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1.
David C. Johnson Steven S. Raman Sohrab A. Mirak Lorna Kwan Amirhossein M. Bajgiran William Hsu Cleo K. Maehara Preeti Ahuja Izak Faiena Aydin Pooli Amirali Salmasi Anthony Sisk Ely R. Felker David S.K. Lu Robert E. Reiter 《European urology》2019,75(5):712-720
Background
Multiparametric magnetic resonance imaging (mpMRI) undoubtedly affects the diagnosis and treatment of localized prostate cancer (CaP). However, clinicians need a better understanding of its accuracy and limitations in detecting individual CaP foci to optimize management.Objective
To determine the per-lesion detection rate for CaP foci by mpMRI and identify predictors of tumor detection.Design, setting, and participants
We carried out a retrospective analysis of a prospectively managed database correlating lesion-specific results from mpMRI co-registered with whole-mount pathology (WMP) prostatectomy specimens from June 2010 to February 2018. Participants include 588 consecutive patients with biopsy-proven CaP undergoing 3-T mpMRI before radical prostatectomy at a single tertiary institution.Outcome measurements and statistical analysis
We measured mpMRI sensitivity in detecting individual CaP and clinically significant (any Gleason score ≥7) CaP foci and predictors of tumor detection using multivariate analysis.Results and limitations
The final analysis included 1213 pathologically confirmed tumor foci in 588 patients with primarily intermediate- (75%) or high-risk (12%) CaP. mpMRI detected 45% of all lesions (95% confidence interval [CI] 42–47%), including 65% of clinically significant lesions (95% CI 61–69%) and nearly 80% of high-grade tumors. Some 74% and 31% of missed solitary and multifocal tumors, respectively, were clinically significant. The majority of missed lesions were small (61.1% ≤1 cm); 28.3% were between 1 and 2 cm, and 10.4% were >2 cm. mpMRI missed at least one clinically significant focus in 34% of patients overall, and in 45% of men with multifocal lesions. On multivariate analysis, smaller, low-grade, multifocal, nonindex tumors with lower prostate-specific antigen density were more likely to be missed. Limitations include selection bias in a prostatectomy cohort, lack of specificity data, an imperfect co-registration process, and uncertain clinical significance for undetected lesions.Conclusions
mpMRI detects less than half of all and less than two-thirds of clinically significant CaP foci. The moderate per-lesion sensitivity and significant proportion of men with undetected tumor foci demonstrate the current limitations of mpMRI.Patient summary
Magnetic resonance imaging of the prostate before surgical removal for prostate cancer finds less than half of all individual prostate cancer tumors. Large, solitary, aggressive tumors are more likely to be visualized on imaging. 相似文献2.
Background
The response to first-line, platinum-based treatment of muscle-invasive bladder cancer has not improved in 3 decades.Objective
To identify genes that influence cisplatin resistance in bladder cancer.Design, setting, and participants
We performed a whole-genome CRISPR screen in a bladder cancer cell line to identify genes that mediate resistance to cisplatin.Outcome measurements and statistical analysis
Targeted validation was performed in two bladder cancer cell lines. The top gene candidate was validated in a publicly available bladder cancer dataset.Results and limitations
From the CRISPR screen, we identified MSH2 as the most significantly enriched gene and mismatch repair as the most significantly enriched pathway that promoted resistance to cisplatin. Bladder cancer cells with knockdown of MSH2 showed a reduction in cisplatin-mediated apoptosis. MSH2 loss did not impact the sensitivity to other chemotherapies, including the cisplatin analog oxaliplatin. Bladder tumors with low MSH2 protein levels, quantified using reverse-phase protein array, showed poorer survival when treated with cisplatin- or carboplatin-based therapy; these results require future validation using immunohistochemistry. Additionally, results are retrospective from patients with primarily high-grade tumors; thus, validation in a controlled clinical trial is needed.Conclusions
We generated in vitro evidence that bladder cancer cell lines depleted of MSH2 are more resistant to cisplatin. We additionally found an association between low MSH2 in bladder tumors and poorer patient survival when treated with platinum-based chemotherapy. If successfully validated prospectively, MSH2 protein level could assist in the selection of patients for chemotherapy.Patient summary
We report the first evidence that MSH2 protein level may contribute to chemotherapy resistance observed in muscle-invasive bladder cancer. MSH2 has potential as a biomarker predictive of response to platinum-based therapy. 相似文献3.
4.
Daniel J. Serie Richard W. Joseph John C. Cheville Thai H. Ho Mansi Parasramka Tracy Hilton R. Houston Thompson Bradley C. Leibovich Alexander S. Parker Jeanette E. Eckel-Passow 《European urology》2017,71(6):979-985
Background
Intratumor molecular heterogeneity has been reported for primary clear cell renal cell carcinoma (ccRCC) tumors; however, heterogeneity in metastatic ccRCC tumors has not been explored.Objective
To evaluate intra- and intertumor molecular heterogeneity in resected metastatic ccRCC tumors.Design, setting, and participants
We identified 111 patients who had tissue available from their primary tumor and at least one metastasis. ClearCode34 genes were analyzed for all tumors.Outcome measurements and statistical analysis
Primary and metastatic tumors were classified as clear cell type A (ccA) or B (ccB) subtypes. Logistic and Cox regression were used to evaluate associations with pathologic features and survival.Results and limitations
Intratumor heterogeneity of ccA/ccB subtypes was observed in 22% (95% confidence interval [CI] 3–60%) of metastatic tumors. Subtype differed across longitudinal metastatic tumors from the same patient in 23% (95% CI 10–42%) of patients and across patient-matched primary and metastatic tumors in 43% (95% CI 32–55%) of patients. Association of subtype with survival was validated in primary ccRCC tumors. The ccA/ccB subtype in metastatic tumors was significantly associated with metastatic tumor location, metastatic tumor grade, and presence of tumor necrosis. A limitation of this study is that we only analyzed patients who had both a nephrectomy and metastasectomy.Conclusions
Approximately one quarter of metastatic tumors displayed intratumor heterogeneity; a similar rate of heterogeneity was observed across longitudinal metastatic tumors. Thus, for biomarker studies it is likely adequate to analyze a single sample per metastatic tumor provided that pathologic review is incorporated into the study design. Subtypes across patient-matched primary and metastatic tumors differed 43% of the time, suggesting that the primary tumor is not a good surrogate for the metastatic tumor.Patient summary
Primary and secondary/metastatic cancers of the kidney differed in nearly one half of ccRCC patients. The pattern of this relationship may affect tumor growth and the most suitable treatment. 相似文献5.
Giorgio Gandaglia Guillaume Ploussard Massimo Valerio Agostino Mattei Cristian Fiori Nicola Fossati Armando Stabile Jean-Baptiste Beauval Bernard Malavaud Mathieu Roumiguié Daniele Robesti Paolo Dell’Oglio Marco Moschini Stefania Zamboni Arnas Rakauskas Francesco De Cobelli Francesco Porpiglia Francesco Montorsi Alberto Briganti 《European urology》2019,75(3):506-514
Background
Available models for predicting lymph node invasion (LNI) in prostate cancer (PCa) patients undergoing radical prostatectomy (RP) might not be applicable to men diagnosed via magnetic resonance imaging (MRI)-targeted biopsies.Objective
To assess the accuracy of available tools to predict LNI and to develop a novel model for men diagnosed via MRI-targeted biopsies.Design, setting, and participants
A total of 497 patients diagnosed via MRI-targeted biopsies and treated with RP and extended pelvic lymph node dissection (ePLND) at five institutions were retrospectively identified.Outcome measurements and statistical analyses
Three available models predicting LNI were evaluated using the area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analyses. A nomogram predicting LNI was developed and internally validated.Results and limitations
Overall, 62 patients (12.5%) had LNI. The median number of nodes removed was 15. The AUC for the Briganti 2012, Briganti 2017, and MSKCC nomograms was 82%, 82%, and 81%, respectively, and their calibration characteristics were suboptimal. A model including PSA, clinical stage and maximum diameter of the index lesion on multiparametric MRI (mpMRI), grade group on targeted biopsy, and the presence of clinically significant PCa on concomitant systematic biopsy had an AUC of 86% and represented the basis for a coefficient-based nomogram. This tool exhibited a higher AUC and higher net benefit compared to available models developed using standard biopsies. Using a cutoff of 7%, 244 ePLNDs (57%) would be spared and a lower number of LNIs would be missed compared to available nomograms (1.6% vs 4.6% vs 4.5% vs 4.2% for the new nomogram vs Briganti 2012 vs Briganti 2017 vs MSKCC).Conclusions
Available models predicting LNI are characterized by suboptimal accuracy and clinical net benefit for patients diagnosed via MRI-targeted biopsies. A novel nomogram including mpMRI and MRI-targeted biopsy data should be used to identify candidates for ePLND in this setting.Patient summary
We developed the first nomogram to predict lymph node invasion (LNI) in prostate cancer patients diagnosed via magnetic resonance imaging-targeted biopsy undergoing radical prostatectomy. Adoption of this model to identify candidates for extended pelvic lymph node dissection could avoid up to 60% of these procedures at the cost of missing only 1.6% patients with LNI. 相似文献6.
Rita Faria Marta O. Soares Eldon Spackman Hashim U. Ahmed Louise C. Brown Richard Kaplan Mark Emberton Mark J. Sculpher 《European urology》2018,73(1):23-30
Background
The current recommendation of using transrectal ultrasound-guided biopsy (TRUSB) to diagnose prostate cancer misses clinically significant (CS) cancers. More sensitive biopsies (eg, template prostate mapping biopsy [TPMB]) are too resource intensive for routine use, and there is little evidence on multiparametric magnetic resonance imaging (MPMRI).Objective
To identify the most effective and cost-effective way of using these tests to detect CS prostate cancer.Design, setting, and participants
Cost-effectiveness modelling of health outcomes and costs of men referred to secondary care with a suspicion of prostate cancer prior to any biopsy in the UK National Health Service using information from the diagnostic Prostate MR Imaging Study (PROMIS).Intervention
Combinations of MPMRI, TRUSB, and TPMB, using different definitions and diagnostic cut-offs for CS cancer.Outcome measurements and statistical analysis
Strategies that detect the most CS cancers given testing costs, and incremental cost-effectiveness ratios (ICERs) in quality-adjusted life years (QALYs) given long-term costs.Results and limitations
The use of MPMRI first and then up to two MRI-targeted TRUSBs detects more CS cancers per pound spent than a strategy using TRUSB first (sensitivity = 0.95 [95% confidence interval {CI} 0.92–0.98] vs 0.91 [95% CI 0.86–0.94]) and is cost effective (ICER = £7,076 [€8350/QALY gained]). The limitations stem from the evidence base in the accuracy of MRI-targeted biopsy and the long-term outcomes of men with CS prostate cancer.Conclusions
An MPMRI-first strategy is effective and cost effective for the diagnosis of CS prostate cancer. These findings are sensitive to the test costs, sensitivity of MRI-targeted TRUSB, and long-term outcomes of men with cancer, which warrant more empirical research. This analysis can inform the development of clinical guidelines.Patient summary
We found that, under certain assumptions, the use of multiparametric magnetic resonance imaging first and then up to two transrectal ultrasound-guided biopsy is better than the current clinical standard and is good value for money. 相似文献7.
Gillian Vandekerkhove Werner J. Struss Matti Annala Heini M.L. Kallio Daniel Khalaf Evan W. Warner Cameron Herberts Elie Ritch Kevin Beja Yulia Loktionova Antonio Hurtado-Coll Ladan Fazli Alan So Peter C. Black Matti Nykter Teuvo Tammela Kim N. Chi Martin E. Gleave Alexander W. Wyatt 《European urology》2019,75(4):667-675
Background
Several systemic therapeutic options exist for metastatic castrate-sensitive prostate cancer (mCSPC). Circulating tumor DNA (ctDNA) can molecularly profile metastatic castration-resistant prostate cancer and can influence decision-making, but remains untested in mCSPC.Objective
To determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically relevant information to a prostate biopsy.Design, setting, and participants
We collected plasma cell-free DNA (cfDNA) from 53 patients newly diagnosed with mCSPC and, where possible, during treatment. Targeted sequencing was performed on cfDNA and DNA from diagnostic prostate tissue.Results and limitations
The median ctDNA fraction was 11% (range 0–84%) among untreated patients but was lower (1.0%, range 0-51%) among patients after short-term (median 22 d) androgen deprivation therapy (ADT). TP53 mutations and DNA repair defects were identified in 47% and 21% of the cohort, respectively. The concordance for mutation detection in matched samples was 80%. Combined ctDNA and tissue analysis identified potential driver alterations in 94% of patients, whereas ctDNA or prostate biopsy alone was insufficient in 19 cases (36%). Limitations include the use of a narrow gene panel and undersampling of primary disease by prostate biopsy.Conclusions
ctDNA provides additional information to a prostate biopsy in men with de novo mCSPC, but ADT rapidly reduces ctDNA availability. Primary tissue and ctDNA share relevant somatic alterations, suggesting that either is suitable for molecular subtyping in de novo mCSPC. The optimal approach for biomarker development should utilize both a tissue and liquid biopsy at diagnosis, as neither captures clinically relevant somatic alterations in all patients.Patient summary
In men with advanced prostate cancer, tumor DNA shed into the bloodstream can be measured via a blood test. The information from this test provides complementary information to a prostate needle biopsy and could be used to guide management strategies.Sequencing data were deposited in the European Genome-phenome Archive (EGA) under study identifier EGAS00001003351. 相似文献8.
9.
10.
Vito Cucchiara Matthew R. Cooperberg Marc Dall’Era Daniel W. Lin Francesco Montorsi Jack A. Schalken Christopher P. Evans 《European urology》2018,73(4):572-582
Context
Although the widespread use of prostate-specific antigen (PSA) has led to an early detection of prostate cancer (PCa) and a reduction of metastatic disease at diagnosis, PSA remains one of the most controversial biomarkers due to its limited specificity. As part of emerging efforts to improve both detection and management decision making, a number of new genomic tools have recently been developed.Objective
This review summarizes the ability of genomic biomarkers to recognize men at high risk of developing PCa, discriminate clinically insignificant and aggressive tumors, and facilitate the selection of therapies in patients with advanced disease.Evidence acquisition
A PubMed-based literature search was conducted up to May 2017. We selected the most recent and relevant original articles and clinical trials that have provided indispensable information to guide treatment decisions.Evidence synthesis
Genome-wide association studies have identified several genetic polymorphisms and inherited variants associated with PCa susceptibility. Moreover, the urine-based assays SelectMDx, Mi-Prostate Score, and ExoDx have provided new insights into the identification of patients who may benefit from prostate biopsy. In men with previous negative pathological findings, Prostate Cancer Antigen 3 and ConfirmMDx predicted the outcome of subsequent biopsy. Commercially available tools (Decipher, Oncotype DX, and Prolaris) improved PCa risk stratification, identifying men at the highest risk of adverse outcome. Furthermore, other biomarkers could assist in treatment selection in castration-resistant PCa. AR-V7 expression predicts resistance to abiraterone/enzalutamide, while poly(ADP-ribose) polymerase-1 inhibitor and platinum-based chemotherapy could be indicated in metastatic patients who are carriers of mutations in DNA mismatch repair genes.Conclusions
Introduction of genomic biomarkers has dramatically improved the detection, prognosis, and risk evaluation of PCa. Despite the progress made in discovering suitable biomarker candidates, few have been used in a clinical setting. Large-scale and multi-institutional studies are required to validate the efficacy and cost utility of these new technologies.Patient summary
Prostate cancer is a heterogeneous disease with a wide variability. Genomic biomarkers in combination with clinical and pathological variables are useful tools to reduce the number of unnecessary biopsies, stratify low-risk from high-risk tumors, and guide personalized treatment decisions. 相似文献11.
Nick van Dijk Samuel A. Funt Christian U. Blank Thomas Powles Jonathan E. Rosenberg Michiel S. van der Heijden 《European urology》2019,75(3):435-444
Context
The abysmal outlook of urothelial cancer (UC) has changed with the introduction of immunotherapy. Still, many patients do not respond and distinctive biomarkers are currently lacking. The rise of this novel armamentarium of immunotherapy treatments, in combination with the complex biology of an immunological tumor response, warrants the development of a comprehensive framework that can provide an overview of important immunological processes at play in individual patients.Objective
To develop a comprehensive framework based on tumor- and host-specific parameters to understand immunotherapy response in UC. This framework can inform rational, biology-driven clinical trials and ultimately guide us toward individualized patient treatment.Evidence acquisition
A literature review was conducted on UC immunotherapy, clinical trial data, and biomarkers of response to checkpoint inhibition.Evidence synthesis
Here, we propose a UC immunogram, based on currently available clinical and translational data. The UC immunogram describes several tumor- and host-specific parameters that are required for successful immunotherapy treatment. These seven parameters are tumor foreignness, immune cell infiltration, absence of inhibitory checkpoints, general performance and immune status, absence of soluble inhibitors, absence of inhibitory tumor metabolism, and tumor sensitivity to immune effectors.Conclusions
Longitudinal integration of individual patient parameters may ultimately lead to personalized and dynamic immunotherapy, to adjust to the Darwinian forces that drive tumor evolution. Incorporating multiparameter biomarkers into quantitative predictive models will be a key challenge to integrate the immunogram into daily clinical practice.Patient summary
Here, we propose the urothelial cancer immunogram, a novel way of describing important immunological characteristics of urothelial cancer patients and their tumors. Seven characteristics determine the chance of having an immunological tumor response. Using this immunogram, we aim to better understand why some patients respond to immunotherapy and some do not, to ultimately improve anticancer therapy. 相似文献12.
13.
Joaquin Mateo Karim Fizazi Silke Gillessen Axel Heidenreich Raquel Perez-Lopez Wim J.G. Oyen Neal Shore Matthew Smith Christopher Sweeney Bertrand Tombal Scott A. Tomlins Johann S. de Bono 《European urology》2019,75(2):285-293
Context
Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have rising prostate-specific antigen (PSA) and castrate testosterone levels, with no radiological findings of metastatic disease on computed tomography and bone scan. Given recent drug approvals for nmCRPC, with many other therapeutics and imaging modalities being developed, management of nmCRPC is a rapidly evolving field that merits detailed investigation.Objective
To review current nmCRPC management practices and identify opportunities for improving care of nmCRPC patients.Evidence acquisition
A literature search up to July 2018 was conducted, including clinical trials and clinical practice guidelines (National Comprehensive Cancer Network, European Society for Medical Oncology, European Association of Urology, Prostate Cancer Clinical Trials Working Group, Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence). Keywords included prostate cancer, nonmetastatic, castration resistance, rising PSA, and biochemical relapse.Evidence synthesis
Recommendations regarding indications for, and frequency of, imaging and PSA testing, as well as for initiating systemic therapy in nmCRPC are based on PSA rise kinetics and symptoms. Both enzalutamide and apalutamide have been shown to significantly increase metastasis-free survival in phase III placebo-controlled randomised trials in nmCRPC patients with PSA doubling time (DT) ≤10 mo. The expected impact of new imaging techniques in the assessment of nmCRPC is also reviewed.Conclusions
nmCRPC is a heterogeneous disease; while observation may be an option for some patients, enzalutamide and apalutamide may be appropriate to treat nmCRPC patients with PSA-DT ≤10 mo. The emergence of more accurate imaging modalities as well as circulating tumour biomarker assays will likely redefine the assessment of nmCRPC in the near future.Patient summary
Herein, we review key literature and clinical practice guidelines to summarise the optimal management of patients with prostate cancer and rising prostate-specific antigen despite castrate testosterone levels, but with no evidence of distant metastasis on traditional imaging. New drugs are being developed for this disease setting; novel imaging and tumour biomarker blood tests are likely to define this disease state more accurately. 相似文献14.
Martijn G. Schouten Marloes van der Leest Morgan Pokorny Martijn Hoogenboom Jelle O. Barentsz Les C. Thompson Jurgen J. Fütterer 《European urology》2017,71(6):896-903
Background
Knowledge of significant prostate (sPCa) locations being missed with magnetic resonance (MR)- and transrectal ultrasound (TRUS)-guided biopsy (Bx) may help to improve these techniques.Objective
To identify the location of sPCa lesions being missed with MR- and TRUS-Bx.Design, setting, and participants
In a referral center, 223 consecutive Bx-naive men with elevated prostate specific antigen level and/or abnormal digital rectal examination were included. Histopathologically-proven cancer locations, Gleason score, and tumor length were determined.Intervention
All patients underwent multi-parametric MRI and 12-core systematic TRUS-Bx. MR-Bx was performed in all patients with suspicion of PCa on multi-parametric MRI (n = 142).Outcome measurements and statistical analysis
Cancer locations were compared between MR- and TRUS-Bx. Proportions were expressed as percentages, and the corresponding 95% confidence intervals were calculated.Results and limitations
In total, 191 lesions were found in 108 patients with sPCa. From these lesion 74% (141/191) were defined as sPCa on either MR- or TRUS-Bx. MR-Bx detected 74% (105/141) of these lesions and 61% (86/141) with TRUS-Bx. TRUS-Bx detected more lesions compared with MR-Bx (140 vs 109). However, these lesions were often low risk (39%). Significant lesions missed with MR-Bx most often had involvement of dorsolateral (58%) and apical (37%) segments and missed segments with TRUS-Bx were located anteriorly (79%), anterior midprostate (50%), and anterior apex (23%).Conclusions
Both techniques have difficulties in detecting apical lesions. MR-Bx most often missed cancer with involvement of the dorsolateral part (58%) and TRUS-Bx with involvement of the anterior part (79%).Patient summary
Both biopsy techniques miss cancer in specific locations within the prostate. Identification of these lesions may help to improve these techniques. 相似文献15.
Sami Hamid Ian A. Donaldson Yipeng Hu Rachael Rodell Barbara Villarini Ester Bonmati Pamela Tranter Shonit Punwani Harbir S. Sidhu Sarah Willis Jan van der Meulen David Hawkes Neil McCartan Ingrid Potyka Norman R. Williams Chris Brew-Graves Alex Freeman Caroline M. Moore Hashim U. Ahmed 《European urology》2019,75(5):733-740
Background
Multiparametric magnetic resonance imaging (mpMRI)-targeted prostate biopsies can improve detection of clinically significant prostate cancer and decrease the overdetection of insignificant cancers. It is unknown whether visual-registration targeting is sufficient or augmentation with image-fusion software is needed.Objective
To assess concordance between the two methods.Design, setting, and participants
We conducted a blinded, within-person randomised, paired validating clinical trial. From 2014 to 2016, 141 men who had undergone a prior (positive or negative) transrectal ultrasound biopsy and had a discrete lesion on mpMRI (score 3–5) requiring targeted transperineal biopsy were enrolled at a UK academic hospital; 129 underwent both biopsy strategies and completed the study.Intervention
The order of performing biopsies using visual registration and a computer-assisted MRI/ultrasound image-fusion system (SmartTarget) on each patient was randomised. The equipment was reset between biopsy strategies to mitigate incorporation bias.Outcome measurements and statistical analysis
The proportion of clinically significant prostate cancer (primary outcome: Gleason pattern ≥3 + 4 = 7, maximum cancer core length ≥4 mm; secondary outcome: Gleason pattern ≥4 + 3 = 7, maximum cancer core length ≥6 mm) detected by each method was compared using McNemar's test of paired proportions.Results and limitations
The two strategies combined detected 93 clinically significant prostate cancers (72% of the cohort). Each strategy detected 80/93 (86%) of these cancers; each strategy identified 13 cases missed by the other. Three patients experienced adverse events related to biopsy (urinary retention, urinary tract infection, nausea, and vomiting). No difference in urinary symptoms, erectile function, or quality of life between baseline and follow-up (median 10.5 wk) was observed. The key limitations were lack of parallel-group randomisation and a limit on the number of targeted cores.Conclusions
Visual-registration and image-fusion targeting strategies combined had the highest detection rate for clinically significant cancers. Targeted prostate biopsy should be performed using both strategies together.Patient summary
We compared two prostate cancer biopsy strategies: visual registration and image fusion. A combination of the two strategies found the most clinically important cancers and should be used together whenever targeted biopsy is being performed. 相似文献16.
Eugene J. Pietzak Emily C. Zabor Aditya Bagrodia Joshua Armenia Wenhuo Hu Ahmet Zehir Samuel Funt Francois Audenet David Barron Noelia Maamouri Qiang Li Min Yuen Teo Maria E. Arcila Michael F. Berger Nikolaus Schultz Guido Dalbagni Harry W. Herr Dean F. Bajorin Gopa Iyer 《European urology》2019,75(2):231-239
Background
Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). It is unknown whether this treatment strategy is appropriate for patients who progress to MIBC after treatment for prior noninvasive disease (secondary MIBC).Objective
To determine whether clinical and genomic differences exist between primary and secondary MIBC treated with NAC and RC.Design, setting, and participants
Clinicopathologic outcomes were compared between 245 patients with clinical T2-4aN0M0-stage primary MIBC and 43 with secondary MIBC treated with NAC and RC at Memorial Sloan Kettering Cancer Center (MSKCC) from 2001 to 2015. Genomic differences were assessed in a retrospective cohort of 385 prechemotherapy specimens sequenced by whole-exome or targeted exon capture by the Cancer Genome Atlas or at MSKCC. Findings were confirmed in an independent validation cohort of 94 MIBC patients undergoing prospective targeted exon sequencing at MSKCC.Outcome measurements and statistical analysis
Pathologic response rates, recurrence-free survival (RFS), bladder cancer-specific survival (CSS), and overall survival (OS) were measured. Differences in somatic genomic alteration rates were compared using Fisher's exact test and the Benjamini-Hochberg false discovery rate method.Results and limitations
Patients with secondary MIBC had lower pathologic response rates following NAC than those with primary MIBC (univariable: 26% vs 45%, multivariable: odds ratio = 0.4 [95% confidence interval = 0.18 ? 0.84] p = 0.02) and significantly worse RFS, CSS, and OS. Patients with secondary MIBC treated with NAC had worse CSS compared with cystectomy alone (p = 0.002). In a separate genomic analysis, we detected significantly more likely deleterious somatic ERCC2 missense mutations in primary MIBC tumors in both the discovery (10.9% [36/330] vs 1.8% [1/55], p = 0.04) and the validation (15.7% [12/70] vs 0% [0/24], p = 0.03) cohort.Conclusions
Patients with secondary MIBC treated with NAC had worse clinical outcomes than similarly treated patients with primary MIBC. ERCC2 mutations predicted to result in increased cisplatin sensitivity were enriched in primary versus secondary MIBC. Prospective validation is still needed, but given the lack of clinical benefit with cisplatin-based NAC in patients with secondary MIBC, upfront RC or enrollment in clinical trials should be considered.Patient summary
A retrospective cohort study of patients with “primary” and “secondary” muscle-invasive bladder cancer (MIBC) treated with chemotherapy before surgical removal of the bladder identified lower response rates and shorter survival in patients with secondary MIBC. Tumor genetic sequencing of separate discovery and validation cohorts revealed that chemotherapy-sensitizing DNA damage repair gene mutations occur predominantly in primary MIBC tumors and may underlie the greater sensitivity of primary MIBC to chemotherapy. Prospective validation is still needed, but patients with secondary MIBC may derive greater benefit from upfront surgery or enrollment in clinical trials rather than from standard chemotherapy. 相似文献17.
Liselotte M.S. Boevé Maarten C.C.M. Hulshof André N. Vis Aeilko H. Zwinderman Jos W.R. Twisk Wim P.J. Witjes Karl P.J. Delaere R. Jeroen A. van Moorselaar Paul C.M.S. Verhagen George van Andel 《European urology》2019,75(3):410-418
Background
The cornerstone of standard treatment for patients with primary bone metastatic prostate cancer (mPCa) is androgen deprivation therapy (ADT). Retrospective studies suggest a survival benefit for treatment of the primary prostatic tumour in mPCa, but to date, no randomised-controlled-trials (RCTs) have been published addressing this issue.Objective
To determine whether overall survival is prolonged by adding local treatment of the primary prostatic tumour with external beam radiation therapy (EBRT) to ADT.Design, setting, and participants
The HORRAD trial is a multicentre RCT recruiting 432 patients with prostate-specific antigen (PSA) >20 ng/ml and primary bone mPCa on bone scan between 2004 and 2014.Intervention
Patients were randomised to either ADT with EBRT (radiotherapy group) or ADT alone (control group).Outcome measurements and statistical analysis
Primary endpoint was overall survival. Secondary endpoint was time to PSA progression. Crude and adjusted analyses were applied to evaluate treatment effect.Results and limitations
Median PSA level was 142 ng/ml and 67% of patients had more than five osseous metastases. Median follow up was 47 mo. Median overall survival was 45 mo (95% confidence interval [CI], 40.4–49.6) in the radiotherapy group and 43 mo (95% CI: 32.6–53.4) in the control group (p = 0.4). No significant difference was found in overall survival (hazard ratio [HR]: 0.90; 95% CI: 0.70–1.14; p = 0.4). Median time to PSA progression in the radiotherapy group was 15 mo (95% CI: 11.8–18.2), compared with 12 mo (95% CI: 10.6–13.4) in the control group. The crude HR (0.78; 95% CI: 0.63–0.97) was statistically significant (p = 0.02).Conclusions
The current RCT comparing ADT to ADT with EBRT to the prostate in patients with primary bone mPCa did not show a significant difference in overall survival, although the CI cannot exclude a substantial survival benefit. Further research is needed to confirm our findings.Patient summary
This study investigated the effect of adding radiation therapy to the prostate to hormonal therapy in prostate cancer patients with metastasis to the bone at diagnosis. In our patient group, additional radiotherapy did not improve overall survival. Further research is needed to confirm our findings.Twitter summary
Adding radiotherapy to the prostate in patients with bone metastatic prostate cancer does not improve overall survival. 相似文献18.
Qiang Fu Le Xu Yiwei Wang Qi Jiang Zheng Liu Junyu Zhang Quan Zhou Han Zeng Shanyou Tong Tao Wang Yangyang Qi Baoying Hu Hangcheng Fu Huyang Xie Lin Zhou Yuan Chang Yu Zhu Bo Dai Jiejie Xu 《European urology》2019,75(5):752-763
Background
Glutamine addiction is a hallmark of clear cell renal cell carcinoma (ccRCC); yet whether glutamine metabolism impacts local immune surveillance is unclear. This knowledge may yield novel immunotherapeutic opportunities.Objective
To seek a potential therapeutic target in glutamine-addicted ccRCC.Design, setting, and participants
Tumors from ccRCC patients from a Shanghai cohort and ccRCC tumor data from The Cancer Genome Atlas (TCGA) cohort were analyzed. In vivo and in vitro studies were conducted with fresh human ccRCC tumors and murine tumor cells.Outcome measurements and statistical analysis
Immune cell numbers and functions were analyzed by flow cytometry. Glutamine and cytokine concentrations were determined. Survival was compared between different subpopulations of patients using Kaplan-Meier and Cox regression analyses.Results and limitations
We found that in ccRCC, high interleukin (IL)-23 expression was significantly associated with poor survival in both TCGA (overall survival [OS] hazard ratio [HR] = 2.04, cancer-specific survival [CSS] HR = 2.95; all p < 0.001) and Shanghai (OS HR = 2.07, CSS HR = 3.92; all p < 0.001) cohorts. IL-23 blockade prolongs the survival of tumor-bearing mice, promotes T-cell cytotoxicity in in vitro cultures of human ccRCC tumors, and augments the therapeutic benefits of anti-PD-1 antibodies. Mechanistically, glutamine consumption by ccRCC tumor cells results in the local deprivation of extracellular glutamine, which induces IL-23 secretion by tumor-infiltrating macrophages via the activation of hypoxia-inducible factor 1α (HIF1α). IL-23 activates regulatory T-cell proliferation and promotes IL-10 and transforming growth factor β expression, thereby suppressing tumor cell killing by cytotoxic lymphocytes. The positive correlations between glutamine metabolism, IL-23 levels, and Treg responses are confirmed in both TCGA cohort and tumors from Shanghai ccRCC patients. Study limitations include the unclear impacts of glutamine deprivation and IL-23 on other immune cells.Conclusions
Macrophage-secreted IL-23 enhanced Treg functions in glutamine-addicted tumors; thus, IL-23 is a promising target for immunotherapy in ccRCC.Patient summary
In this study, we analyzed the immune components in glutamine-addicted clear cell renal cell carcinoma (ccRCC) tumors from two patient cohorts and conducted both in vitro and in vivo studies. We found that ccRCC tumor cell-intrinsic glutamine metabolism orchestrates immune evasion via interleukin (IL)-23, and IL-23–high patients had significantly poorer survival than IL-23–low patients. IL-23 should thus be considered a therapeutic target in ccRCC, either alone or in combination with immune checkpoint inhibitors. 相似文献19.
Daniel J. Canter Julia Reid Maria Latsis Margaret Variano Shams Halat Saradha Rajamani Kristen E. Gurtner Zaina Sangale Michael Brawer Steven Stone Stephen Bardot 《European urology》2019,75(3):515-522
Background
Better prostate cancer risk stratification is necessary to inform medical management, especially for African American (AA) men, for whom outcomes are particularly uncertain.Objective
To evaluate the utility of both a cell cycle progression (CCP) score and a clinical cell-cycle risk (CCR) score to predict clinical outcomes in a large cohort of men with prostate cancer highly enriched in an AA patient population.Design, setting, and participants
Patients were diagnosed with clinically localized adenocarcinoma of the prostate and treated at The Ochsner Clinic (New Orleans, LA, USA) from January 2006 to December 2011. CCP scores were derived from archival formalin-fixed, paraffin-embedded biopsy tissue. CCR scores were calculated as the combination of molecular (CCP score) and clinical (Cancer of the Prostate Risk Assessment [CAPRA] score) components.Intervention
Active treatment (radical prostatectomy, radiation therapy alone, or radiation and hormone therapy) or watchful waiting.Outcome measurements and statistical analysis
The primary outcome was progression to metastatic disease. Association with outcomes was evaluated via Cox proportional hazards survival analysis and likelihood ratio tests.Results and limitations
The final cohort included 767 men, of whom 281 (36.6%) were AA. After accounting for ancestry, treatment, and CAPRA in multivariable analysis, the CCP score remained a significant predictor of metastatic disease (hazard ratio [HR] 2.04; p < 0.001), and there was no interaction with ancestry (p = 0.20) or treatment (p = 0.09). The CCR score was highly prognostic (HR 3.86; p < 0.001), and as with the CCP score, there was no interaction with ancestry (p = 0.24) or treatment (p = 0.32). Limitations include the retrospective study design and the use of self-reported ancestry information.Conclusions
A CCR score provided significant prognostic information regardless of ancestry. The findings demonstrate that AA men in this study cohort appear to have similar prostate cancer outcomes to non-AA patients after accounting for all available molecular and clinicopathologic variables.Patient summary
In this study we evaluated the ability of a combined molecular and clinical score to predict the progression of localized prostate cancer. We found that the combined molecular and clinical score predicted progression to metastasis regardless of patient ancestry or treatment. This suggests that the combined molecular and clinical score may be a valuable tool for determining the risk of metastasis in men with newly diagnosed prostate cancer in order to make appropriate treatment decisions. 相似文献20.
Börje Ljungberg Laurance Albiges Yasmin Abu-Ghanem Karim Bensalah Saeed Dabestani Sergio Fernández-Pello Montes Rachel H. Giles Fabian Hofmann Milan Hora Markus A. Kuczyk Teele Kuusk Thomas B. Lam Lorenzo Marconi Axel S. Merseburger Thomas Powles Michael Staehler Rana Tahbaz Alessandro Volpe Axel Bex 《European urology》2019,75(5):799-810