Publications by authors named "Syed A Hussain"

104 Publications

Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial.

Eur Urol 2022 May 13. Epub 2022 May 13.

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

Background: BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer (MIBC), demonstrated improvement in locoregional control by adding fluorouracil and mitomycin C to radiotherapy (James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477-88). There are limited data on long-term recurrence risk.

Objective: To determine whether benefit of adding chemotherapy to radiotherapy for MIBC is maintained in the long term.

Design, Setting, And Participants: A phase 3 randomised controlled 2 × 2 factorial trial was conducted. Between 2001 and 2008, 458 patients with T2-T4a N0M0 MIBC were enrolled; 360 were randomised to radiotherapy (178) or chemoradiotherapy (182), and 218 were randomised to standard whole-bladder radiotherapy (108) or reduced high-dose-volume radiotherapy (111). The median follow-up time was 9.9 yr. The trial is registered (ISRCTN68324339).

Intervention: Radiotherapy: 55 Gy in 20 fractions over 4 wk or 64 Gy in 32 fractions over 6.5 wk; concurrent chemotherapy: 5-fluorouracil and mitomycin C.

Outcome Measurements And Statistical Analysis: Locoregional control (primary endpoint), invasive locoregional control, toxicity, rate of salvage cystectomy, disease-free survival (DFS), metastasis-free survival (MFS), bladder cancer-specific survival (BCSS), and overall survival. Cox regression was used. The analysis of efficacy outcomes was by intention to treat.

Results And Limitations: Chemoradiotherapy improved locoregional control (hazard ratio [HR] 0.61 [95% confidence interval {CI} 0.43-0.86], p = 0.004) and invasive locoregional control (HR 0.55 [95% CI 0.36-0.84], p = 0.006). This benefit translated, albeit nonsignificantly, for disease-related outcomes: DFS (HR 0.78 [95% CI 0.60-1.02], p = 0.069), MFS (HR 0.78, [95% CI 0.58-1.05], p = 0.089), overall survival (HR = 0.88 [95% CI 0.69-1.13], p = 0.3), and BCSS (HR 0.79 [95% CI 0.59-1.06], p = 0.11). The 5-yr cystectomy rate was 14% (95% CI 9-21%) with chemoradiotherapy versus 22% (95% CI 16-31%) with radiotherapy alone (HR 0.54, [95% CI 0.31-0.95], p = 0.034). No differences were seen between standard and reduced high-dose-volume radiotherapy.

Conclusions: Long-term findings confirm the benefit of adding concomitant 5-fluorouracil and mitomycin C to radiotherapy for MIBC.

Patient Summary: We looked at long-term outcomes of a phase 3 clinical trial testing radiotherapy with or without chemotherapy for patients with invasive bladder cancer. We concluded that the benefit of adding chemotherapy to radiotherapy was maintained over 10 yr.
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http://dx.doi.org/10.1016/j.eururo.2022.04.017DOI Listing
May 2022

Effect of Robot-Assisted Radical Cystectomy With Intracorporeal Urinary Diversion vs Open Radical Cystectomy on 90-Day Morbidity and Mortality Among Patients With Bladder Cancer: A Randomized Clinical Trial.

JAMA 2022 May 15. Epub 2022 May 15.

Division of Surgery and Interventional Science, University College London, London, England.

Importance: Robot-assisted radical cystectomy is being performed with increasing frequency, but it is unclear whether total intracorporeal surgery improves recovery compared with open radical cystectomy for bladder cancer.

Objectives: To compare recovery and morbidity after robot-assisted radical cystectomy with intracorporeal reconstruction vs open radical cystectomy.

Design, Setting, And Participants: Randomized clinical trial of patients with nonmetastatic bladder cancer recruited at 9 sites in the UK, from March 2017-March 2020. Follow-up was conducted at 90 days, 6 months, and 12 months, with final follow-up on September 23, 2021.

Interventions: Participants were randomized to receive robot-assisted radical cystectomy with intracorporeal reconstruction (n = 169) or open radical cystectomy (n = 169).

Main Outcomes And Measures: The primary outcome was the number of days alive and out of the hospital within 90 days of surgery. There were 20 secondary outcomes, including complications, quality of life, disability, stamina, activity levels, and survival. Analyses were adjusted for the type of diversion and center.

Results: Among 338 randomized participants, 317 underwent radical cystectomy (mean age, 69 years; 67 women [21%]; 107 [34%] received neoadjuvant chemotherapy; 282 [89%] underwent ileal conduit reconstruction); the primary outcome was analyzed in 305 (96%). The median number of days alive and out of the hospital within 90 days of surgery was 82 (IQR, 76-84) for patients undergoing robotic surgery vs 80 (IQR, 72-83) for open surgery (adjusted difference, 2.2 days [95% CI, 0.50-3.85]; P = .01). Thromboembolic complications (1.9% vs 8.3%; difference, -6.5% [95% CI, -11.4% to -1.4%]) and wound complications (5.6% vs 16.0%; difference, -11.7% [95% CI, -18.6% to -4.6%]) were less common with robotic surgery than open surgery. Participants undergoing open surgery reported worse quality of life vs robotic surgery at 5 weeks (difference in mean European Quality of Life 5-Dimension, 5-Level instrument scores, -0.07 [95% CI, -0.11 to -0.03]; P = .003) and greater disability at 5 weeks (difference in World Health Organization Disability Assessment Schedule 2.0 scores, 0.48 [95% CI, 0.15-0.73]; P = .003) and at 12 weeks (difference in WHODAS 2.0 scores, 0.38 [95% CI, 0.09-0.68]; P = .01); the differences were not significant after 12 weeks. There were no statistically significant differences in cancer recurrence (29/161 [18%] vs 25/156 [16%] after robotic and open surgery, respectively) and overall mortality (23/161 [14.3%] vs 23/156 [14.7%]), respectively) at median follow-up of 18.4 months (IQR, 12.8-21.1).

Conclusions And Relevance: Among patients with nonmetastatic bladder cancer undergoing radical cystectomy, treatment with robot-assisted radical cystectomy with intracorporeal urinary diversion vs open radical cystectomy resulted in a statistically significant increase in days alive and out of the hospital over 90 days. However, the clinical importance of these findings remains uncertain.

Trial Registration: ISRCTN Identifier: ISRCTN13680280; ClinicalTrials.gov Identifier: NCT03049410.
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http://dx.doi.org/10.1001/jama.2022.7393DOI Listing
May 2022

Disparities in Representation of Women, Older Adults and Racial/Ethnic Minorities in Immune Checkpoint Inhibitor Trials.

Am J Med 2022 Apr 25. Epub 2022 Apr 25.

Mayo Clinic,Phoenix, AZ.

Purpose: We aim to describe reporting and representation of minority patient populations in immune checkpoint inhibitor (ICI) clinical trials and assess predictors of enrollment disparity.

Methods: Trial-level data were acquired from eligible phase II/III trials. Population-based estimates were acquired from the SEER 18 and Global Burden of Disease incidence databases. Trials reporting race, age, and sex were summarized using descriptive statistics. Enrollment-incidence ratio (EIR) was used to assess representation of subgroups. Average annual percentage change (AAPC) in EIR was calculated using Joinpoint Regression Analysis. Trial-level characteristics associated with EIR were assessed using multivariable linear regression.

Results: 107 trials with 48,095 patients were identified. Participation of Black, White, Asian, Native American, Pacific Islander and Hispanic participants was reported in 65 (61%), 77 (72%), 68 (64%), 40 (37%) and 24 trials (22%) respectively. Subgroup analyses of clinical outcomes by race, age and sex were reported in 17 (22%), 62 (78%) and 57 (57%) trials respectively. Women (trial proportion [TP]: 32%; EIR: 0.90 [95% CI: 0.84-0.96]), patients aged ≥65 years (TP: 42%; EIR: 0.78 [95% CI: 0.72-0.84]), Black participants (TP: 1.9%; EIR: 0.17 [95% CI: 0.13-0.22]) and Hispanics (TP: 5.9%; EIR: 0.67 [95% CI: 0.53-0.82]) were underrepresented. Representation of Black patients decreased significantly from 2009-2020 (APC: -23.13). Black participants were significantly underrepresented in phase III trials (p<0.001).

Conclusion: The reporting of participation by racial/ethnic subgroup categories is inadequate and women, older adults, and racial/ethnic minorities are significantly underrepresented in ICI clinical trials.
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http://dx.doi.org/10.1016/j.amjmed.2022.03.042DOI Listing
April 2022

Addition of nintedanib or placebo to neoadjuvant gemcitabine and cisplatin in locally advanced muscle-invasive bladder cancer (NEOBLADE): a double-blind, randomised, phase 2 trial.

Lancet Oncol 2022 May 11;23(5):650-658. Epub 2022 Apr 11.

University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.

Background: Recurrence is common after neoadjuvant chemotherapy and radical treatment for muscle-invasive bladder cancer. We investigated the effect of adding nintedanib to neoadjuvant chemotherapy on response and survival in muscle-invasive bladder cancer.

Methods: NEOBLADE was a parallel-arm, double-blind, randomised, placebo-controlled, phase 2 trial of neoadjuvant gemcitabine and cisplatin chemotherapy with nintedanib or placebo in locally advanced muscle-invasive bladder cancer. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 15 hospitals in the UK. Patients were randomly assigned (1:1) to nintedanib or placebo using permuted blocks with random block sizes of two or four, stratified by centre and glomerular filtration rate. Treatments were allocated using an interactive web-based system, and patients and investigators were masked to treatment allocation throughout the study. Patients received oral nintedanib (150 mg or 200 mg twice daily for 12 weeks) or placebo, in addition to usual neoadjuvant chemotherapy with intravenous gemcitabine 1000 mg/m on days 1 and 8 and intravenous cisplatin 70 mg/m on day 1 of a 3-weekly cycle. The primary endpoint was pathological complete response rate, assessed at cystectomy or at day 8 of cyclde 3 (plus or minus 7 days) if cystectomy did not occur. Primary analyses were done in the intention-to-treat population. The trial is registered with EudraCT, 2012-004895-01, and ISRCTN, 56349930, and has completed planned recruitment.

Findings: Between Dec 4, 2014, and Sept 3, 2018, 120 patients were recruited and were randomly allocated to receive nintedanib (n=57) or placebo (n=63). The median follow-up for the study was 33·5 months (IQR 14·0-44·0). Pathological complete response in the intention-to-treat population was reached in 21 (37%) of 57 patients in the nintedanib group and 20 (32%) of 63 in the placebo group (odds ratio [OR] 1·25, 70% CI 0·84-1·87; p=0·28). Grade 3 or worse toxicities were observed in 53 (93%) of 57 participants who received nintedanib and 50 (79%) of 63 patients in the placebo group (OR 1·65, 95% CI 0·74-3·65; p=0·24). The most common grade 3 or worse adverse events were thromboembolic events (17 [30%] of 57 patients in the nintedanib group vs 13 [21%] of 63 patients in the placebo group [OR 1·63, 95% CI 0·71-3·76; p=0·29]) and decreased neutrophil count (22 [39%] in the nintedanib group vs seven [11%] in the placebo group [5·03, 1·95-13·00; p=0·0006]). 45 treatment-related serious adverse events occurred in the nintedanib group and 43 occurred in the placebo group. One treatment-related death occurred in the placebo group, which was due to myocardial infarction.

Interpretation: The addition of nintedanib to chemotherapy was safe but did not improve the rate of pathological complete response in muscle-invasive bladder cancer.

Funding: Boehringer Ingelheim.
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http://dx.doi.org/10.1016/S1470-2045(22)00158-9DOI Listing
May 2022

Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial.

Nat Commun 2022 Apr 6;13(1):1878. Epub 2022 Apr 6.

David Geffen School of Medicine, Division of Hematology and Oncology, UCLA, Los Angeles, CA, USA.

The RANGE study (NCT02426125) evaluated ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with platinum-refractory advanced urothelial carcinoma (UC). Here, we use programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) and transcriptome analysis to evaluate the association of immune and angiogenesis pathways, and molecular subtypes, with overall survival (OS) in UC. Higher PD-L1 IHC and immune pathway scores, but not angiogenesis scores, are associated with greater ramucirumab OS benefit. Additionally, Basal subtypes, which have higher PD-L1 IHC and immune/angiogenesis pathway scores, show greater ramucirumab OS benefit compared to Luminal subtypes, which have relatively lower scores. Multivariable analysis suggests patients from East Asia as having lower immune/angiogenesis signature scores, which correlates with decreased ramucirumab OS benefit. Our data highlight the utility of multiple biomarkers including PD-L1, molecular subtype, and immune phenotype in identifying patients with UC who might derive the greatest benefit from treatment with ramucirumab.
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http://dx.doi.org/10.1038/s41467-022-29441-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987042PMC
April 2022

Association Between 1958G > A Variant and non-Syndromic Cleft lip and Palate: An Updated Meta-Analysis.

Cleft Palate Craniofac J 2021 Dec 14:10556656211046486. Epub 2021 Dec 14.

Department of Plastic Surgery, Sri Ramachandra Institute of Higher Education and Research, Chennai, India.

Introduction: Non-syndromic cleft lip and palate (NSCLP) is one of the most common and challenging congenital deformities worldwide. Previous research has linked the methylenetetrahydrofolate dehydrogenase1 (MTHFD1) gene to orofacial cleft (OFC) susceptibility via a complex metabolism. Studies analyzing the 1958G > A variant and NSCLP are contradictory. This study aims to evaluate the association between the 1958G > A variant and NSCLP by meta-analysis.

Methods: PubMed, Web of Science, MEDLINE, and Google Scholar databases were searched to retrieve the eligible studies. A fixed- or random-effect model was used to calculate pooled odds ratio (OR) and 95% confidence interval (CI). All analyses were calculated by Metagenyo software. To detect heterogeneity, the Cochrane Q and I statistics were used. The publication bias was estimated using funnel plots and Egger's test.

Results: Our study suggested that the 1958G > A variant allele "A" does not appear to increase the risk of NSCLP (A vs G random effect model: Overall   = .501, OR  =  1.07, CI  =  0.88-1.31; Asians   = .245, OR  =  1.29, CI  =  0.84-1.97; Caucasians   = .658, OR  =  0.95, CI  =  0.76-1.19). Similarly, mutant genotypes also did not exhibit increased risk for NSCLP in the overall populations as well in subgroup analysis by ethnicity (AA  +  AG vs GG: Overall   = .684, OR  =  1.06, CI  =  0.80-1.39; Asians   = .240, OR  =  1.47, CI  =  0.77-2.78; Caucasians   = .923, OR  =  0.99, CI  =  0.85-1.16).

Conclusions: Our data suggest no association between the 1958G > A variant and NSCLP. Additional well-designed studies are needed to better understand the role of polymorphisms in the etiopathogenesis of NSCLP.
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http://dx.doi.org/10.1177/10556656211046486DOI Listing
December 2021

Bladder cancer: shedding light on the most promising investigational drugs in clinical trials.

Expert Opin Investig Drugs 2021 Aug 14;30(8):837-855. Epub 2021 Jul 14.

Department of Oncology and Metabolism, Academic Unit of Oncology, University of Sheffield Medical School, Sheffield, UK.

: Urothelial cancers (UC) include tumors of the bladder, upper tract, and proximal urethra. Bladder cancer (BC) arises from urothelial cells lining the bladder and accounts for 90-95% of UC. BC is responsible for approximately 500,000 new cases and has a dismal prognosis with 200,000 deaths annually globally. However, immune checkpoint inhibitors (ICIs) and antibody-drug conjugates are rapidly changing the treatment landscape. Novel therapies are building on this success and are being intensively investigated in clinical trials.: This paper examines the clinical trial data by searching Medline through January 2021 and clinicaltrials.gov and conference proceedings from the latest ASCO and ESMO meetings. We summarize the emerging data from clinical trials and offer insights into mechanisms of novel agents, nuances in clinical trial designs, and future directions.: Approval of multiple ICIs, Enfortumab Vedotin (EV), Erdatfitinib and switch maintenance strategy with Avelumab, represent major advances in metastatic disease. ICI agents and EV are well poised to move forward for treating the early stages of bladder cancer. Finally, molecular characterization of the tumor offers hope for personalized treatment approaches.
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http://dx.doi.org/10.1080/13543784.2021.1948999DOI Listing
August 2021

Clinical Outcomes of Platinum-ineligible Patients with Advanced Urothelial Carcinoma Treated With First-line PD1/L1 Inhibitors.

Clin Genitourin Cancer 2021 10 20;19(5):425-433. Epub 2021 Apr 20.

Dana-Farber Cancer Institute, Boston, MA. Electronic address:

Background: PD1/L1 inhibitors are approved by FDA as first-line therapy for patients with advanced urothelial carcinoma (aUC) who are cisplatin-ineligible with high tumor PD-L1 expression or are platinum-ineligible regardless of PD-L1 expression. However, the outcomes when employing PD1/L1 inhibitors for platinum-ineligible patients are unclear. This retrospective analysis evaluates the clinical outcomes of first-line PD1/L1 inhibitors in patients with aUC deemed to be platinum-ineligible.

Methods: Data were retrospectively collected from 8 academic institutions. The following criteria were used to define platinum ineligibility: creatinine clearance (CrCl) < 30 mL/min; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 3; CrCl 30 to 59 mL/min and ECOG PS 2; elderly and/or comorbidities. Patient characteristics, responses and treatment-related toxicities were identified. Survival curves were estimated by the Kaplan-Meier method. A Cox regression analysis was conducted to explore the association of baseline variables with response and survival.

Results: A total of 79 platinum-ineligible patients with aUC were eligible. Patients were treated with atezolizumab (51.9%), pembrolizumab (35.5%), nivolumab (8.9%), or durvalumab (3.8%). The objective response rate was 27.9%. The median overall survival was 45 weeks (95% confidence interval [CI], 32-80), and the median treatment failure-free survival was 16 weeks (95% CI, 9-18). Treatment-related toxicity of any grade and grade ≥ 3 was seen in 41.8% and 31.7% of patients, respectively. Anemia and liver metastasis were associated with worse survival.

Conclusion: The efficacy of first-line PD1/L1 inhibitors for platinum-ineligible patients with aUC in the real world appears comparable to those reported in trials of unselected cisplatin-ineligible patients, whereas grade ≥ 3 toxicities appear more common. Further validation is required including data based on PD-L1 status and other biomarkers. Platinum-ineligible patients with aUC warrant evaluation of novel, safe, and effective agents.
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http://dx.doi.org/10.1016/j.clgc.2021.04.008DOI Listing
October 2021

A Living, Interactive Systematic Review and Network Meta-analysis of First-line Treatment of Metastatic Renal Cell Carcinoma.

Eur Urol 2021 Dec 3;80(6):712-723. Epub 2021 Apr 3.

Mayo Clinic, Rochester, MN, USA.

Context: Identifying the most effective first-line treatment for metastatic renal cell carcinoma (mRCC) is challenging as rapidly evolving data quickly outdate the existing body of evidence, and current approaches to presenting the evidence in user-friendly formats are fraught with limitations.

Objective: To maintain living evidence for contemporary first-line treatment for previously untreated mRCC.

Evidence Acquisition: We have created a living, interactive systematic review (LISR) and network meta-analysis for first-line treatment of mRCC using data from randomized controlled trials comparing contemporary treatment options with single-agent tyrosine kinase inhibitors. We applied an advanced programming and artificial intelligence-assisted framework for evidence synthesis to create a living search strategy, facilitate screening and data extraction using a graphical user interface, automate the frequentist network meta-analysis, and display results in an interactive manner.

Evidence Synthesis: As of October 22, 2020, the LISR includes data from 14 clinical trials. Baseline characteristics are summarized in an interactive table. The cabozantinib + nivolumab combination (CaboNivo) is ranked the highest for the overall response rate, progression-free survival, and overall survival, whereas ipilimumab + nivolumab (NivoIpi) is ranked the highest for achieving a complete response (CR). NivoIpi, and atezolizumab + bevacizumab (AteBev) were ranked highest (lowest toxicity) and CaboNivo ranked lowest for treatment-related adverse events (AEs). Network meta-analysis results are summarized as interactive tables and plots, GRADE summary-of-findings tables, and evidence maps.

Conclusions: This innovative living and interactive review provides the best current evidence on the comparative effectiveness of multiple treatment options for patients with untreated mRCC. Trial-level comparisons suggest that CaboNivo is likely to cause more AEs but is ranked best for all efficacy outcomes, except NivoIpi offers the best chance of CR. Pembrolizumab + axitinib and NivoIpi are acceptable alternatives, except NivoIpi may not be preferred for patients with favorable risk. Although network meta-analysis provides rankings with statistical adjustments, there are inherent biases in cross-trial comparisons with sparse direct evidence that does not replace randomized comparisons.

Patient Summary: It is challenging to decide the best option among the several treatment combinations of immunotherapy and targeted treatments for newly diagnosed metastatic kidney cancer. We have created interactive evidence summaries of multiple treatment options that present the benefits and harms and evidence certainty for patient-important outcomes. This evidence is updated as soon as new studies are published.
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http://dx.doi.org/10.1016/j.eururo.2021.03.016DOI Listing
December 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

A baseline quantitative assessment of deep-sea benthic fauna of the Gulf of Aqaba (Northern Saudi Arabia, Red Sea).

Mar Pollut Bull 2021 Mar 27;164:112028. Epub 2021 Jan 27.

Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, P. B. No. 391, Dhahran 31261, Saudi Arabia; Deputy-Ministry for Environment, Ministry of Environment, Water and Agriculture, Riyadh, Saudi Arabia.

The Gulf of Aqaba (hereafter 'the Gulf') is a narrow, semi-enclosed, warm, high saline, and oligotrophic water body. This baseline study provides the first quantitative data on deep-sea (207-1281 m depth) benthos of the Gulf. Fifty-five benthic species (predominantly polychaetes) with a density of 160-670 ind. m, species richness of 11-25, and Shannon-Wiener diversity (H') of 3.14-4.17 bits. ind. were recorded from nine stations. The density and H' of benthos of the Gulf are comparable with those of the Red Sea, while both are lower than those reported from the Arabian Sea and the Mediterranean Sea. The good-high ecological status of benthic communities indicates the absence of major stress in the deep-sea habitats of the Gulf. As large-scale urbanization is proposed in the Saudi coastal areas of the Gulf, this study is expected to provide a baseline dataset for future environmental impact assessments.
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http://dx.doi.org/10.1016/j.marpolbul.2021.112028DOI Listing
March 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

Perioperative Treatment in Muscle-invasive Bladder Cancer: Analysis of Secondary Endpoints in a Randomized Trial Comparing Gemcitabine and Cisplatin Versus Dose-dense Methotrexate, Vinblastine, Adriamycin, and Cisplatin.

Eur Urol 2021 02 2;79(2):222-224. Epub 2020 Oct 2.

Department of Oncology and Metabolism, Academic Unit of Oncology, University of Sheffield Medical School, Sheffield, UK. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2020.09.018DOI Listing
February 2021

Factors Associated with Good Patient Outcomes Following Convalescent Plasma in COVID-19: A Prospective Phase II Clinical Trial.

Infect Dis Ther 2020 Dec 20;9(4):913-926. Epub 2020 Sep 20.

Trinity Health of New England, Hartford, CT, USA.

Introduction: Coronavirus disease 2019 (COVID-19) is a viral respiratory syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This novel virus was discovered in Wuhan City, Hubei Province, China, in December 2019. As of September 6, 2020, confirmed cases have risen to more than 27,000,000 worldwide and more than 885,000 people have died. Currently, no cure or standard treatment for COVID-19 exists. We conducted a prospective single-arm open-label phase II clinical trial assessing the safety and efficacy of convalescent plasma in hospitalized patients with COVID-19.

Methods: Convalescent plasma with sufficient total anti-SARS-CoV-2 IgG titer (1:320) obtained from recovered donors was administered to adult patients with either severe or critical COVID-19 illness. Primary outcomes were adverse events in association with plasma administration, and hospital mortality. Secondary outcomes included disease progression, recovery, length of stay, and hospital discharge.

Results: Of the 38 patients included in the analysis, 24 (63%) recovered and were discharged, and 14 (37%) died. Patients who received convalescent plasma early in the disease course (severe illness group) as compared to the patients that received convalescent plasma later in the disease progression (critical illness group) had significantly lower hospital mortality 13% vs 55% (p < 0.02) and shorter mean hospital length of stay 15.4 vs 33 days (p < 0.01). One patient experienced a transient transfusion reaction. No other adverse effects of convalescent plasma infusion were observed.

Conclusions: Our results suggest that convalescent plasma with adequate anti-SARS-CoV-2 antibody titer is safe and has the potential for positive impact on clinical outcomes including recovery and survival if given to patients early in the course of COVID-19 disease.

Trial Registration: ClinicalTrials.gov. Identifier, NCT04343261, IND #19805.
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http://dx.doi.org/10.1007/s40121-020-00341-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502154PMC
December 2020

SARS-CoV-2 serology and virology trends in donors and recipients of convalescent plasma.

Transfus Apher Sci 2020 Dec 25;59(6):102922. Epub 2020 Aug 25.

Trinity Health Of New England, Hartford, CT, United States.

SARS-CoV-2 has infected millions worldwide. The virus is novel, and currently there is no approved treatment. Convalescent plasma may offer a treatment option. We evaluated trends of IgM/IgG antibodies/plasma viral load in donors and recipients of convalescent plasma. 114/139 (82 %) donors had positive IgG antibodies. 46/114 donors tested positive a second time by NP swab. Among those retested, the median IgG declined (p < 0.01) between tests. 25/139 donors with confirmed SARS-CoV-2 were negative for IgG antibodies. This suggests that having had the infection does not necessarily convey immunity, or there is a short duration of immunity associated with a decline in antibodies. Plasma viral load obtained on 35/39 plasma recipients showed 22 (62.9 %) had non-detectable levels on average 14.5 days from positive test versus 6.2 days in those with detectable levels (p < 0.01). There was a relationship between IgG and viral load. IgG was higher in those with non-detectable viral loads. There was no relationship between viral load and blood type (p = 0.87) or death (0.80). Recipients with detectable viral load had lower IgG levels; there was no relationship between viral load, blood type or death.
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http://dx.doi.org/10.1016/j.transci.2020.102922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446657PMC
December 2020

Correction: Inhibitor SBFI26 suppresses the malignant progression of castration-resistant PC3-M cells by competitively binding to oncogenic FABP5.

Oncotarget 2020 Aug 4;11(31):3025. Epub 2020 Aug 4.

Molecular Pathology Laboratory, Department of Molecular and Clinical Cancer Medicine, Liverpool University, Liverpool, L3 9TA, United Kingdom.

[This corrects the article DOI: 10.18632/oncotarget.16055.].
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http://dx.doi.org/10.18632/oncotarget.27690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415401PMC
August 2020

Survey of the Impact of COVID-19 on Oncologists' Decision Making in Cancer.

JCO Glob Oncol 2020 08;6:1248-1257

Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Purpose: To understand readiness measures taken by oncologists to protect patients and health care workers from the novel coronavirus (COVID-19) and how their clinical decision making was influenced by the pandemic.

Methods: An online survey was conducted between March 24 and April 29, 2020.

Results: A total of 343 oncologists from 28 countries participated. The median age was 43 years (range, 29-68 years), and the majority were male (62%). At the time of the survey, nearly all participants self-reported an outbreak in their country (99.7%). Personal protective equipment was available to all participants, of which surgical mask was the most common (n = 308; 90%). Telemedicine, in the form of phone or video encounters, was common and implemented by 80% (n = 273). Testing patients with cancer for COVID-19 via reverse transcriptase polymerase chain reaction before systemic treatment was not routinely implemented: 58% reported no routine testing, 39% performed testing in selected patients, and 3% performed systematic testing in all patients. The most significant factors influencing an oncologist's decision making regarding choice of systemic therapy included patient age and comorbidities (81% and 92%, respectively). Although hormonal treatments and tyrosine kinase inhibitors were considered to be relatively safe, cytotoxic chemotherapy and immune therapies were perceived as being less safe or unsafe by participants. The vast majority of participants stated that during the pandemic they would use less chemotherapy, immune checkpoint inhibitors, and steroids. Although treatment in neoadjuvant, adjuvant, and first-line metastatic disease was less affected, most of the participants stated that they would be more hesitant to recommend second- or third-line therapies in metastatic disease.

Conclusion: Decision making by oncologists has been significantly influenced by the ongoing COVID-19 pandemic.
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http://dx.doi.org/10.1200/GO.20.00300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456315PMC
August 2020

The Impact of Centralised Services on Metric Reflecting High-quality Performance: Outcomes from 1110 Consecutive Radical Cystectomies at a Single Centre.

Eur Urol Focus 2021 May 21;7(3):554-565. Epub 2020 Jun 21.

Academic Urology Unit, University of Sheffield, Sheffield, UK; Department of Urology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. Electronic address:

Background: The 2002 National Institute for Health and Care Excellence guidance on centralisation of radical cystectomy (RC) coincided with changes in practice: use of neoadjuvant chemotherapy (NAC) and pelvic lymph node dissection (PLND), and RC for high-risk non-muscle-invasive bladder cancer (HR-NMIBC).

Objective: To report the outcomes of RC at a single centre and to compare trends in survival with respect to centralisation and change in RC practice.

Design, Setting, And Participants: Data were collected retrospectively between 1 January 1994 and 31 December 2016. Patients with urothelial cell carcinoma (UCC) were selected. Outcomes from 1994 to 2007 (before centralisation, era 1) were compared with those from 2008 to 2016 (after centralisation, era 2).

Outcome Measurements And Statistical Analysis: The primary outcome was disease-specific mortality. Secondary outcomes were survival and use of NAC and PLND.

Results And Limitations: Overall, 1100 RCs (era 1, 316; era 2, 794) were performed for UCC. Median (interquartile range [IQR]) follow-up was 28.5 (11.9-57.4) mo. RC for NMIBC was 36.2% versus 51.3% (p<0.001), NAC use was 2.2% versus 31.6% (p<0.001), and PLND use was 59.7% versus 76.4% (p<0.001) in era 1 versus era 2. The 30-d (1.6% [era 1] vs 0.8% [era 2], p=0.21) and 90-d (4.1% vs 2.6%, p=0.2) mortality rates did not differ with respect to RC year. Five-year disease-specific survival (DSS) was 56.0% in era 1 versus 79.0% in era 2 (p<0.001). RC for patients aged ≥75 yr was 13.9% versus 28.1% (p<0.001) and 30-d mortality in this group was 4.5% versus 0% (p=0.001) in era 1 versus era 2. The study is limited by its retrospective design.

Conclusions: Centralisation was associated with higher rates of NAC and PLND use, and increased RC performed for older patients and patients with HR-NMIBC. DSS was higher and RC appeared to be safer for older patients (fewer postoperative mortalities) after centralisation.

Patient Summary: We looked at outcomes from bladder removal for bladder cancer. Survival outcomes improved following centralisation of services. Surgery appeared to be safer for older patients, as there were fewer postoperative mortalities after centralisation. Centralisation of radical cystectomy (RC) services was associated with higher rates of neoadjuvant chemotherapy and pelvic lymph node dissection use, and increased usage of RC for older patients with high-risk non-muscle-invasive bladder cancer. Survival outcomes from RC were superior after centralisation and safer for older patients undergoing RC (fewer postoperative mortalities).
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http://dx.doi.org/10.1016/j.euf.2020.05.011DOI Listing
May 2021

Optimum Sample Thickness for Trace Analyte Detection with Field-Resolved Infrared Spectroscopy.

Anal Chem 2020 06 13;92(11):7508-7514. Epub 2020 May 13.

Max Planck Institute of Quantum Optics, Hans-Kopfermann-Straße 1, Garching 85748, Germany.

The strong absorption of liquid water in the infrared (IR) molecular fingerprint region constitutes a challenge for applications of vibrational spectroscopy in chemistry, biology, and medicine. While high-power IR laser sources enable the penetration of ever thicker aqueous samples, thereby mitigating the detrimental effects of strong attenuation on detection sensitivity, a basic advantage of heterodyne-measurement-based methods has-to the best of our knowledge-not been harnessed in broadband IR measurements to date. Here, employing field-resolved spectroscopy (FRS), we demonstrate in theory and experiment fundamental advantages of techniques whose signal-to-noise ratio (SNR) scales linearly with the electric field over those whose SNR scales linearly with radiation intensity, including conventional Fourier-transform infrared (FTIR) and direct absorption spectroscopy. Field-scaling brings about two major improvements. First, it squares the measurement dynamic range. Second, we show that the optimum interaction length with samples for SNR-maximized measurements is twice the value usually considered to be optimum for FTIR devices. In order to take full advantage of these properties, the measurement must not be significantly affected by technical noise, such as intensity fluctuations, which are common for high-power sources. Recently, it has been shown that subcycle, nonlinear gating of the molecular fingerprint signal renders FRS robust against intensity noise. Here, we quantitatively demonstrate this advantage of FRS for thick aqueous samples. We report sub-μg/mL detection sensitivities for transmission path lengths up to 80 μm and a limit of detection in the lower μg/mL range for transmission paths as long as 200 μm.
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http://dx.doi.org/10.1021/acs.analchem.9b05744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304664PMC
June 2020

CD40L membrane retention enhances the immunostimulatory effects of CD40 ligation.

Sci Rep 2020 01 15;10(1):342. Epub 2020 Jan 15.

Institute of Translational Medicine, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, 2nd Floor Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK.

In carcinomas, the nature of CD40 ligand shapes the outcome of CD40 ligation. To date, the consequences of membrane-bound CD40L (mCD40L) on its immune-stimulatory function are unknown. Here, we examined the impact of mCD40L versus soluble CD40L (sCD40L) on T24 bladder carcinoma gene expression profiling. Of 410 differentially expressed genes, 286 were upregulated and 124 downregulated by mCD40L versus sCD40L. Gene ontology enrichment analysis revealed immune-stimulatory function as the most significant enriched biological process affected by upregulated transcripts, while those downregulated were critical for cell growth and division. Furthermore, immature dendritic cells (iDC) responded to mCD40L with enhanced maturation and activation over sCD40L evidenced by higher expression levels of CD83, CD86, HLA-DR and CD54, increased secretion of IL12 and IL10 and higher tumour-antigen (TA) uptake capacity. Furthermore, autologus CD3+ T cells responded to TA-loaded mCD40L-activated DC with increased proliferation and cytotoxic response (CD107a and IFN-γ-producing CD3+ CD8+ T cells) to the tumour-loaded autologous PBMCs compared to sCD40L. Thus, these data indicate that mCD40L enhances the immunostimulatory capacity over sCD40L. Furthermore, the ability of mCD40L to also directly induce cell death in CD40-expressing carcinomas, subsequently releasing tumour-specific antigens into the tumour microenvironment highlights the potential for mCD40L as a multi-faceted anti-cancer immunotherapeutic.
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http://dx.doi.org/10.1038/s41598-019-57293-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962220PMC
January 2020

Field-resolved infrared spectroscopy of biological systems.

Nature 2020 01 1;577(7788):52-59. Epub 2020 Jan 1.

Ludwig Maximilians University München, Garching, Germany.

The proper functioning of living systems and physiological phenotypes depends on molecular composition. Yet simultaneous quantitative detection of a wide variety of molecules remains a challenge. Here we show how broadband optical coherence opens up opportunities for fingerprinting complex molecular ensembles in their natural environment. Vibrationally excited molecules emit a coherent electric field following few-cycle infrared laser excitation, and this field is specific to the sample's molecular composition. Employing electro-optic sampling, we directly measure this global molecular fingerprint down to field strengths 10 times weaker than that of the excitation. This enables transillumination of intact living systems with thicknesses of the order of 0.1 millimetres, permitting broadband infrared spectroscopic probing of human cells and plant leaves. In a proof-of-concept analysis of human blood serum, temporal isolation of the infrared electric-field fingerprint from its excitation along with its sampling with attosecond timing precision results in detection sensitivity of submicrograms per millilitre of blood serum and a detectable dynamic range of molecular concentration exceeding 10. This technique promises improved molecular sensitivity and molecular coverage for probing complex, real-world biological and medical settings.
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http://dx.doi.org/10.1038/s41586-019-1850-7DOI Listing
January 2020

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

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial.

Lancet Oncol 2020 01 18;21(1):105-120. Epub 2019 Nov 18.

Institut Català d'Oncologia L'Hospitalet, Institut d'Investigacio Biomedica de Bellvitge, University of Barcelona, Barcelona, Spain.

Background: Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonist-plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.

Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m (60 mg/m in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.

Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5-13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3-4·8] vs 2·8 months [2·6-2·9]; HR 0·696 [95% CI 0·573-0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9-11·4) in the ramucirumab group versus 7·9 months (7·0-9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724-1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.

Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population.

Funding: Eli Lilly and Company.
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http://dx.doi.org/10.1016/S1470-2045(19)30668-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880PMC
January 2020

Incidence, Patterns, and Outcomes with Adjuvant Chemotherapy for Residual Disease After Neoadjuvant Chemotherapy in Muscle-invasive Urinary Tract Cancers.

Eur Urol Oncol 2020 10 31;3(5):671-679. Epub 2019 Jan 31.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Patients with residual muscle-invasive urinary tract cancer after neoadjuvant chemotherapy (NAC) have a high risk of recurrence.

Objective: To retrospectively evaluate whether additional adjuvant chemotherapy (AC) improves outcomes compared with surveillance in patients with significant residual disease despite NAC.

Design, Setting, And Participants: We identified 474 patients who received NAC from the Retrospective International Study of Cancers of the Urothelium database, of whom 129 had adverse residual disease (≥ypT3 and/or ypN).

Outcome Measurements And Statistical Analysis: Time to relapse (TTR) was the primary endpoint assessed starting from 2mo after surgery to minimize immortal time bias. Secondary endpoints included overall survival (OS), incidence of AC use, and chemotherapy patterns. Kaplan-Meier and Cox regression models estimated TTR, OS, and associations with AC, adjusting for the type of NAC, age, and pathological stage in multivariable analyses.

Results And Limitations: A total of 106 patients underwent surveillance, while 23 received AC. Gemcitabine-cisplatin was the most frequent regimen employed in both settings (30.4%), and the majority (82.6%) of the patients switched to a different regimen. Median follow-up was 30mo. Over 50% of patients developed a recurrence. Median TTR was 16mo (range: <1-108mo). Longer median TTR was observed with AC compared with surveillance (18 vs 10mo, p=0.06). Risk of relapse significantly decreased with AC when adjusted in multivariable analyses (p=0.01). The subgroup analyses of ypT4b/ypN patients (AC: 19; surveillance: 50) who received AC had significantly greater median TTR (20 vs 9mo; hazard ratio 0.43; 95% confidence interval: 0.21-0.89). No difference in OS was found. Limitations include the retrospective design.

Conclusions: The utilization of AC after NAC in patients with high-risk residual disease is not frequent in clinical practice but might reduce the risk of recurrence. Further investigation is needed in this high-risk population to identify optimal therapy and to improve clinical outcomes such as the ongoing adjuvant immunotherapy trials.

Patient Summary: We found that administering additional chemotherapy in patients who had significant residual disease despite preoperative chemotherapy is not frequent in clinical practice. While it might reduce the risk of recurrence, it did not clearly increase overall survival. We encourage participation in the ongoing immunotherapy trials to see whether we can improve outcomes using a different type of therapy that stimulates the immune system.
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http://dx.doi.org/10.1016/j.euo.2018.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449851PMC
October 2020

Mutation Analysis of the FGFR3-encoding gene Does Not Predict Response to Checkpoint Inhibitor Treatment in Metastatic Bladder Cancer.

Eur Urol 2019 11 27;76(5):604-606. Epub 2019 Jul 27.

Department of Oncology and Metabolism, Academic Oncology Unit, University of Sheffield Medical School, Sheffield, UK. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2019.07.034DOI Listing
November 2019

Safe Use of Immune Checkpoint Inhibitors in the Multidisciplinary Management of Urological Cancer: The European Association of Urology Position in 2019.

Eur Urol 2019 Sep 21;76(3):368-380. Epub 2019 Jun 21.

Department of Urology, University Hospitals Leuven, Leuven, Belgium.

Immune checkpoint inhibitors (ICIs) are now used routinely to treat advanced or metastatic urothelial and renal cell carcinoma, among other cancers. Furthermore, multiple trials are currently exploring their role in adjuvant, neoadjuvant, and noninvasive (eg, high-grade non-muscle-invasive bladder cancer) settings. Consequently, urologists are increasingly confronted with patients who are on, have recently received, or will be treated with ICI therapy. The care of these patients is likely to be shared between urologists and medical oncologists, with additional occasional support of other medical specialties. Therefore, it is important that urologists have good knowledge of immune-related side effects. Here, we provide advice on prevention, early diagnosis, and clinical management of the most relevant toxicities to strengthen urologists' insight and, thus, role in the multidisciplinary management in the new immunotherapy era. PATIENT SUMMARY: Immune therapy is a common treatment for many patients with advanced cancer. We describe common side effects of this treatment, and advise how they are best prevented and managed.
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http://dx.doi.org/10.1016/j.eururo.2019.05.041DOI Listing
September 2019

From Clinical Trials to Real-life Clinical Practice: The Role of Immunotherapy with PD-1/PD-L1 Inhibitors in Advanced Urothelial Carcinoma.

Eur Urol Oncol 2018 12 2;1(6):486-500. Epub 2018 Jul 2.

Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Context: A number of PD-1/PD-L1 inhibitors have recently been approved for use in patients with locally advanced or metastatic urothelial carcinoma (UC) on the basis of results from several clinical trials.

Objective: To review the evidence from these trials and consider what it means for the use of these drugs in first-line and post-platinum settings in real-life clinical practice.

Evidence Acquisition: PubMed was searched for full reports of clinical trials of single-agent PD-1/PD-L1 inhibitors in advanced UC. Twelve publications were included.

Evidence Synthesis: Responses to PD-1/PD-L1 inhibitors appear to be durable but are only achieved in 17-26% of patients. These drugs offer different toxicity and efficacy profiles to standard chemotherapy regimens. This should be considered when choosing a treatment strategy for each patient.

Conclusions: PD-1/PD-L1 inhibitors represent a major step forward in the management of advanced UC, although several questions remain regarding their optimal use in routine clinical practice. A validated predictive biomarker of response is yet to be defined, and this is perhaps the most significant unmet need for currently available drugs.

Patient Summary: We reviewed the results from clinical trials that investigated how well certain types of anticancer drugs called PD-1/PD-L1 inhibitors worked in patients with bladder cancer. We found that more research is required to identify (1) the factors that might predict which patients with bladder cancer will respond to PD-1/PD-L1 inhibitors and (2) the optimum duration of treatment with these drugs.
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http://dx.doi.org/10.1016/j.euo.2018.05.011DOI Listing
December 2018

Interferometric delay tracking for low-noise Mach-Zehnder-type scanning measurements.

Opt Express 2019 Feb;27(4):4789-4798

Precise delay control is of paramount importance in optical pump-probe measurements. Here, we report on a high-precision delay tracking technique for mechanical scanning measurements in a Mach-Zehnder interferometer configuration. The setup employs a 1.55-µm continuous-wave laser beam propagating along the interferometer arms. Sinusoidal phase modulation at 30 MHz, and demodulation of the interference signal at the fundamental frequency and its second harmonic, enables delay tracking with sampling rates of up to 10 MHz. At an interferometer arm length of 1 m, root-mean-square error values of the relative delay tracking below 10 attoseconds for both stationary and mechanically scanned (0.2 mm/s) operation are demonstrated. By averaging several scans, a precision of the delay determination better than 1 as is reached. We demonstrate this performance with a mechanical chopper periodically interrupting one of the interferometer arms, which opens the door to the combination of high-sensitivity lock-in detection with (sub-)attosecond-precision relative delay determination.
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http://dx.doi.org/10.1364/OE.27.004789DOI Listing
February 2019
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