Publications by authors named "George N Thalmann"

229 Publications

[Cancer follow-up care].

Urologe A 2022 May 31;61(5):475-476. Epub 2022 Mar 31.

Urologische Universitätsklinik, Inselspital, Anna Seiler Haus, Freiburgstraße 18, 3010, Bern, Schweiz.

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http://dx.doi.org/10.1007/s00120-022-01821-8DOI Listing
May 2022

Tumor microenvironment mechanisms and bone metastatic disease progression of prostate cancer.

Cancer Lett 2022 04 17;530:156-169. Epub 2022 Jan 17.

Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland. Electronic address:

During disease progression from primary towards metastatic prostate cancer (PCa), and in particular bone metastases, the tumor microenvironment (TME) evolves in parallel with the cancer clones, altering extracellular matrix composition (ECM), vasculature architecture, and recruiting specialized tumor-supporting cells that favor tumor spread and colonization at distant sites. We introduce the clinical profile of advanced metastatic PCa in terms of common genetic alterations. Findings from recently developed models of PCa metastatic spread are discussed, focusing mainly on the role of the TME (mainly matrix and fibroblast cell types), at distinct stages: premetastatic niche orchestrated by the primary tumor towards the metastatic site and bone metastasis. We report evidence of premetastatic niche formation, such as the mechanisms of distant site conditioning by extracellular vesicles, chemokines and other tumor-derived mechanisms, including altered cancer cell-ECM interactions. Furthermore, evidence supporting the similarities of stroma alterations among the primary PCa and bone metastasis, and contribution of TME to androgen deprivation therapy resistance are also discussed. We summarize the available bone metastasis transgenic mouse models of PCa from a perspective of pro-metastatic TME alterations during disease progression and give an update on the current diagnostic and therapeutic radiological strategies for bone metastasis clinical management.
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http://dx.doi.org/10.1016/j.canlet.2022.01.015DOI Listing
April 2022

A Phase 1/2 Single-arm Clinical Trial of Recombinant Bacillus Calmette-Guérin (BCG) VPM1002BC Immunotherapy in Non-muscle-invasive Bladder Cancer Recurrence After Conventional BCG Therapy: SAKK 06/14.

Eur Urol Oncol 2022 04 7;5(2):195-202. Epub 2022 Jan 7.

SAKK Coordinating Center, Bern, Switzerland.

Background: VPM1002BC is a genetically modified Mycobacterium bovis bacillus Calmette-Guérin (BCG) strain with potentially improved immunogenicity and attenuation.

Objective: To report on the efficacy, safety, tolerability and quality of life of intravesical VPM1002BC for the treatment of non-muscle-invasive bladder cancer (NMIBC) recurrence after conventional BCG therapy.

Design, Setting, And Participants: We designed a phase 1/2 single-arm trial (NCT02371447). Patients with recurrent NMIBC after BCG induction ± BCG maintenance therapy and intermediate to high risk for cancer progression were eligible.

Intervention: Patients were scheduled for standard treatment of six weekly instillations with VPM1002BC followed by maintenance for 1 yr. Treatment was stopped in cases of recurrence.

Outcome Measurements And Statistical Analysis: The primary endpoint was defined as the recurrence-free rate (RFR) in the bladder 60 wk after trial registration. The sample size was calculated based on the assumption that ≥30% of the patients would be without recurrence at 60 wk after registration.

Results And Limitations: After exclusion of two ineligible patients, 40 patients remained in the full analysis set. All treated tumours were of high grade and 27 patients (67.5%) presented with carcinoma in situ. The recurrence-free rate in the bladder at 60 wk after trial registration was 49.3% (95% confidence interval [CI] 32.1-64.4%) and remained at 47.4% (95% CI 30.4-62.6%] at 2 yr and 43.7% (95% CI 26.9-59.4%) at 3 yr after trial registration. At the same time, progression to muscle-invasive disease had occurred in three patients and metastatic disease in four patients. Treatment-related grade 1, 2, and 3 adverse events (AEs) were observed in 14.3%, 54.8%, and 4.8% of the patients, respectively. No grade ≥4 AEs occurred. Two of the 42 patients did not tolerate five or more instillations during induction. Limitations include the single-arm trial design and the low number of patients for subgroup analysis.

Conclusions: At 1 yr after treatment start, almost half of the patients remained recurrence-free after therapy with VPM100BC. The primary endpoint of the study was met and the therapy is safe and well tolerated.

Patient Summary: We conducted a trial of VPM100BC, a genetically modified bacillus Calmette-Guérin (BCG) strain for treatment of bladder cancer not invading the bladder muscle. At 1 year after the start of treatment, almost half of the patients with a recurrence after previous conventional BCG were free from non-muscle-invasive bladder cancer (NMIBC). The results are encouraging and VPM1002BC merits further evaluation in randomised studies for patients with NMIBC.
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http://dx.doi.org/10.1016/j.euo.2021.12.006DOI Listing
April 2022

Re: Impact of the Implementation of the EAU Guidelines Recommendation on Reporting and Grading of Complications in Patients Undergoing Robot-assisted Radical Cystectomy: A Systematic Review.

Eur Urol 2022 02 15;81(2):214-215. Epub 2021 Dec 15.

Department of Urology, The University of Melbourne, The Royal Melbourne Hospital, Melbourne, Australia; Department of Urology, University of Bern, Bern, Switzerland; The Australian Medical Robotics Academy, Melbourne, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2021.11.029DOI Listing
February 2022

Effect of Simulation-based Training on Surgical Proficiency and Patient Outcomes: A Randomised Controlled Clinical and Educational Trial.

Eur Urol 2022 Apr 14;81(4):385-393. Epub 2021 Nov 14.

MRC Centre for Transplantation, King's College London, King's Health Partners, London, UK; Urology Centre, Guy's and St. Thomas' NHS Foundation Trust, King's Health Partners, London, UK.

Background: It is hypothesised that simulation enhances progression along the initial phase of the surgical learning curve.

Objective: To evaluate whether residents undergoing additional simulation, compared to conventional training, are able to achieve proficiency sooner with better patient outcomes.

Design, Setting, And Participants: This international, multicentre, randomised controlled trial recruited 94 urology residents with experience of zero to ten procedures and no prior exposure to simulation in ureterorenoscopy, selected as an index procedure.

Intervention: Participants were randomised to simulation or conventional operating room training, as is the current standard globally, and followed for 25 procedures or over 18 mo.

Outcome Measurements And Statistical Analysis: The number of procedures required to achieve proficiency, defined as achieving a score of ≥28 on the Objective Structured Assessment of Technical Skill (OSATS) scale over three consecutive operations, was measured. Surgical complications were evaluated as a key secondary outcome. This trial is registered at www.isrctn.com as ISCRTN 12260261.

Results And Limitations: A total of 1140 cases were performed by 65 participants, with proficiency achieved by 21 simulation and 18 conventional participants over a median of eight and nine procedures, respectively (hazard ratio [HR] 1.41, 95% confidence interval [CI] 0.72-2.75). More participants reached proficiency in the simulation arm in flexible ureterorenoscopy, requiring a lower number of procedures (HR 0.89, 95% CI 0.39-2.02). Significant differences were observed in overall comparison of OSATS scores between the groups (mean difference 1.42, 95% CI 0.91-1.92; p < 0.001), with fewer total complications (15 vs 37; p = 0.003) and ureteric injuries (3 vs 9; p < 0.001) in the simulation group.

Conclusions: Although the number of procedures required to reach proficiency was similar, simulation-based training led to higher overall proficiency scores than for conventional training. Fewer procedures were required to achieve proficiency in the complex form of the index procedure, with fewer serious complications overall.

Patient Summary: This study investigated the effect of simulation training in junior surgeons and found that it may improve performance in real operating settings and reduce surgical complications for complex procedures.
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http://dx.doi.org/10.1016/j.eururo.2021.10.030DOI Listing
April 2022

The 2021 Updated European Association of Urology Guidelines on Metastatic Urothelial Carcinoma.

Eur Urol 2022 Jan 3;81(1):95-103. Epub 2021 Nov 3.

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

Context: Treatment of metastatic urothelial carcinoma is currently undergoing a rapid evolution.

Objective: This overview presents the updated European Association of Urology (EAU) guidelines for metastatic urothelial carcinoma.

Evidence Acquisition: A comprehensive scoping exercise covering the topic of metastatic urothelial carcinoma is performed annually by the Guidelines Panel. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries, resulting in yearly guideline updates.

Evidence Synthesis: Platinum-based chemotherapy is the recommended first-line standard therapy for all patients fit to receive either cisplatin or carboplatin. Patients positive for programmed death ligand 1 (PD-L1) and ineligible for cisplatin may receive immunotherapy (atezolizumab or pembrolizumab). In case of nonprogressive disease on platinum-based chemotherapy, subsequent maintenance immunotherapy (avelumab) is recommended. For patients without maintenance therapy, the recommended second-line regimen is immunotherapy (pembrolizumab). Later-line treatment has undergone recent advances: the antibody-drug conjugate enfortumab vedotin demonstrated improved overall survival and the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib appears active in case of FGFR3 alterations.

Conclusions: This 2021 update of the EAU guideline provides detailed and contemporary information on the treatment of metastatic urothelial carcinoma for incorporation into clinical practice.

Patient Summary: In recent years, several new treatment options have been introduced for patients with metastatic urothelial cancer (including bladder cancer and cancer of the upper urinary tract and urethra). These include immunotherapy and targeted treatments. This updated guideline informs clinicians and patients about optimal tailoring of treatment of affected patients.
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http://dx.doi.org/10.1016/j.eururo.2021.09.026DOI Listing
January 2022

A longitudinal study evaluating interim assessment of neoadjuvant chemotherapy for bladder cancer.

BJU Int 2021 Aug 21. Epub 2021 Aug 21.

Department of Urology, University Hospital of Bern, University of Bern, Bern, Switzerland.

Objectives: To evaluate the usefulness of radiological re-staging after two and four cycles of neoadjuvant chemotherapy (NAC), the impact of re-staging on further patient management, and the correlation between clinical and final pathological tumour stage at radical cystectomy (RC).

Patients And Methods: We conducted a longitudinal, single-centre, cohort study of prospectively collected consecutive patients who underwent NAC and RC for urothelial muscle-invasive bladder cancer between July 2001 and December 2017. Patients underwent repeated computed tomography scans for re-staging after two cycles of NAC and after completion of NAC before RC.

Results: Of 180 patients, 110 had ≥four cycles of NAC and had complete imaging available. In the entire cohort, further patient management was only changed in 2/180 patients (1.1%) after two cycles of NAC based on radiological findings. Patients who were stable after two cycles but then downstaged after at least four cycles of NAC had a similarly lowered risk of death (hazard ratio [HR] 0.53). Only one patient downstaged after two cycles was subsequently upstaged after four cycles. Clinical downstaging was observed in 51 patients (46%), 55 patients (50%) had no change in clinical stage and four patients (3.6%) were clinically upstaged. Patients clinically downstaged after four cycles of NAC had a lower risk of death (HR 0.49, 95% confidence interval 0.25-0.94; P = 0.033) compared to those with no change or upstaged after completion of NAC.

Conclusions: Re-staging of muscle-invasive bladder cancer after two cycles of NAC offers little additional information, rarely changes patient management, and may therefore be omitted, whereas re-staging after completion of NAC by CT is a strong predictor of overall survival.
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http://dx.doi.org/10.1111/bju.15579DOI Listing
August 2021

Dose-intensified Versus Conventional-dose Salvage Radiotherapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: The SAKK 09/10 Randomized Phase 3 Trial.

Eur Urol 2021 09 14;80(3):306-315. Epub 2021 Jun 14.

Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Switzerland.

Background: Salvage radiotherapy (SRT) is utilized for biochemical progression of prostate cancer after radical prostatectomy (RP).

Objective: To report the outcomes of the SAKK 09/10 trial comparing conventional and dose-intensified SRT.

Design, Setting, And Participants: SAKK 09/10 was a randomized, multicenter, phase 3 trial that recruited men with biochemical progression after RP.

Intervention: Patients were randomly assigned to conventional-dose (64 Gy) or dose-intensified SRT (70 Gy) to the prostate bed without hormonal therapy.

Outcome Measurements And Statistical Analysis: The primary endpoint was freedom from biochemical progression (FFBP). Secondary endpoints included clinical progression-free survival (PFS), time to hormonal treatment, overall survival (OS), acute and late toxicity (Common Terminology Criteria for Adverse Events v4.0), and quality of life (QoL).

Results And Limitations: Between February 2011 and April 2014, 350 patients were randomly assigned to 64 Gy (n = 175) or 70 Gy (n = 175). Median prostate-specific antigen at randomization was 0.3 ng/ml. After median follow-up of 6.2 yr, the median FFBP was 8.2 yr in the 64 Gy arm and 7.6 in the 70 Gy arm (log-rank p = 0.4), with a hazard ratio of 1.14 (95% confidence interval 0.82-1.60). The 6-year FFBP rates were 62% and 61%, respectively. No significant differences in clinical PFS, time to hormonal treatment, or OS were observed. Late grade 2 and 3 genitourinary toxicity was observed in 35 (21%) and 13 (7.9%) patients in the 64 Gy arm, and 46 (26%) and seven (4%) in the 70 Gy arm, respectively (p = 0.8). Late grade 2 and 3 gastrointestinal toxicity was observed in 12 (7.3%) and seven patients (4.2%) in the 64 Gy arm, and 35 (20%) and four (2.3%) in the 70 Gy arm, respectively (p = 0.009). There were no significant differences in QoL.

Conclusions: Conventional-dose SRT to the prostate bed is sufficient in patients with early biochemical progression of prostate cancer after RP.

Patient Summary: The optimal radiation therapy dose for patients who have increased tumor markers after surgery for prostate cancer is unclear. We found that administering a higher dose only increased the gastrointestinal side effects without providing any benefits to the patient. This clinical trial is registered on ClinicalTrials.gov as NCT01272050.
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http://dx.doi.org/10.1016/j.eururo.2021.05.033DOI Listing
September 2021

Impact of Pelvic Lymph Node Dissection and Its Extent on Perioperative Morbidity in Patients Undergoing Radical Prostatectomy for Prostate Cancer: A Comprehensive Systematic Review and Meta-analysis.

Eur Urol Oncol 2021 04 6;4(2):134-149. Epub 2021 Mar 6.

Department of Urology and Division of Experimental Oncology, Urological Research Institute (URI), IRCCS San Raffaele Scientific Institute, Milan, Italy.

Context: Pelvic lymph node dissection (PLND) yields the most accurate staging in patients undergoing radical prostatectomy (RP) for prostate cancer (PCa), although it can be associated with morbidity.

Objective: To systematically evaluate the impact of PLND extent on perioperative morbidity in patients undergoing RP. A new PLND-related complication assessment tool is proposed.

Evidence Acquisition: A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) was conducted. MEDLINE/PubMed, Scopus, Embase and Web of Science databases were searched to yield studies discussing perioperative complications following RP and PLND. The extent of PLND was classified according to the European Association of Urology PCa guidelines. Studies were categorized according to the extent of PLND. Intra- and postoperative complications were classified as "strongly," "likely," or "unlikely" related to PLND. Anatomical site of perioperative complications was recorded. A cumulative meta-analysis of comparative studies was conducted using Review Manager 5.3 (Cochrane Collaboration, Oxford, UK).

Evidence Synthesis: Our search generated 3645 papers, with 176 studies meeting the inclusion criteria. Details of 77 303 patients were analyzed. Of these studies, 84 (47.7%), combining data on 28 428 patients, described intraoperative complications as an outcome of interest. Overall, 534 (1.8%) patients reported one or more intraoperative complications. Postoperative complications were reported in 151 (85.7%) studies, combining data on 73 629 patients. Overall, 10 401 (14.1%) patients reported one or more postoperative complication. The most reported postoperative complication strongly related to PLND was lymphocele (90.6%). The pooled meta-analysis revealed that RP + limited PLND/standard PLND had a significantly decreased risk of experiencing any intraoperative complication (risk ratio [RR]: 0.55; p =  0.01) and postoperative complication strongly related to PLND (RR: 0.46; p =  <0.00001), particularly for lymphocele formation (RR: 0.52; p =  0.0003) and thromboembolic events (RR: 0.59; p =  0.008), when compared with extended/superextended PLND. The extent of PLND was confirmed to be an independent predictor of lymphocele formation (RR: 1.77; p <  0.00001).

Conclusions: The perioperative morbidity of PLND in patients undergoing RP and PLND for PCa significantly correlates with the extent of PLND. More standardized reporting of intra- and postoperative complications is needed to better estimate the direct impact of PLND extent on perioperative morbidity.

Patient Summary: Pelvic lymph node dissection (PLND) is the most accurate method for staging in patients undergoing radical prostatectomy for prostate cancer, although it can be associated with complications. This study aims to systematically evaluate the impact of PLND extent on perioperative complications in these patients. We found that intra- and postoperative complications correlate significantly with the extent of PLND. A more rigorous assessment and thorough reporting of perioperative complications are recommended.
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http://dx.doi.org/10.1016/j.euo.2021.02.001DOI Listing
April 2021

Patient-derived xenografts and organoids model therapy response in prostate cancer.

Nat Commun 2021 02 18;12(1):1117. Epub 2021 Feb 18.

Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland.

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.
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http://dx.doi.org/10.1038/s41467-021-21300-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892572PMC
February 2021

Seminal Vesical Sparing Cystectomy for Bladder Cancer is Feasible with Good Functional Results without Impairing Oncological Outcomes: A Longitudinal Long-Term Propensity-Matched Single Center Study.

J Urol 2021 Jun 3;205(6):1629-1640. Epub 2021 Feb 3.

Department of Urology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Purpose: Seminal vesicle-sparing radical cystectomy has been reported to improve short-term functional results without compromising oncological outcomes. However, there is still a lack of data on long-term outcomes after seminal vesicle-sparing radical cystectomy. The aim of this study was to compare oncological and functional outcomes in patients after seminal vesicle-sparing vs nonseminal vesicle-sparing radical cystectomy.

Materials And Methods: Oncological and functional outcomes of 470 consecutive patients after radical cystectomy and orthotopic ileal reservoir from 2000 to 2017 were evaluated. They were stratified into 6 groups according to nerve-sparing and seminal vesicle-sparing status as attempted during surgery: no sparing at all (55), unilateral nerve sparing (159), bilateral nerve sparing (132), unilateral seminal vesicle-sparing and unilateral nerve sparing (30), unilateral seminal vesicle sparing and bilateral nerve sparing (45), and bilateral seminal vesicle sparing (49) and used propensity modeling to adjust for preoperative differences.

Results: Median followup among the entire cohort was 64 months. Among the 6 groups, our analysis showed no difference in local recurrence-free survival (p=0.173). However, progression-free, cancer-specific and overall survival were more favorable in patients with seminal vesicle-sparing radical cystectomy (p <0.001, p=0.006 and p <0.001, respectively). Proportions of patients with erectile function recovery were higher in the seminal vesicle-sparing groups at all time points in all analyses, respectively, with pronounced earlier recovery in patients with bilateral seminal vesicle sparing. Importantly, patients with seminal vesicle sparing were significantly less in need of erectile aids to achieve erection and intercourse. Over the whole period, daytime urinary-continence was significantly better in the seminal vesicle sparing groups (OR 2.64 to 5.21).

Conclusions: In a highly selected group of patients, seminal vesicle sparing radical cystectomy is oncologically safe and results in excellent functional outcomes that are reached at an earlier time point after surgery and remain superior over a longer period of time.
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http://dx.doi.org/10.1097/JU.0000000000001635DOI Listing
June 2021

Stroma Transcriptomic and Proteomic Profile of Prostate Cancer Metastasis Xenograft Models Reveals Prognostic Value of Stroma Signatures.

Cancers (Basel) 2020 12 15;12(12). Epub 2020 Dec 15.

Urology Research Laboratory, Department for BioMedical Research, University of Bern, Murtenstrasse 35, 3008 Bern, Switzerland.

Resistance acquisition to androgen deprivation treatment and metastasis progression are a major clinical issue associated with prostate cancer (PCa). The role of stroma during disease progression is insufficiently defined. Using transcriptomic and proteomic analyses on differentially aggressive patient-derived xenografts (PDXs), we investigated whether PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern. RNA sequencing was performed on the PCa PDXs BM18 (castration-sensitive) and LAPC9 (castration-resistant), representing different disease stages. Using organism-specific reference databases, the human-specific transcriptome (tumor) was identified and separated from the mouse-specific transcriptome (stroma). To identify proteomic changes in the tumor (human) versus the stroma (mouse), we performed human/mouse cell separation and subjected protein lysates to quantitative Tandem Mass Tag labeling and mass spectrometry. Tenascin C (TNC) was among the most abundant stromal genes, modulated by androgen levels in vivo and highly expressed in castration-resistant LAPC9 PDX. The tissue microarray of primary PCa samples ( = 210) showed that TNC is a negative prognostic marker of the clinical progression to recurrence or metastasis. Stroma markers of osteoblastic PCa bone metastases seven-up signature were induced in the stroma by the host organism in metastatic xenografts, indicating conserved mechanisms of tumor cells to induce a stromal premetastatic signature. A 50-gene list stroma signature was identified based on androgen-dependent responses, which shows a linear association with the Gleason score, metastasis progression and progression-free survival. Our data show that metastatic PCa PDXs, which differ in androgen sensitivity, trigger differential stroma responses, which show the metastasis risk stratification and prognostic biomarker potential.
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http://dx.doi.org/10.3390/cancers12123786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768471PMC
December 2020

Editorial Comment.

J Urol 2021 01 28;205(1):182. Epub 2020 Oct 28.

Department of Urology, University of Bern, Anna Seiler Haus, Inselspital, Bern, Switzerland.

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http://dx.doi.org/10.1097/JU.0000000000001345.02DOI Listing
January 2021

Routine Preoperative Bone Scintigraphy Has Limited Impact on the Management of Patients with Invasive Bladder Cancer.

Eur Urol Focus 2021 Sep 12;7(5):1052-1060. Epub 2020 Oct 12.

Department of Urology, University Hospital of Bern, University of Bern, Bern, Switzerland; Department of Urology, University Hospital of Lausanne (CHUV), University of Lausanne, Lausanne, Switzerland.

Background: According to current guidelines, bone scintigraphy is not routinely indicated in patients with invasive bladder cancer prior to radical cystectomy unless specific symptoms are present. These guidelines, however, are based on sparse data of low quality.

Objective: To assess the clinical impact of routine staging bone scintigraphy on further patient management.

Design, Setting, And Participants: A retrospective, single-center study of 1287 consecutive patients, who were scheduled to undergo radical cystectomy due to invasive bladder cancer between January 2000 and December 2017, was conducted. All patients were prospectively followed up according to our institutional protocol.

Intervention: Bone scintigraphy as staging imaging prior to radical cystectomy.

Outcome Measurements And Statistical Analysis: The primary endpoint was the change in intended patient management. Secondary endpoints were the need for additional imaging, the diagnostic performance of baseline bone scintigraphy, and the association between clinical and radiological findings on bone metastases and survival. Logistic and Cox regression models were used for univariate and multivariate analyses.

Results And Limitations: Of 1287 patients scheduled for radical cystectomy, 1148 (89%) underwent bone scintigraphy as staging imaging. Overall, baseline bone scintigraphy led to a change in the intended management in 19/1148 (1.7%) patients. Additional imaging was performed in 44/1148 (4%) patients. Although positive bone scintigraphy findings were associated with the occurrence/development of bone metastases, the diagnostic performance of baseline bone scintigraphy was generally poor (positive predictive value, negative predictive value, sensitivity, and specificity were 56%, 89%, 27%, and 96%, respectively). Higher clinical tumor stage and the nonperformance of cystectomy had negative impacts on cancer-specific survival and overall survival, while positive bone scintigraphy was associated with worse cancer-specific survival. This study was limited by its retrospective nature and the lack of follow-up bone scintigraphy in all patients.

Conclusions: These results demonstrate the limited value of bone scintigraphy in the staging of invasive bladder cancer and do not support its routine use.

Patient Summary: In this study, we looked at the clinical impact of bone scintigraphy on the diagnostics of patients with invasive bladder cancer. We found that routine staging bone scintigraphy had limited impact on further patient management. We conclude that bone scintigraphy should not be part of routine staging in patients with invasive bladder cancer.
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http://dx.doi.org/10.1016/j.euf.2020.09.016DOI Listing
September 2021

Continent diversion: five decades of developments and evolution.

BJU Int 2020 12 1;126(6):653-660. Epub 2020 Oct 1.

Department of Urology, University of Bern, Bern, Switzerland.

Objective: To provide a chronological overview of the evolution of continent urinary diversion (CUD) over the last 50 years and to highlight important milestones.

Methods: We performed an extensive literature review and analysed different forms of urinary diversion worldwide. After the evaluation of surgical techniques, we assessed the advantages and disadvantages of assorted CUD approaches based on published long-term follow-up data.

Results: A wide variety of surgical options for CUD is available and feasible to date, although consensus among urologists regarding the 'gold standard' is still lacking. Several forms of orthotopic bladder substitutes and continent cutaneous urinary reservoirs have been shown to provide excellent long-term results.

Conclusion: The last 50 years of CUD have seen constant evolution and refinement of techniques, but the best surgical approach remains unclear and there is no 'one-size-fits-all' option, but rather tailor-made approaches are necessary to ensure patient satisfaction.
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http://dx.doi.org/10.1111/bju.15239DOI Listing
December 2020

Cationic amphiphilic drugs as potential anticancer therapy for bladder cancer.

Mol Oncol 2020 12 16;14(12):3121-3134. Epub 2020 Oct 16.

Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

More effective therapy for patients with either muscle-invasive or high-risk non-muscle-invasive urothelial carcinoma of the bladder (UCB) is an unmet clinical need. For this, drug repositioning of clinically approved drugs represents an interesting approach. By repurposing existing drugs, alternative anticancer therapies can be introduced in the clinic relatively fast, because the safety and dosing of these clinically approved pharmacological agents are generally well known. Cationic amphiphilic drugs (CADs) dose-dependently decreased the viability of a panel of human UCB lines in vitro. CADs induced lysosomal puncta formation, a hallmark of lysosomal leakage. Intravesical instillation of the CAD penfluridol in an orthotopic mouse xenograft model of human UCB resulted in significantly reduced intravesical tumor growth and metastatic progression. Furthermore, treatment of patient-derived ex vivo cultured human UCB tissue caused significant partial or complete antitumor responses in 97% of the explanted tumor tissues. In conclusion, penfluridol represents a promising treatment option for bladder cancer patients and warrants further clinical evaluation.
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http://dx.doi.org/10.1002/1878-0261.12793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718956PMC
December 2020

[Urologic Emergencies: Paraphimosis].

Ther Umsch 2020 Jun;77(5):223-225

Universitätsklinik für Urologie, Inselspital Bern.

Urologic Emergencies: Paraphimosis Paraphimosis presents a rare but acute urological emergency whereby the foreskin becomes entrapped behind the coronary sulcus of the penis. Therapy is quick and feasible, even in an outpatient setting. In most cases compression of the preputial edema and subsequent reposition of the prepuce is sufficient. Rarely, surgical intervention in form of a dorsal incision of the constriction is required. With partial or full phimosis being the underlying condition, paraphimosis occurs predominantly in infants and toddlers. However, persistent or secondary phimosis can lead to paraphimosis in advanced age.
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http://dx.doi.org/10.1024/0040-5930/a001182DOI Listing
June 2020

Evolution of Urothelial Bladder Cancer in the Context of Molecular Classifications.

Int J Mol Sci 2020 Aug 7;21(16). Epub 2020 Aug 7.

Department of BioMedical Research, Urology Research Laboratory, University of Bern, 3008 Bern, Switzerland.

Bladder cancer is a heterogeneous disease that is not depicted by current classification systems. It was originally classified into non-muscle invasive and muscle invasive. However, clinically and genetically variable tumors are summarized within both classes. A definition of three groups may better account for the divergence in prognosis and probably also choice of treatment. The first group represents mostly non-invasive tumors that reoccur but do not progress. Contrarily, the second group represent non-muscle invasive tumors that likely progress to the third group, the muscle invasive tumors. High throughput tumor profiling improved our understanding of the biology of bladder cancer. It allows the identification of molecular subtypes, at least three for non-muscle invasive bladder cancer (Class I, Class II and Class III) and six for muscle-invasive bladder cancer (luminal papillary, luminal non-specified, luminal unstable, stroma-rich, basal/squamous and neuroendocrine-like) with distinct clinical and molecular phenotypes. Molecular subtypes can be potentially used to predict the response to treatment (e.g., neoadjuvant chemotherapy and immune checkpoint inhibitors). Moreover, they may allow to characterize the evolution of bladder cancer through different pathways. However, to move towards precision medicine, the understanding of the biological meaning of these molecular subtypes and differences in the composition of cell subpopulations will be mandatory.
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http://dx.doi.org/10.3390/ijms21165670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461199PMC
August 2020

The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis.

Cancers (Basel) 2020 Jul 13;12(7). Epub 2020 Jul 13.

Department for BioMedical Research, Urology Research Laboratory, University of Bern, 3008 Bern, Switzerland.

Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor-stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.
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http://dx.doi.org/10.3390/cancers12071887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409163PMC
July 2020

Dual-mTOR Inhibitor Rapalink-1 Reduces Prostate Cancer Patient-Derived Xenograft Growth and Alters Tumor Heterogeneity.

Front Oncol 2020 23;10:1012. Epub 2020 Jun 23.

Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland.

Bone metastasis is the leading cause of prostate cancer (PCa) mortality, frequently marking the progression to castration-resistant PCa. Dysregulation of the androgen receptor pathway is a common feature of castration-resistant PCa, frequently appearing in association with mTOR pathway deregulations. Advanced PCa is also characterized by increased tumor heterogeneity and cancer stem cell (CSC) frequency. CSC-targeted therapy is currently being explored in advanced PCa, with the aim of reducing cancer clonal divergence and preventing disease progression. In this study, we compared the molecular pathways enriched in a set of bone metastasis from breast and prostate cancer from snap-frozen tissue. To further model PCa drug resistance mechanisms, we used two patient-derived xenografts (PDX) models of bone-metastatic PCa, BM18, and LAPC9. We developed organoids assay and tumor slice drug assays to investigate the effects of mTOR- and CSC-targeting compounds. We found that both PDXs could be effectively targeted by treatment with the bivalent mTORC1/2 inhibitor Rapalink-1. Exposure of LAPC9 to Rapalink-1 but not to the CSC-targeting drug disulfiram blocked mTORC1/2 signaling, diminished expression of metabolic enzymes involved in glutamine and lipid metabolism and reduced the fraction of CD44 and ALDEFluor cells, . Mice treated with Rapalink-1 showed a significantly delayed tumor growth compared to control and cells recovered from the tumors of treated animals showed a marked decrease of CD44 expression. Taken together these results highlight the increased dependence of advanced PCa on the mTOR pathway, supporting the development of a targeted approach for advanced, bone metastatic PCa.
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http://dx.doi.org/10.3389/fonc.2020.01012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324765PMC
June 2020

European Association of Urology Guidelines on Primary Urethral Carcinoma-2020 Update.

Eur Urol Oncol 2020 08 27;3(4):424-432. Epub 2020 Jun 27.

Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.

Context: Primary urethral carcinoma (PUC) is a rare cancer accounting for <1% of all genitourinary malignancies.

Objective: To provide updated practical recommendations for the diagnosis and management of PUC.

Evidence Acquisition: A systematic search interrogating Ovid (Medline), EMBASE, and the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews was performed.

Evidence Synthesis: Urothelial carcinoma of the urethra is the predominant histological type of PUC (54-65%), followed by squamous cell carcinoma (16-22%) and adenocarcinoma (10-16%). Diagnosis of PUC depends on urethrocystoscopy with biopsy and urinary cytology. Pathological staging and grading are based on the tumour, node, metastasis (TNM) classification and the 2016 World Health Organization grading systems. Local tumour extent and regional lymph nodes are assessed by magnetic resonance imaging, and the presence of distant metastases is assessed by computed tomography of the thorax/abdomen and pelvis. For all patients with localised distal tumours (≤T2N0M0), partial urethrectomy or urethra-sparing surgery is a valid treatment option, provided that negative intraoperative surgical margins can be achieved. Prostatic Ta-Tis-T1 PUC can be treated with repeat transurethral resection of the prostate and bacillus Calmette-Guérin. In prostatic or proximal ≥ T2N0 disease, neoadjuvant cisplatin-based chemotherapy should be considered prior to radical surgery. All patients with locally advanced disease (≥T3N0-2M0) should be discussed within a multidisciplinary team. In men with locally advanced squamous cell carcinoma, curative radiotherapy combined with radiosensitising chemotherapy can be offered for definitive treatment and genital preservation. In patients with local urethral recurrence, salvage surgery or radiotherapy can be offered. For patients with distant metastatic disease, systemic therapy based on tumour characteristics can be evaluated.

Conclusions: These updated European Association of Urology guidelines provide up-to-date guidance for the contemporary diagnosis and management of patients with suspected PUC.

Patient Summary: Primary urethral carcinoma (PUC) is a very rare, but aggressive disease. These updated European Association of Urology guidelines provide evidence-based guidance for clinicians treating patients with PUC.
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http://dx.doi.org/10.1016/j.euo.2020.06.003DOI Listing
August 2020

European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines.

Eur Urol 2021 01 29;79(1):82-104. Epub 2020 Apr 29.

Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Context: This overview presents the updated European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC).

Objective: To provide practical evidence-based recommendations and consensus statements on the clinical management of MMIBC with a focus on diagnosis and treatment.

Evidence Acquisition: A broad and comprehensive scoping exercise covering all areas of the MMIBC guideline has been performed annually since its 2017 publication (based on the 2016 guideline). Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries, resulting in yearly guideline updates. A level of evidence and a grade of recommendation were assigned. Additionally, the results of a collaborative multistakeholder consensus project on advanced bladder cancer (BC) have been incorporated in the 2020 guidelines, addressing those areas where it is unlikely that prospective comparative studies will be conducted.

Evidence Synthesis: Variant histologies are increasingly reported in invasive BC and are relevant for treatment and prognosis. Staging is preferably done with (enhanced) computerised tomography scanning. Treatment decisions are still largely based on clinical factors. Radical cystectomy (RC) with lymph node dissection remains the recommended treatment in highest-risk non-muscle-invasive and muscle-invasive nonmetastatic BC, preceded by cisplatin-based neoadjuvant chemotherapy (NAC) for invasive tumours in "fit" patients. Selected men and women benefit from sexuality sparing RC, although this is not recommended as standard therapy. Open and robotic RC show comparable outcomes, provided the procedure is performed in experienced centres. For open RC 10, the minimum selected case load is 10 procedures per year. If bladder preservation is considered, chemoradiation is an alternative in well-selected patients without carcinoma in situ and after maximal resection. Adjuvant chemotherapy should be considered if no NAC was given. Perioperative immunotherapy can be offered in clinical trial setting. For fit metastatic patients, cisplatin-based chemotherapy remains the first choice. In cisplatin-ineligible patients, immunotherapy in Programmed Death Ligand 1 (PD-L1)-positive patients or carboplatin in PD-L1-negative patients is recommended. For second-line treatment in metastatic disease, pembrolizumab is recommended. Postchemotherapy surgery may prolong survival in responders. Quality of life should be monitored in all phases of treatment and follow-up. The extended version of the guidelines is available at the EAU website: https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/.

Conclusions: This summary of the 2020 EAU MMIBC guideline provides updated information on the diagnosis and treatment of MMIBC for incorporation into clinical practice.

Patient Summary: The European Association of Urology Muscle-invasive and Metastatic Bladder Cancer (MMIBC) Panel has released an updated version of their guideline, which contains information on histology, staging, prognostic factors, and treatment of MMIBC. The recommendations are based on the current literature (until the end of 2019), with emphasis on high-level data from randomised clinical trials and meta-analyses and on the findings of an international consensus meeting. Surgical removal of the bladder and bladder preservation are discussed, as well as the use of chemotherapy and immunotherapy in localised and metastatic disease.
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http://dx.doi.org/10.1016/j.eururo.2020.03.055DOI Listing
January 2021

An Exploratory Study of Dose Escalation Standard Focal High-Intensity Focused Ultrasound for Treating Nonmetastatic Prostate Cancer.

J Endourol 2020 06 5;34(6):641-646. Epub 2020 May 5.

Imperial Urology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.

Analysis of treatment success regarding oncological recurrence rate between standard and dose escalation focal high-intensity focused ultrasound (HIFU) of prostate cancer. In this analysis of our prospectively maintained HIFU (Sonablate 500) database, 598 patients were identified who underwent a focal HIFU (Sonablate 500) between March 2007 and November 2016. Follow-up occurred with 3-monthly clinic visits and prostate specific antigen (PSA) testing in the first year. Thereafter, PSA was measured 6-monthly or annually at least. Routine and for-cause multiparametric MRI (mpMRI) was conducted with biopsy for MRI suspicion of recurrence. Treatments were delivered in a quadrant or hemiablation fashion depending on the gland volume as well as tumor volume and location. Before mid-2015, standard focal HIFU was used (two HIFU blocks); after this date, some urologists conducted dose escalation focal HIFU (three overlapping HIFU blocks). Propensity matching was used to ensure two matched groups, leading to 162 cases for this analysis. Treatment failure was defined by any secondary treatment (systemic therapy, cryotherapy, radiotherapy, prostatectomy, or further HIFU), metastasis from prostate cancer without further treatment, tumor recurrence with Gleason score ≥7 (≥3 + 4) on prostate biopsy without further treatment, or prostate cancer-related mortality. Complications and side-effects were also compared. Median age was 64.5 years (interquartile range [IQR] 60-73.5) in the standard focal-HIFU group and 64.5 years (IQR 60-69) in the dose-escalation group. Median prostate volume was 37 mL (IQR 17-103) in the standard group and 47.5 mL (IQR 19-121) in the dose-escalation group. As tumor volume on mpMRI and Gleason score were major matching criteria, these were identical with 0.43 mL (IQR 0.05-2.5) and Gleason 3 + 3 = 6 in 1 out of 32 (3%), 3 + 4 = 7 in 27 out of 32 (84%), and 4 + 3 = 7 in 4 out of 32 (13%). Recurrence in treated areas was found in 10 out of 32 (31%) when standard treatment zones were applied, and in 6 out of 32 (19%) of dose-escalation focal HIFU ( = 0.007). This exploratory study shows that dose escalation focal HIFU may achieve higher rates of disease control compared with standard focal HIFU. Further prospective comparative studies are needed.
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http://dx.doi.org/10.1089/end.2019.0613DOI Listing
June 2020

Prostate Specific Antigen Criteria to Diagnose Failure of Cancer Control following Focal Therapy of Nonmetastatic Prostate Cancer Using High Intensity Focused Ultrasound.

J Urol 2020 Apr 13;203(4):734-742. Epub 2020 Jan 13.

Division of Surgery and Interventional Sciences, University College London, London, United Kingdom.

Purpose: We determined whether prostate specific antigen criteria after focal high intensity focused ultrasound to treat prostate cancer could diagnose treatment failure.

Materials And Methods: A total of 598 patients in a prospectively maintained national database underwent focal high intensity focused ultrasound with a Sonablate® 500 device from March 2007 to November 2016. Followup consisted of 3-month clinic visits and prostate specific antigen testing in year 1 with prostate specific antigen measurement every 6 to 12 months and multiparametric magnetic resonance imaging with biopsy for magnetic resonance imaging suspicious for recurrence. Treatment failure was considered any secondary treatment, tumor recurrence with Gleason 3 + 4 or greater disease on prostate biopsy without further treatment or metastasis and/or prostate cancer related mortality. To diagnose failure we evaluated a series of nadir + x thresholds with x values of 0.1 to 2.0 ng/ml.

Results: Median patient age was 65 years (IQR 60-71) and the median Gleason score was 7 (range 6-9). Gleason 3 + 4 or greater disease was present in 80% of cases. Tumors were radiologically staged as T1c-T2c in 522 of the 596 patients (88%) and as T3a/b in 74 (12.4%). Baseline median prostate specific antigen was 7.80 ng/ml (IQR 5.96-10.45) in failed cases and 6.77 ng/ml (IQR 2.65-9.71) in cases without failure. Optimal performance according to the Youden index to indicate the most appropriate nadir + x at all analyzed time points at 3-month intervals showed that nadir + 1.0 ng/ml would have 27.3% to 100% sensitivity and 39.4% to 85.6% specificity depending on the time of evaluation in the first 3 years. Nadir + 1.5 ng/ml showed 18.2% to 100% sensitivity and 60.6% to 91.8% specificity with nadir + 2.0 ng/ml leading to similar sensitivity and specificity ranges. Nadir + 1.0 ng/ml at 12 months and nadir + 1.5 ng/ml at 24 and 36 months had 100% sensitivity and 96.1% to 100% negative predictive value.

Conclusions: Following focal high intensity focused ultrasound a prostate specific antigen nadir of 1.0 ng/ml at 12 months and 1.5 ng/ml at 24 to 36 months might be used to triage men requiring magnetic resonance imaging and biopsy. These data need prospective validation.
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http://dx.doi.org/10.1097/JU.0000000000000747DOI Listing
April 2020

Complication reporting with the Bern Comprehensive Complication Index CCI after open radical prostatectomy: A longitudinal long-term single-center study.

Urol Oncol 2020 03 31;38(3):79.e1-79.e8. Epub 2019 Dec 31.

Department of Urology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. Electronic address:

Objective: To impartially optimize complication reporting in patients after open radical prostatectomy (ORP) and pelvic lymph node dissection (PLND) by adopting the modified Bern Comprehensive Complication Index (CCI). ORP and PLND are associated with relevant postoperative morbidity. The CCI-ranging from 0 (no complications) to 100 (death)-is a tool that aims to integrate all complications occuring within 90 days postoperatively weighted by severity in a single formula.

Methods: In an observational single-center cohort, 90-day postoperative complications of 1,123 consecutive patients undergoing standardized ORP and PLND between 1996 and 2017 were evaluated. Prospectively collected complications were graded according to the Clavien-Dindo Classification. Grade I to II complications were defined as minor and grade IIIa to V as major. Finally, the recently developed modified Bern CCI using an exponential function, which transforms the sum of the weights into a value between 0 and 100 and the original CCI for each patient were extracted and compared. The correlation between the modified Bern and original CCI values was depicted graphically.

Results: The complication rate was 42%, with 18% minor and 24% major complications. With the original CCI, the threshold of 100 was exceeded in 1 patient who had a maximal index value of 101 within 90d postoperatively. The maximal value of the Bern CCI was 97.5. Mean Bern and original CCI scores and standard deviations were 6.2 (11.3) and 7.6 (12.2) at 30 days, and 9.3 (13.9) and 10.7 (14.2) at 90 days.

Conclusions: The Bern CCI provides a more precise depiction of postoperative morbidity and represents the burden in patients with >1 complication after ORP and PLND more accurately than the original CCI allowing for a more reliable evaluation of quality of care and recovery. It therefore warrants consideration for standardized reporting of complications after ORP and PLND.
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http://dx.doi.org/10.1016/j.urolonc.2019.09.021DOI Listing
March 2020

The Importance of Hospital and Surgeon Volume as Major Determinants of Morbidity and Mortality After Radical Cystectomy for Bladder Cancer: A Systematic Review and Recommendations by the European Association of Urology Muscle-invasive and Metastatic Bladder Cancer Guideline Panel.

Eur Urol Oncol 2020 04 19;3(2):131-144. Epub 2019 Dec 19.

Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.

Context: In bladder cancer patients treated with radical cystectomy (RC), controversy exists regarding the impact of the annual hospital volume (HV) and/or surgeon volume (SV) on oncological outcomes and quality of care.

Objective: A systematic review was performed to evaluate the impact of HV and SV on clinical outcomes. Primary outcomes included in-hospital, 30-d, and 90-d mortality. Secondary outcomes included complications, long-term survival, positive surgical margin rate, lymphadenectomy performance, length of hospital stay, neobladder performance, and blood loss/transfusion rate.

Evidence Acquisition: Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched. Comparative studies published after the year of 2000 including patients who underwent RC for bladder cancer were eligible for inclusion. Partial cystectomy was an exclusion criterion. Risk of bias (RoB) assessment was performed according to the ROBINS-1 tool.

Evidence Synthesis: After screening of 1190 abstracts, 39 studies recruiting 549 542 patients were included. All studies were retrospective observation cohort studies (level of evidence 3). Twenty-two studies reported on HV only, six studies on SV only, and 12 on both. Higher HV, specifically an HV of >10, was associated with improved primary and secondary outcomes in most studies. In addition, there is some evidence that an HV of >20 improves outcomes. For SV, limited and conflicting data are reported. Most studies had moderate to high RoB. The results were synthesized narratively.

Conclusions: Acknowledging the lower level of evidence, HV is likely associated with in-hospital, 30- and 90-d mortality, as well as the secondary outcomes assessed. Based on this study, the European Association of Urology Muscle-invasive and Metastatic Bladder Cancer Guideline Panel recommends hospitals to perform at least 10, and preferably >20, RCs annually or refer the patient to a center that reaches this number. For SV, limited and conflicting data are available. The available evidence suggests HV rather than SV to be the main driver of perioperative outcomes.

Patient Summary: Current literature suggests that the number of bladder removal operations per hospital per year is associated with postoperative survival as well as the quality of care provided.
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http://dx.doi.org/10.1016/j.euo.2019.11.005DOI Listing
April 2020

Preoperative plasma fatty acid metabolites inform risk of prostate cancer progression and may be used for personalized patient stratification.

BMC Cancer 2019 Dec 16;19(1):1216. Epub 2019 Dec 16.

Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland.

Background: Little is known about the relationship between the metabolite profile of plasma from pre-operative prostate cancer (PCa) patients and the risk of PCa progression. In this study we investigated the association between pre-operative plasma metabolites and risk of biochemical-, local- and metastatic-recurrence, with the aim of improving patient stratification.

Methods: We conducted a case-control study within a cohort of PCa patients recruited between 1996 and 2015. The age-matched primary cases (n = 33) were stratified in low risk, high risk without progression and high risk with progression as defined by the National Comprehensive Cancer Network. These samples were compared to metastatic (n = 9) and healthy controls (n = 10). The pre-operative plasma from primary cases and the plasma from metastatic patients and controls were assessed with untargeted metabolomics by LC-MS. The association between risk of progression and metabolite abundance was calculated using multivariate Cox proportional-hazard regression and the relationship between metabolites and outcome was calculated using median cut-off normalized values of metabolite abundance by Log-Rank test using the Kaplan Meier method.

Results: Medium-chain acylcarnitines (C6-C12) were positively associated with the risk of PSA progression (p = 0.036, median cut-off) while long-chain acylcarnitines (C14-C16) were inversely associated with local (p = 0.034) and bone progression (p = 0.0033). In primary cases, medium-chain acylcarnitines were positively associated with suberic acid, which also correlated with the risk of PSA progression (p = 0.032, Log-Rank test). In the metastatic samples, this effect was consistent for hexanoylcarnitine, L.octanoylcarnitine and decanoylcarnitine. Medium-chain acylcarnitines and suberic acid displayed the same inverse association with tryptophan, while indoleacetic acid, a breakdown product of tryptophan metabolism was strongly associated with PSA (p = 0.0081, Log-Rank test) and lymph node progression (p = 0.025, Log-Rank test). These data were consistent with the increased expression of indoleamine 2,3 dioxygenase (IDO1) in metastatic versus primary samples (p = 0.014). Finally, functional experiments revealed a synergistic effect of long chain fatty acids in combination with dihydrotestosterone administration on the transcription of androgen responsive genes.

Conclusions: This study strengthens the emerging link between fatty acid metabolism and PCa progression and suggests that measuring levels of medium- and long-chain acylcarnitines in pre-operative patient plasma may provide a basis for improving patient stratification.
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http://dx.doi.org/10.1186/s12885-019-6418-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916032PMC
December 2019

EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort: Under the Auspices of the EAU-ESMO Guidelines Committees.

Eur Urol 2020 02 19;77(2):223-250. Epub 2019 Nov 19.

Department of Biomedical Sciences, Humanitas University, Milan, Italy; Humanitas Research Hospital, Milan, Italy.

Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.

Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.

Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.

Setting: Online Delphi survey and consensus conference.

Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.

Outcome Measurements And Statistical Analysis: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).

Results And Limitations: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.

Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.

Patient Summary: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.
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http://dx.doi.org/10.1016/j.eururo.2019.09.035DOI Listing
February 2020
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