT112 MRE11 knockdown cells expressing ectopic isoform 1 or 2.

Results: Of the 189 germline DNA samples, 22 contained both the A minor allele and G major allele with the remaining wild type containing only the G major allele. LOH was identified in seven of 17 available tumour samples. Tumour isoform 2 expression was found to be significantly higher ( = 0.007) in patients's samples containing the A minor allele compared to those with only the G major allele ( = 23). In the TCGA database we found 16% (66 out of 406) of bladder tumours heterozygous for the SNP and only two homozygous, and a significant relative increase of isoform 2 usage ( = 0.017). We identified no significant difference in radio sensitivity between bladder cancer cells expressing either isoform.

Conclusions: In this study the isoform 2 was not found to be associated with increased cellular sensitivity to radiation. We conclude that the previously reported association between the germline rs1805363 SNP and poor survival in MIBC patients following RT is unlikely to be related to the DNA damage response function of isoform 2.
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http://dx.doi.org/10.3233/BLC-190209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949534PMC
August 2019

High-intensity Focused Ultrasound for the Treatment of Prostate Cancer: A National Cohort Study Focusing on the Development of Stricture and Fistulae.

Eur Urol Focus 2021 03 7;7(2):340-346. Epub 2020 Jan 7.

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. Electronic address:

Background: High-intensity focused ultrasound (HIFU) is a novel therapy for prostate cancer. Owing to a lack of long-term data, HIFU is recommended for use only in the context of research.

Objective: To examine the trend for HIFU use nationally and rates of strictures and fistulae.

Design, Setting, And Participants: Patients undergoing HIFU for prostate cancer between April 2007 and March 2018 were studied in an English national database (Hospital Episode Statistics). Data on complications were included for patients with a minimum of 1-yr follow-up. Analysis of complications was controlled for other interventions.

Outcome Measures And Statistical Analysis: Descriptive analyses of HIFU rates and the incidence of strictures and fistulae were carried out. Cox and logistic regression models were built for urethral stricture incidence.

Results And Limitations: A total of 2320 HIFU treatments among 1990 patients were identified. The median age was 67yr (interquartile range 61-72). Some 1742 patients met the criteria for follow-up analysis. The highest-volume centre performed 1513 HIFU procedures, followed by 194 at the second highest. The number of HIFU procedures increased annually, rising from 196 to 283 per year. There were 208 patients (11.9%) who went on to have radiotherapy and 102 (5.9%) radical prostatectomy after HIFU. Following HIFU, stricture developed in 133/1290 patients (10.3%) and urinary fistula in 16/1240 (1.3%) before any further intervention. More recent years for HIFU were associated with a lower likelihood of stricture formation (2016/2017 vs 2007/2008: hazard ratio 0.30, 95% confidence interval 0.11-0.79; p=0.015). Limitations include the lack of staging information and unknown rates of HIFU outside of publicly funded health care.

Conclusions: HIFU is performed at a large number of low-volume centres and complication rates do not differ from those for established therapies.

Patient Summary: This report highlights the trend for provision of high-intensity focused ultrasound treatment for prostate cancer in England. The results suggest that the rate of urethral structural complications may not be lower than that for established prostate cancer treatments.
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http://dx.doi.org/10.1016/j.euf.2019.11.014DOI Listing
March 2021

Patient-reported Quality of Life Outcomes in Patients Treated for Muscle-invasive Bladder Cancer with Radiotherapy ± Chemotherapy in the BC2001 Phase III Randomised Controlled Trial.

Eur Urol 2020 02 13;77(2):260-268. Epub 2019 Dec 13.

University of Birmingham, Birmingham, UK; University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

Background: BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer, demonstrated improvement of local control and bladder cancer-specific survival from the addition of concomitant 5-fluorouracil and mitomycin C to radiotherapy.

Objective: To determine the impact of treatment on the health-related quality of life (HRQoL) of BC2001 participants.

Design, Setting, And Participants: 458 UK patients with T2-T4a N0 M0 transitional cell carcinoma of the bladder.

Intervention: Patients were randomised to the chemotherapy comparison (radiotherapy, 178, or chemoradiotherapy, 182); and/or to the radiotherapy comparison (standard, 108, or reduced high-dose volume radiotherapy, 111).

Outcome Measurements And Statistical Analysis: Patients completed Functional Assessment of Cancer Therapy-Bladder (FACT-BL) questionnaires at baseline, end of treatment (EoT), and 6, 12, 24, 36, 48, and 60 months after radiotherapy. The primary endpoint was change from baseline in the bladder cancer subscale (BLCS) at 12 months.

Results And Limitations: Data were available for 331 (92%) and 204 (93%) participants at baseline and for 192 (54%) and 114 (52%) at 12 months for the chemotherapy and radiotherapy comparisons, respectively. HRQoL declined at EoT (BLCS -5.06 [99% confidence interval: -6.12 to -4.00, p< 0.001]; overall FACT-B TOTAL score -8.22 [-10.76 to -5.68, p< 0.01]), recovering to baseline at 6 months and remaining similar to baseline subsequently. There was no significant difference between randomised groups at any time point.

Conclusions: Immediately following (chemo)radiotherapy, a significant proportion of patients report declines in HRQoL, which improve to baseline after 6 months. Two-thirds of patients report stable or improved HRQoL on long-term follow-up. There is no evidence of impairment in HRQoL resulting from the addition of chemotherapy.

Patient Summary: Quality of life of bladder cancer patients treated with radiotherapy±chemotherapy deteriorates during treatment, but improves to at least pretreatment levels within 6 months. Addition of chemotherapy to radiotherapy does not affect patient-reported quality of life.
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http://dx.doi.org/10.1016/j.eururo.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983941PMC
February 2020

Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes: A Meta-analysis of Individual Patient Data From Randomized Clinical Trials.

JAMA Oncol 2020 02;6(2):206-216

Université Paris Sud, Orsay, France.

Importance: Both α-emitting and β-emitting bone-targeted radioisotopes (RIs) have been developed to treat men with metastatic castration-resistant prostate cancer (CRPC). Only 1 phase 3 randomized clinical trial has demonstrated an overall survival (OS) benefit from an α-emitting RI, radium 223 (223Ra), vs standard of care. Yet no head-to-head comparison has been done between α-emitting and β-emitting RIs.

Objective: To assess OS in men with bone metastases from CRPC treated with bone-targeted RIs and to compare the effects of α-emitting RIs with β-emitting RIs.

Data Sources: PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings between January 1993 and June 2013 were reviewed. Key terms included randomized trials, radioisotopes, radiopharmaceuticals, and prostate cancer. Data were collected, checked, and analyzed from February 2017 to October 2018.

Study Selection: Selected trials included patients with prostate cancer, recruited more than 50 patients from January 1993 to June 2013, compared RI use with no RI use (placebo, external radiotherapy, or chemotherapy), and were randomized. Patients were diagnosed with histologically proven prostate cancer and disease progression after both surgical or chemical castration and have evidence of bone metastasis. Nine randomized clinical trials were identified as eligible, but 3 were excluded for insufficient data.

Data Extraction And Synthesis: Individual patient data were requested for each eligible trial, and all data were checked with a standard procedure. The log-rank test stratified by trial was used to estimate hazard ratios (HRs), and a similar fixed-effects (FE) model was used to estimate odds ratios (ORs). The between-trial heterogeneity of treatment effects was evaluated by Cochran test and I2 and was accounted by a random-effects (RE) model.

Main Outcomes And Measures: Overall survival; secondary outcomes were symptomatic skeletal event (SSE)-free survival and adverse events.

Results: Based on 6 randomized clinical trials including 2081 patients, RI use was significantly associated with OS compared with no RI use (HR, 0.86; 95% CI, 0.77-0.95; P = .004) with high heterogeneity (χ25 = 24.46; P < .001; I2 = 80%), but this association disappeared when using an RE model (HR, 0.80; 95% CI, 0.61-1.06; P = .12; τ2 = 0.08). The heterogeneity is explained both by the type of RI and by the inclusion of 2 outlier trials that included 275 patients; the OS benefit was significantly higher with the α-emitting RI 223Ra (HR, 0.70; 95% CI, 0.58-0.83) but not significant with the β-emitting RI strontium-89 (HR, 0.96; 95% CI, 0.84-1.10) (P for interaction = .004). Excluding the outlier trials led to an overall HR of 0.82 (95% CI, 0.73-0.92; P < .001) (between-trial heterogeneity: χ23 = 6.51; P = .09; I2 = 54%) using an FE model and an HR of 0.80 (95% CI, 0.65-0.99; P = .04; τ2 = 0.02) using an RE model. The HR for SSE-free survival was 0.81 (95% CI, 0.69-0.93; P = .004) (between-trial heterogeneity: χ23 = 6.71; P = .08; I2 = 55%) when using an FE model and was 0.76 (95% CI, 0.58-1.01; P = .06; τ2 = 0.04) when using an RE model. There were more hematological toxic effects with RI use compared with no RI use (OR, 1.48; 95% CI, 1.17-1.88; P = .001).

Conclusions And Relevance: In metastatic CRPC, a significant improvement of OS and SSE-free survival was obtained with bone-targeted α-emitting but not β-emitting RIs. Caution is necessary for generalizability of these results, given the between-trial heterogeneity.
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http://dx.doi.org/10.1001/jamaoncol.2019.4097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990736PMC
February 2020

Radiotherapy for metastatic prostate cancer-Authors' reply.

Lancet 2019 09;394(10201):830

Medical Research Council Clinical Trials Unit at University College London, London, UK.

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http://dx.doi.org/10.1016/S0140-6736(19)31829-XDOI Listing
September 2019

Abiraterone in "High-" and "Low-risk" Metastatic Hormone-sensitive Prostate Cancer.

Eur Urol 2019 12 23;76(6):719-728. Epub 2019 Aug 23.

The Christie and Royal Salford Hospitals, Manchester, UK; Genito Urinary Cancer Research Group and the FASTMAN Centre of Excellence, Division of Cancer Sciences, The University of Manchester, Manchester, UK. Electronic address:

Background: Abiraterone acetate received licencing for use in only "high-risk" metastatic hormone-naïve prostate cancer (mHNPC) following the LATITUDE trial findings. However, a "risk"-related effect was not seen in the STAMPEDE trial. There remains uncertainty as to whether men with LATITUDE "low-risk" M1 disease benefit from androgen deprivation therapy (ADT) combined with abiraterone acetate and prednisolone (AAP).

Objective: Evaluation of heterogeneity of effect between LATITUDE high- and low-risk M1 prostate cancer patients receiving ADT + AAP in the STAMPEDE trial.

Design, Setting, And Participants: A post hoc subgroup analysis of the 2017 STAMPEDE "abiraterone comparison". Staging scans for M1 patients contemporaneously randomised to ADT or ADT + AAP within the STAMPEDE trial were evaluated centrally and blind to treatment assignment. Stratification was by risk according to the criteria set out in the LATITUDE trial. Exploratory subgroup stratification incorporated the CHAARTED criteria.

Outcome Measurements And Statistical Analysis: The primary outcome measure was overall survival (OS) and the secondary outcome measure was failure-free survival (FFS). Further exploratory analysis evaluated clinical skeletal-related events, progression-free survival (PFS), and prostate cancer-specific death. Standard Cox-regression and Kaplan-Meier survival estimates were employed for analysis.

Results And Limitations: A total of 901 M1 STAMPEDE patients were evaluated after exclusions. Of the patients, 428 (48%) were identified as having a low risk and 473 (52%) a high risk. Patients receiving ADT + AAP had significantly improved OS (low-risk hazard ratio [HR]: 0.66, 95% confidence interval or CI [0.44-0.98]) and FFS (low-risk HR: 0.24, 95% CI [0.17-0.33]) compared with ADT alone. Heterogeneity of effect was not seen between low- and high-risk groups for OS or FFS. For OS benefit in low risk, the number needed to treat was four times greater than that for high risk. However, this was not observed for the other measured endpoints.

Conclusions: Men with mHNPC gain treatment benefit from ADT + AAP irrespective of risk stratification for "risk" or "volume".

Patient Summary: Coadministration of abiraterone acetate and prednisolone with androgen deprivation therapy (ADT) is associated with prolonged overall survival and disease control, compared with ADT alone, in all men with metastatic disease starting hormone therapy for the first time.
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http://dx.doi.org/10.1016/j.eururo.2019.08.006DOI Listing
December 2019
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