Publications by authors named "Ashutosh Tewari"

232 Publications

Comparative analysis of 1152 African-American and European-American men with prostate cancer identifies distinct genomic and immunological differences.

Commun Biol 2021 Jun 3;4(1):670. Epub 2021 Jun 3.

Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P < 0.001) and ETS (P = 0.02) expression, decreased SPINK1 expression (P < 0.001), and basal-like (P < 0.001) molecular subtypes. After adjusting for confounders, the AAM group was associated with higher expression of CRYBB2, GSTM3, and inflammation genes (IL33, IFNG, CCL4, CD3, ICOSLG), and lower expression of mismatch repair genes (MSH2, MSH6) (p < 0.001 for all). At the pathway level, the AAM group had higher expression of genes sets related to the immune response, apoptosis, hypoxia, and reactive oxygen species. EAM group was associated with higher levels of fatty acid metabolism, DNA repair, and WNT/beta-catenin signaling. Based on cell lines data, AAM were predicted to have higher potential response to DNA damage. In conclusion, biological characteristics of prostate tumor were substantially different in AAM when compared to EAM.
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http://dx.doi.org/10.1038/s42003-021-02140-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175556PMC
June 2021

A COVID-19 Test Triage Tool, Predicting Negative Results and Reducing the Testing Burden on Healthcare Systems During a Pandemic.

Front Med (Lausanne) 2021 29;8:563465. Epub 2021 Apr 29.

Department of Urology, Icahn School of Medicine, Mount Sinai Hospitals, New York, NY, United States.

Detecting and isolating cases of COVID-19 are amongst the key elements listed by the WHO to reduce transmission. This approach has been reported to reduce those symptomatic with COVID-19 in the population by over 90%. Testing is part of a strategy that will save lives. Testing everyone maybe ideal, but it is not practical. A risk tool based on patient demographics and clinical parameters has the potential to help identify patients most likely to test negative for SARS-CoV-2. If effective it could be used to aide clinical decision making and reduce the testing burden. At the time of this analysis, a total of 9,516 patients with symptoms suggestive of Covid-19, were assessed and tested at Mount Sinai Institutions in New York. Patient demographics, clinical parameters and test results were collected. A robust prediction pipeline was used to develop a risk tool to predict the likelihood of a positive test for Covid-19. The risk tool was analyzed in a holdout dataset from the cohort and its discriminative ability, calibration and net benefit assessed. Over 48% of those tested in this cohort, had a positive result. The derived model had an AUC of 0.77, provided reliable risk prediction, and demonstrated a superior net benefit than a strategy of testing everybody. When a risk cut-off of 70% was applied, the model had a negative predictive value of 96%. Such a tool could be used to help aide but not replace clinical decision making and conserve vital resources needed to effectively tackle this pandemic.
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http://dx.doi.org/10.3389/fmed.2021.563465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116585PMC
April 2021

Computer extracted gland features from H&E predicts prostate cancer recurrence comparably to a genomic companion diagnostic test: a large multi-site study.

NPJ Precis Oncol 2021 May 3;5(1):35. Epub 2021 May 3.

Department of Urology, Case Western Reserve University, Cleveland, OH, USA.

Existing tools for post-radical prostatectomy (RP) prostate cancer biochemical recurrence (BCR) prognosis rely on human pathologist-derived parameters such as tumor grade, with the resulting inter-reviewer variability. Genomic companion diagnostic tests such as Decipher tend to be tissue destructive, expensive, and not routinely available in most centers. We present a tissue non-destructive method for automated BCR prognosis, termed "Histotyping", that employs computational image analysis of morphologic patterns of prostate tissue from a single, routinely acquired hematoxylin and eosin slide. Patients from two institutions (n = 214) were used to train Histotyping for identifying high-risk patients based on six features of glandular morphology extracted from RP specimens. Histotyping was validated for post-RP BCR prognosis on a separate set of n = 675 patients from five institutions and compared against Decipher on n = 167 patients. Histotyping was prognostic of BCR in the validation set (p < 0.001, univariable hazard ratio [HR] = 2.83, 95% confidence interval [CI]: 2.03-3.93, concordance index [c-index] = 0.68, median years-to-BCR: 1.7). Histotyping was also prognostic in clinically stratified subsets, such as patients with Gleason grade group 3 (HR = 4.09) and negative surgical margins (HR = 3.26). Histotyping was prognostic independent of grade group, margin status, pathological stage, and preoperative prostate-specific antigen (PSA) (multivariable p < 0.001, HR = 2.09, 95% CI: 1.40-3.10, n = 648). The combination of Histotyping, grade group, and preoperative PSA outperformed Decipher (c-index = 0.75 vs. 0.70, n = 167). These results suggest that a prognostic classifier for prostate cancer based on digital images could serve as an alternative or complement to molecular-based companion diagnostic tests.
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http://dx.doi.org/10.1038/s41698-021-00174-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093226PMC
May 2021

Increased Hospitalization and Mortality from COVID-19 in Prostate Cancer Patients.

Cancers (Basel) 2021 Apr 1;13(7). Epub 2021 Apr 1.

Department of Urology and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Background: Cancer patients with COVID-19 have a poor disease course. Among tumor types, prostate cancer and COVID-19 share several risk factors, and the interaction of prostate cancer and COVID-19 is purported to have an adverse outcome.

Methods: This was a single-institution retrospective study on 286,609 patients who underwent the COVID-19 test at Mount Sinai Hospital system from March 2020 to December 2020. Chi-square/Fisher's exact tests were used to summarize baseline characteristics of categorical data, and Mann-Whitney U test was used for continuous variables. Univariable logistic regression analysis to compare the hospitalization and mortality rates and the strength of association was obtained by the odds ratio and confidence interval.

Results: This study aimed to compare hospitalization and mortality rates between men with COVID-19 and prostate cancer and those who were COVID-19-positive with non-prostate genitourinary malignancy or any solid cancer, and with breast cancer patients. We also compared our studies to others that reported the incidence and severity of COVID-19 in prostate cancer patients. Our studies highlight that patients with prostate cancer had higher susceptibility to COVID-19-related pathogenesis, resulting in higher mortality and hospitalization rates. Hospitalization and mortality rates were higher in prostate cancer patients with COVID-19 when compared with COVID-19 patients with non-prostate genitourinary (GU) malignancies.
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http://dx.doi.org/10.3390/cancers13071630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037308PMC
April 2021

Small Molecule, Multimodal, [F]-PET and Fluorescence Imaging Agent Targeting Prostate-Specific Membrane Antigen: First-in-Human Study.

Clin Genitourin Cancer 2021 Mar 19. Epub 2021 Mar 19.

Department of Nuclear Medicine, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey.

Background: A first-in-human study of [F]-BF3-Cy3-ACUPA, a small-molecule contrast agent that can be unimolecularly both positron emitting and fluorescent, is conducted to determine its: its safety, biodistribution, radiation dosimetry, feasibility in tumor detection by preoperative positron emission tomography (PET), as well as its intraoperative fluorescence imaging utility in patients with prostate-specific membrane antigen positive (PSMA) tumors.

Methods: Ten patients aged 66 ± 7 years received a 6.5 ± 3.2 mCi intravenous injection of [F]-BF3-Cy3-ACUPA and underwent PET/computed tomography (CT) imaging. Radiation dosimetry of [F]-BF3-Cy3-ACUPA, normal organ biodistribution, and tumor uptakes were examined. Two patients were prescheduled for radical prostatectomy (RP) with extended pelvic lymphadenectomy approximately 24 hours following [F]-BF3-Cy3-ACUPA injection and imaging. Without reinjection, intraoperative fluorescence imaging was performed on freshly excised tissue during RP. Frozen sections of excised tissue during RP were submitted for confirmatory histopathology and multiphoton fluorescence and brightfield microscopy.

Results: Absorbed doses by organs including the kidneys and salivary glands were similar to 68Ga-PSMA-11 imaging. [F]-BF3-Cy3-ACUPA physiologic radiotracer accumulation and urinary/biliary excretion closely resembled the distribution of other published PSMA tracers including [F]-JK-PSMA-7, [F]-PSMA-1007, [F]-DCFPyL, and [F]-DCFBC. F-BF3-Cy3-ACUPA was retained in PSMA cancer in patients for at least 24 hours, allowing for intraoperative fluorescence assessment of the prostate and of the embedded prostate cancer without contrast reinjection. After 24 hours, the majority of contrast had decayed or cleared from the blood pool. Preoperative PET and fluorescence imaging findings were confirmed with final histopathology and multiphoton microscopy.

Conclusion: Our first-in-human results demonstrate that [F]-BF3-Cy3-ACUPA is both safe and useful in humans. Larger trials with this PET tracer are expected to further define its capabilities and its clinical role in the management of PSMA tumors, especially in prostate cancer.
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http://dx.doi.org/10.1016/j.clgc.2021.03.011DOI Listing
March 2021

Racial disparity in prostate cancer in the African American population with actionable ideas and novel immunotherapies.

Cancer Rep (Hoboken) 2021 Feb 17:e1341. Epub 2021 Feb 17.

The Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: African Americans (AAs) in the United States are known to have a higher incidence and mortality for Prostate Cancer (PCa). The drivers of this epidemiological disparity are multifactorial, including socioeconomic factors leading to lifestyle and dietary issues, healthcare access problems, and potentially tumor biology.

Recent Findings: Although recent evidence suggests once access is equal, AA men have equal outcomes to Caucasian American (CA) men, differences in PCa incidence remain, and there is much to do to reverse disparities in mortality across the USA. A deeper understanding of these issues, both at the clinical and molecular level, can facilitate improved outcomes in the AA population. This review first discusses PCa oncogenesis in the context of its diverse hallmarks before benchmarking key molecular and genomic differences for PCa in AA men that have emerged in the recent literature. Studies have emphasized the importance of tumor microenvironment that contributes to both the unequal cancer burden and differences in clinical outcome between the races. Management of comorbidities like obesity, hypertension, and diabetes will provide an essential means of reducing prostate cancer incidence in AA men. Although requiring further AA specific research, several new treatment strategies such as immune checkpoint inhibitors used in combination PARP inhibitors and other emerging vaccines, including Sipuleucel-T, have demonstrated some proven efficacy.

Conclusion: Genomic profiling to integrate clinical and genomic data for diagnosis, prognosis, and treatment will allow physicians to plan a "Precision Medicine" approach to AA men. There is a pressing need for further research for risk stratification, which may allow early identification of AA men with higher risk disease based on their unique clinical, genomic, and immunological profiles, which can then be mapped to appropriate clinical trials. Treatment options are outlined, with a concise description of recent work in AA specific populations, detailing several targeted therapies, including immunotherapy. Also, a summary of current clinical trials involving AA men is presented, and it is important that policies are adopted to ensure that AA men are actively recruited. Although it is encouraging that many of these explore the lifestyle and educational initiatives and therapeutic interventions, there is much still work to be done to reduce incidence and mortality in AA men and equalize current racial disparities.
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http://dx.doi.org/10.1002/cnr2.1340DOI Listing
February 2021

Immune Escape in Prostate Cancer: Known and Predicted Mechanisms and Targets.

Urol Clin North Am 2020 Nov 9;47(4S):e9-e16. Epub 2020 Dec 9.

The Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1272, New York, NY 10029, USA.

Complex immune evasion mechanisms and lack of biomarkers predicting responsiveness to immune checkpoint blockade therapies compromise immunotherapy's therapeutic efficacy for patients with prostate cancer. The authors review established and nominated immune evasion mechanisms in prostate cancer and discuss how the precise treatment strategies can be developed to improve efficacy of immunotherapy.
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http://dx.doi.org/10.1016/j.ucl.2020.10.004DOI Listing
November 2020

The Tumor Microenvironment and Immunotherapy in Prostate and Bladder Cancer.

Urol Clin North Am 2020 Nov;47(4S):e17-e54

The Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1272, New York, NY-10029, USA. Electronic address:

Bladder cancer has been successfully treated with immunotherapy, whereas prostate cancer is a cold tumor with inadequate immune-related treatment response. A greater understanding of the tumor microenvironment and methods for harnessing the immune system to address tumor growth will be needed to improve immunotherapies for both prostate and bladder cancer. Here, we provide an overview of prostate and bladder cancer, including fundamental aspects of the disease and treatment, the elaborate cellular makeup of the tumor microenvironment, and methods for exploiting relevant pathways to develop more effective treatments.
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http://dx.doi.org/10.1016/j.ucl.2020.10.005DOI Listing
November 2020

Social Determinants Predict Outcomes in Data From a Multi-Ethnic Cohort of 20,899 Patients Investigated for COVID-19.

Front Public Health 2020 24;8:571364. Epub 2020 Nov 24.

Department of Urology, Icahn School of Medicine at Mount Sinai Hospitals, New York, NY, United States.

The COVID-19 pandemic exploits existing inequalities in social determinants of health (SDOH) in disease burden and access to healthcare. Few studies have examined these emerging disparities using indicators of SDOH. To evaluate predictors of COVID-19 test positivity, morbidity, and mortality and their implications for inequalities in SDOH and for future policies and health care improvements. A cross sectional analysis was performed on all patients tested for COVID-19 on the basis of symptoms with either a history of travel to at risk regions or close contact with a confirmed case, across the Mount Sinai Health System (MSHS) up until April 26th 2020. Primary outcome was death from COVID-19 and secondary outcomes were test positivity, and morbidity (e.g., hospitalization and intubation caused by COVID-19). Of 20,899 tested patients, 8,928 tested positive, 1,701 were hospitalized, 684 were intubated, and 1,179 died from COVID-19. Age, sex, race/ethnicity, New York City borough (derived from first 3 digits of zip-code), and English as preferred language were significant predictors of test positivity, hospitalization, intubation and COVID-19 mortality following multivariable logistic regression analyses. People residing in poorer boroughs were more likely to be burdened by and die from COVID-19. Our results highlight the importance of integrating comprehensive SDOH data into healthcare efforts with at-risk patient populations.
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http://dx.doi.org/10.3389/fpubh.2020.571364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722480PMC
December 2020

A novel imaging based Nomogram for predicting post-surgical biochemical recurrence and adverse pathology of prostate cancer from pre-operative bi-parametric MRI.

EBioMedicine 2021 Jan 13;63:103163. Epub 2020 Dec 13.

Center for Computational Imaging and Personalized Diagnostics, Case Western Reserve University, Cleveland, OH, USA; Louis Stokes Cleveland Veterans Administration Medical Center, USA. Electronic address:

Background: We developed and validated an integrated radiomic-clinicopathologic nomogram (RadClip) for post-surgical biochemical recurrence free survival (bRFS) and adverse pathology (AP) prediction in men with prostate cancer (PCa). RadClip was further compared against extant prognostics tools like CAPRA and Decipher.

Methods: A retrospective study of 198 patients with PCa from four institutions who underwent pre-operative 3 Tesla MRI followed by radical prostatectomy, between 2009 and 2017 with a median 35-month follow-up was performed. Radiomic features were extracted from prostate cancer regions on bi-parametric magnetic resonance imaging (bpMRI). Cox Proportional-Hazards (CPH) model warped with minimum redundancy maximum relevance (MRMR) feature selection was employed to select bpMRI radiomic features for bRFS prediction in the training set (D, N = 71). In addition, a bpMRI radiomic risk score (RadS) and associated nomogram, RadClip, were constructed in D and then compared against the Decipher, pre-operative (CAPRA), and post-operative (CAPRA-S) nomograms for bRFS and AP prediction in the testing set (D, N = 127).

Findings: "RadClip yielded a higher C-index (0.77, 95% CI 0.65-0.88) compared to CAPRA (0.68, 95% CI 0.57-0.8) and Decipher (0.51, 95% CI 0.33-0.69) and was found to be comparable to CAPRA-S (0.75, 95% CI 0.65-0.85). RadClip resulted in a higher AUC (0.71, 95% CI 0.62-0.81) for predicting AP compared to Decipher (0.66, 95% CI 0.56-0.77) and CAPRA (0.69, 95% CI 0.59-0.79)."

Interpretation: RadClip was more prognostic of bRFS and AP compared to Decipher and CAPRA. It could help pre-operatively identify PCa patients at low risk of biochemical recurrence and AP and who therefore might defer additional therapy.

Funding: The National Institutes of Health, the U.S. Department of Veterans Affairs, and the Department of Defense.
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http://dx.doi.org/10.1016/j.ebiom.2020.103163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744939PMC
January 2021

Clinical stage molecule PT150 is a modulator of glucocorticoid and androgen receptors with antiviral activity against SARS-CoV-2.

Cell Cycle 2020 12 11;19(24):3632-3638. Epub 2020 Dec 11.

Department of Animal, Dairy, and Veterinary Sciences, Utah State University , Logan, UT, USA.

PT150 is a clinical-stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an antidepressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 µM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) modulating molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.
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http://dx.doi.org/10.1080/15384101.2020.1859752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738205PMC
December 2020

Management of patients who opt for radical prostatectomy during the coronavirus disease 2019 (COVID-19) pandemic: an international accelerated consensus statement.

BJU Int 2021 06 10;127(6):729-741. Epub 2021 Mar 10.

Department of Urology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Objective: Coronavirus disease-19 (COVID-19) pandemic caused delays in definitive treatment of patients with prostate cancer. Beyond the immediate delay a backlog for future patients is expected. The objective of this work is to develop guidance on criteria for prioritisation of surgery and reconfiguring management pathways for patients with non-metastatic prostate cancer who opt for surgical treatment. A second aim was to identify the infection prevention and control (IPC) measures to achieve a low likelihood of coronavirus disease 2019 (COVID-19) hazard if radical prostatectomy (RP) was to be carried out during the outbreak and whilst the disease is endemic.

Methods: We conducted an accelerated consensus process and systematic review of the evidence on COVID-19 and reviewed international guidance on prostate cancer. These were presented to an international prostate cancer expert panel (n = 34) through an online meeting. The consensus process underwent three rounds of survey in total. Additions to the second- and third-round surveys were formulated based on the answers and comments from the previous rounds. The Consensus opinion was defined as ≥80% agreement and this was used to reconfigure the prostate cancer pathways.

Results: Evidence on the delayed management of patients with prostate cancer is scarce. There was 100% agreement that prostate cancer pathways should be reconfigured and measures developed to prevent nosocomial COVID-19 for patients treated surgically. Consensus was reached on prioritisation criteria of patients for surgery and management pathways for those who have delayed treatment. IPC measures to achieve a low likelihood of nosocomial COVID-19 were coined as 'COVID-19 cold' sites.

Conclusion: Reconfiguring management pathways for patients with prostate cancer is recommended if significant delay (>3-6 months) in surgical management is unavoidable. The mapped pathways provide guidance for such patients. The IPC processes proposed provide a framework for providing RP within an environment with low COVID-19 risk during the outbreak or when the disease remains endemic. The broader concepts could be adapted to other indications beyond prostate cancer surgery.
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http://dx.doi.org/10.1111/bju.15299DOI Listing
June 2021

The male external urethral sphincter is autonomically innervated.

Clin Anat 2021 Mar 22;34(2):263-271. Epub 2020 Dec 22.

UMR 1195, University Paris Sud, INSERM, Université Paris-Saclay, Le Kremlin-Bicetre, France.

Introduction: The aim of the present study was to describe autonomic urethral sphincter (US) innervation using specific muscular and neuronal antibody markers and 3D reconstruction.

Material And Methods: We performed en-bloc removal of the entire pelvis of three male human fetuses between 18 and 40 weeks. Serial whole mount sections (5 μm intervals) were stained and investigated. The sections were stained with Masson's trichrome and Eosin Hematoxylin, and immunostained with: anti-SMA antibody for smooth muscle; anti-S100 antibody for all nerves; and anti-PMP22 antibody, anti-TH antibody, anti-CGRP antibody, anti-NOS antibody for somatic, adrenergic, sensory and nitrergic nerve fibers, respectively. The slides were digitized for 3D reconstruction to improve topographical understanding. An animated reconstruction of the autonomic innervation of the US was generated.

Results: The external and internal US are innervated by autonomic nerves of the inferior hypogastric plexus (IHP). These nerves are sympathetic (positive anti-TH antibody), sensory (positive anti-CGRP antibody), and nitrergic (positive anti-NOS antibody). Some autonomic fibers run within the neurovascular bundles, posterolaterally. Others run from the IHP to the posteromedial aspect of the prostate apex, above an through the rectourethral muscle. The external US is also innervated by somatic nerves (positive anti-PMP22 antibody) arising from the pudendal nerve, joining the midline but remaining below the rectourethral.

Conclusions: This study provides anatomical evidence of an autonomic component in the innervation of the external US that travels in the neurovascular bundle. During radical prostatectomy, the rectourethral muscle and the neurovascular bundles are to be preserved, particularly during apical dissection.
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http://dx.doi.org/10.1002/ca.23698DOI Listing
March 2021

Molecular tracing of prostate cancer lethality.

Oncogene 2020 12 12;39(50):7225-7238. Epub 2020 Oct 12.

Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Prostate cancer is diagnosed mostly in men over the age of 50 years, and has favorable 5-year survival rates due to early cancer detection and availability of curative surgical management. However, progression to metastasis and emergence of therapeutic resistance are responsible for the majority of prostate cancer mortalities. Recent advancement in sequencing technologies and computational capabilities have improved the ability to organize and analyze large data, thus enabling the identification of novel biomarkers for survival, metastatic progression and patient prognosis. Large-scale sequencing studies have also uncovered genetic and epigenetic signatures associated with prostate cancer molecular subtypes, supporting the development of personalized targeted-therapies. However, the current state of mainstream prostate cancer management does not take full advantage of the personalized diagnostic and treatment modalities available. This review focuses on interrogating biomarkers of prostate cancer progression, including gene signatures that correspond to the acquisition of tumor lethality and those of predictive and prognostic value in progression to advanced disease, and suggest how we can use our knowledge of biomarkers and molecular subtypes to improve patient treatment and survival outcomes.
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http://dx.doi.org/10.1038/s41388-020-01496-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880612PMC
December 2020

Diagnostic and methodological evaluation of studies on the urinary shedding of SARS-CoV-2, compared to stool and serum: A systematic review and meta-analysis.

Cell Mol Biol (Noisy-le-grand) 2020 Sep 30;66(6):148-156. Epub 2020 Sep 30.

Urology Department of Icahn School of Medicine, Mount Sinai Hospitals, NY, USA.

Investigating the infectivity of body fluid can be useful for preventative measures in the community and ensuring safety in the operating rooms and on the laboratory practices. We performed a literature search of clinical trials, cohorts, and case series using PubMed/MEDLINE, Google Scholar, and Cochrane library, and downloadable database of CDC. We excluded case reports and searched all-language articles for review and repeated until the final drafting. The search protocol was registered in the PROSPERO database. Thirty studies with urinary sampling for viral shedding were included. A total number of 1,271 patients were enrolled initially, among which 569 patients had undergone urinary testing. Nine studies observed urinary viral shedding in urine from 41 patients. The total incidence of urinary SARS-CoV-2 shedding was 8%, compared to 21.3% and 39.5 % for blood and stool, respectively. The summarized risk ratio (RR) estimates for urine positive rates compared to the pharyngeal rate was 0.08. The pertaining RR urine compared to blood and stool positive rates were 0.20 and 0.33, respectively. Our review concludes that not only the SARS-CoV-2 can be excreted in the urine in eight percent of patients but also its incidence may have associations with the severity of the systemic disease, ICU admission, and fatality rates. Moreover, the findings in our review suggest that a larger population size may reveal more positive urinary cases possibly by minimizing biases.
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September 2020

Immunotherapy for Genitourinary Cancers: New Opportunities for Clinical Impact.

Urol Clin North Am 2020 Nov;47(4):xi-xii

Department of Urology, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, One Gustave L. Levy Place, Box 1272 L6-57, New York, NY 10029, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ucl.2020.08.001DOI Listing
November 2020

Immunotherapy for Metastatic Prostate Cancer: Current and Emerging Treatment Options.

Urol Clin North Am 2020 Nov 28;47(4):487-510. Epub 2020 Sep 28.

Department of Urology and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

The advent of immunotherapy has revolutionized cancer treatment. Prostate cancer has an immunosuppressive microenvironment and a low tumor mutation burden, resulting in low neoantigen expression. The consensus was that immunotherapy would be less effective in prostate cancer. However, recent studies have reported that prostate cancer does have a high number of DNA damage and repair gene defects. Immunotherapies that have been tested in prostate cancer so far have been mainly vaccines and checkpoint inhibitors. A combination of genomically targeted therapies, with approaches to alleviate immune response and thereby make the tumor microenvironment immunologically hot, is promising.
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http://dx.doi.org/10.1016/j.ucl.2020.07.010DOI Listing
November 2020

Immunotherapy in prostate cancer: current state and future perspectives.

Ther Adv Urol 2020 Jan-Dec;12:1756287220951404. Epub 2020 Sep 3.

Department of Urology, Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USA.

Metastatic castrate resistant prostate cancer (PCa) remains an incurable entity. In the era of immunotherapy, the complex PCa microenvironment poses a unique challenge to the successful application of this class of agents. However, in the last decade, a tremendous effort has been made to explore this field of therapeutics. In this review, the physiology of the cancer immunity cycle is highlighted in the context of the prostate tumor microenvironment, and the current evidence for use of various classes of immunotherapy agents including vaccines (dendritic cell based, viral vector based and DNA/mRNA based), immune checkpoint inhibitors, Chimeric antigen receptor T cell therapy, antibody-mediated radioimmunotherapy, antibody drug conjugates, and bispecific antibodies, is consolidated. Finally, the future directions for combinatorial approaches to combat PCa are discussed.
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http://dx.doi.org/10.1177/1756287220951404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476347PMC
September 2020

The Resilient Child: Sex-Steroid Hormones and COVID-19 Incidence in Pediatric Patients.

J Endocr Soc 2020 Sep 28;4(9):bvaa106. Epub 2020 Jul 28.

Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York.

Coronavirus disease-2019 (COVID-19), a disease caused by Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, has become an unprecedented global health emergency, with fatal outcomes among adults of all ages in the United States, and the highest incidence and mortality in adult men. As the pandemic evolves there is limited understanding of a potential association between symptomatic viral infection and age. To date, there is no knowledge of the role children (prepubescent, ages 9-13 years) play as "silent" vectors of the virus, with themselves being asymptomatic. Throughout different time frames and geographic locations, the current evidence on COVID-19 suggests that children are becoming infected at a significantly lower rate than other age groups-as low as 1%. Androgens upregulate the protease TMPRSS2 (type II transmembrane serine protease-2), which facilitates efficient virus-host cell fusion with the epithelium of the lungs, thus increasing susceptibility to SARS-CoV-2 infection and development of severe COVID-19. Owing to low levels of steroid hormones, prepubertal children may have low expression of TMPRSS2, thereby limiting the viral entry into host cells. As the world anticipates a vaccine against SARS-CoV-2, the role of prepubescent children as vectors transmitting the virus must be interrogated to prepare for a potential resurgence of COVID-19. This review discusses the current evidence on the low incidence of COVID-19 in children and the effect of sex-steroid hormones on SARS-CoV-2 viral infection and clinical outcomes of pediatric patients. On reopening society at large, schools will need to implement heightened health protocols with the knowledge that children as the "silent" viral transmitters can significantly affect the adult populations.
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http://dx.doi.org/10.1210/jendso/bvaa106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448286PMC
September 2020

Added value of systematic biopsy in men with a clinical suspicion of prostate cancer undergoing biparametric MRI-targeted biopsy: multi-institutional external validation study.

World J Urol 2020 Aug 10. Epub 2020 Aug 10.

Department of Urology, University of Turku and Turku University Hospital, Turku, Finland.

Purpose: We aimed to develop and externally validate a nomogram based on MRI volumetric parameters and clinical information for deciding when SBx should be performed in addition to TBx in man with suspicious prostate MRI.

Materials And Methods: Retrospective analyses of single (IMPROD, NCT01864135) and multi-institution (MULTI-IMPROD, NCT02241122) clinical trials. All men underwent a unique rapid biparametric magnetic resonance imaging (IMPROD bpMRI) consisting of T2-weighted imaging and three separate DWI acquisitions. Men with IMPROD bpMRI Likert scores of 3-5 were included. Logistic regression models were developed using IMPROD trial (n = 122) and validated using MULTI-IMPROD trial (n = 262) data. The model's performance was evaluated in the terms of PCa detection with Gleason Grade Group 1 (clinically insignificant prostate cancer, iPCa) and > 1 (clinically significant prostate cancer, csPCa). Net benefits and decision curve analyses (DCA) were compared. Combined biopsies were used for reference.

Results: The developed nomogram included age, PSA, prostate volume, MRI suspicion score (IMPROD bpMRI Likert or PIRADsv2.1 score), MRI-suspicion lesion volume percentage, and lesion location. All these variables were significant predictors of csPCa in SBx in multivariable analysis. In the validation cohort (n = 262) using different nomogram cutoffs, 19-43% of men would have avoided SBx while missing 1-4% of csPCa and avoiding detection of 9-20% of iPCa. Similar performance was found for nomograms using IMPROD bpMRI Likert score or v2.1.

Conclusions: The developed nomogram demonstrated potential to select men with a clinical suspicion of PCa who would benefit from performing SBx in addition to TBx. Public access to the nomogram is provided at: https://petiv.utu.fi/multiimprod/ .
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http://dx.doi.org/10.1007/s00345-020-03393-8DOI Listing
August 2020

Prostate Cancer in a Patient with Giant Prostatic Hyperplasia: The Robotic Approach to a Difficult Problem.

J Endourol Case Rep 2019 30;5(3):99-101. Epub 2019 Aug 30.

Department of Urology, Icahn School of Medicine at Mount Sinai Hospital, New York, New York.

The robotic approach toward radical prostatectomy for prostate cancer has only recently become widespread. Two of the advantages of the robotic approach have been described to be the optical magnification afforded by camera and the ability to reach deep into the pelvis. These advantages are particularly salient in cases where the pelvis is particularly narrow or the prostate is particularly large. In this report, we describe the management of a patient with two simultaneous prostatic diseases: prostate cancer and a massive prostate weighing 560 g causing urinary retention and hematuria, who underwent robot-assisted radical prostatectomy for prostate removal. To the best of our knowledge, this is the largest prostate to be removed through the means of robot-assisted surgery.
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http://dx.doi.org/10.1089/cren.2019.0024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383426PMC
August 2019

Contemporary Techniques of Prostate Dissection for Robot-assisted Prostatectomy.

Eur Urol 2020 10 1;78(4):583-591. Epub 2020 Aug 1.

Department of Urology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Background: Over the years, several techniques for performing robot-assisted prostatectomy have been implemented in an effort to achieve optimal oncological and functional outcomes.

Objective: To provide an evidence-based description and video-based illustration of currently available dissection techniques for robotic prostatectomy.

Design, Setting, And Participants: A literature search was performed to retrieve articles describing different surgical approaches and techniques for robot-assisted radical prostatectomy (RARP) and to analyze data supporting their use. Video material was provided by experts in the field to illustrate these approaches and techniques.

Surgical Procedure: Multiple surgical approaches are available: extraperitoneal, transvesical, transperitoneal posterior, transperitoneal anterior, Retzius sparing, and transperineal. Surgical techniques for prostatic dissection sensu strictu are the following: omission of the endopelvic fascia dissection, bladder neck preservation, incremental nerve sparing by means of an antegrade or retrograde approach, and preservation of the puboprostatic ligaments and dorsal venous complex. Recently, techniques for total or partial prostatectomy have been described.

Measurements: Different surgical approaches and techniques for robotic prostatectomy have been analyzed.

Results And Limitations: Two randomized controlled trials evaluating the extraperitoneal versus the transperitoneal approach have demonstrated similar results. Level I evidence on the Retzius-sparing approach demonstrated earlier return to continence than the traditional anterior approach. The question whether Retzius-sparing RARP is associated with a higher rate of positive surgical margins is still open due to the intrinsic bias in terms of surgical expertise in the available comparative studies. This technique also offers an advantage in patients who have received kidney transplantation. Retrospective evidence suggests that the more the anatomical dissection (eg., more periprostatic tissue is preserved), the better the functional outcome in terms of continence. Yet, two randomized controlled trials evaluating the different techniques of dissection have so far been produced. Partial prostatectomies should not be offered outside clinical trials.

Conclusions: Several techniques and approaches are available for prostate dissection during RARP. While the Retzius-sparing approach seems to provide earlier return to continence than the traditional anterior transperitoneal approach, no technique has been proved to be superior to other(s) in terms of long-term outcomes in randomized studies.

Patient Summary: We have summarized available approaches for the surgical treatment of prostate cancer. Specifically, we described the different techniques that can be adopted for the surgical removal of the prostate using robotic technology.
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http://dx.doi.org/10.1016/j.eururo.2020.07.017DOI Listing
October 2020

Pseudouridine as a novel biomarker in prostate cancer.

Urol Oncol 2021 01 22;39(1):63-71. Epub 2020 Jul 22.

Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029.

Epitranscriptomic analysis has recently led to the profiling of modified nucleosides in cancer cell biological matrices, helping to elucidate their functional roles in cancer and reigniting interest in exploring their use as potential markers of cancer development and progression. Pseudouridine, one of the most well-known and the most abundant of the RNA nucleotide modifications, is the C5-glycoside isomer of uridine and its distinctive physiochemical properties allows it to perform many essential functions. Pseudouridine functionally (a) confers rigidity to local RNA structure by enhancing RNA stacking, engaging in a cooperative effect on neighboring nucleosides that overall contributes to RNA stabilization (b) refines the structure of tRNAs, which influences their decoding activity (c) facilitates the accuracy of decoding and proofreading during translation and efficiency of peptide bond formation, thus collectively improving the fidelity of protein biosynthesis and (e) dynamically regulates mRNA coding and translation. Biochemical synthesis of pseudouridine is carried out by pseudouridine synthases. In this review we discuss the evidence supporting an association between elevated pseudouridine levels with the incidence and progression of human prostate cancer and the translational significance of the value of this modified nucleotide as a novel biomarker in prostate cancer progression to advanced disease.
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http://dx.doi.org/10.1016/j.urolonc.2020.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880613PMC
January 2021

Urologic oncology practice during COVID-19 pandemic: A systematic review on what can be deferrable vs. nondeferrable.

Urol Oncol 2020 10 26;38(10):783-792. Epub 2020 Jun 26.

Department of Urology, Division of Urologic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Purpose: To provide a review of high-risk urologic cancers and the feasibility of delaying surgery without impacting oncologic or mortality outcomes.

Materials And Methods: A thorough literature review was performed using PubMed and Google Scholar to identify articles pertaining to surgical delay and genitourinary oncology. We reviewed all relevant articles pertaining to kidney, upper tract urothelial cell, bladder, prostate, penile, and testicular cancer in regard to diagnostic, surgical, or treatment delay.

Results: The majority of urologic cancers rely on surgery as primary treatment. Treatment of unfavorable intermediate or high-risk prostate cancer, can likely be delayed for 3 to 6 months without affecting oncologic outcomes. Muscle-invasive bladder cancer and testicular cancer can be treated initially with chemotherapy. Surgical management of T3 renal masses, high-grade upper tract urothelial carcinoma, and penile cancer should not be delayed.

Conclusion: The majority of urologic oncologic surgeries can be safely deferred without impacting long-term cancer specific or overall survival. Notable exceptions are muscle-invasive bladder cancer, high-grade upper tract urothelial cell, large renal masses, testicular and penile cancer. Joint decision making among providers and patients should be encouraged. Clinicians must manage emotional anxiety and stress when decisions around treatment delays are necessary as a result of a pandemic.
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http://dx.doi.org/10.1016/j.urolonc.2020.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318929PMC
October 2020

Access and socioeconomic status play an important role in outcomes for African American patients with prostate cancer.

Cancer 2020 09 9;126(18):4257-4258. Epub 2020 Jul 9.

Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York.

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http://dx.doi.org/10.1002/cncr.33063DOI Listing
September 2020

Sex differences in SARS-CoV-2 infection rates and the potential link to prostate cancer.

Commun Biol 2020 07 8;3(1):374. Epub 2020 Jul 8.

Department of Urology and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

The recent outbreak of infections and the pandemic caused by SARS-CoV-2 represent one of the most severe threats to human health in more than a century. Emerging data from the United States and elsewhere suggest that the disease is more severe in men. Knowledge gained, and lessons learned, from studies of the biological interactions and molecular links that may explain the reasons for the greater severity of disease in men, and specifically in the age group at risk for prostate cancer, will lead to better management of COVID-19 in prostate cancer patients. Such information will be indispensable in the current and post-pandemic scenarios.
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http://dx.doi.org/10.1038/s42003-020-1088-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343823PMC
July 2020

Estimated Costs Associated With Radiation Therapy for Positive Surgical Margins During Radical Prostatectomy.

JAMA Netw Open 2020 03 2;3(3):e201913. Epub 2020 Mar 2.

Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York.

Importance: Prostate cancer is the most common malignant neoplasm among men and is the one with the highest positive surgical margin (PSM) rate. This high rate is due to the difficulty in balancing the risk of extraprostatic disease and excising periprostatic structures, which ultimately affects patients' quality of life. In the case of a PSM, the appropriateness of adjuvant radiation therapy (aRT) should be discussed. The financial burden of PSMs on health systems has not been investigated.

Objective: To estimate the financial costs associated with a PSM during radical prostatectomy on the basis of the odds of undergoing aRT.

Design, Setting, And Participants: This cohort study used data on men with prostate cancer from the US National Cancer Database (January 1, 2010, through December 31, 2015). Data were requested in March 2019, accessed in April 2019, and analyzed in August 2019.

Exposure: Treatment with radical prostatectomy followed by aRT, if indicated.

Main Outcomes And Measures: The attributable risk fraction of PSMs on undergoing aRT was estimated from a logistic regression with aRT administration as the outcome. The analysis was adjusted for patients' socioeconomic and demographic characteristics and tumor characteristics. The aRT cost for the year 2019 was calculated using the Medicare Physician Fee Schedule and the Hospital Outpatient Prospective Payment System. The fraction of this cost attributable to a PSM was estimated according to its attributable risk fraction.

Results: In total, 230 175 men were identified (median [interquartile range] age at diagnosis, 62.0 [56.0-67.0] years). Overall, 22.8% of the patients had a PSM. Patients with PSMs were more likely than those without PSMs to be older (median [interquartile range] age, 62.0 [56.0-66.0] years vs 62.0 [57.0-67.0] years) and nonwhite (9320 patients [17.8%] vs 29 872 patients [16.8%]), to have higher comorbidity scores (1604 patients [3.1%] vs 4884 patients [2.7%] with a Charlson-Deyo Comorbidity Index score ≥2) and worse tumor characteristics (category T3 and T4 disease, 26 394 patients [50.3%] vs 36 040 patients [20.3%]), and to have lower socioeconomic indicators (median annual income <$30 000, 5708 patients [10.9%] vs 17 874 patients [10.1%]; proportion of individuals without a high school degree in the area ≥29%, 6925 patients [13.2%] vs 22 648 patients [12.7%]). In addition, PSMs were documented more frequently at nonacademic institutions than academic ones (31 702 patients [60.5%] vs 20 714 patients [39.5%]). A total of 11 585 patients (5.0%) underwent aRT, and 7698 of them (3.3%) had a PSM at the final pathology examination. When controlling for patients' socioeconomic and demographic characteristics and tumor characteristics, men with PSMs were more likely than those with negative margins to undergo aRT, with an odds ratio of 3.79 (95% CI, 3.63-3.96; P < .001). The attributable risk fraction of the presence of a PSM on aRT was 44% (95% CI, 42%-45%). The attributable cost of a PSM was calculated as $17 356 (95% CI, $16 567-$17 751). Assuming 60 000 prostatectomies in 2019 and similar trends of PSM and aRT, the overall health burden attributable to PSMs was calculated to be $52 068 000 (95% CI, $49 701 000-$53 253 000).

Conclusions And Relevance: The estimated aRT cost attributable to the presence of a PSM was $17 356, resulting in $52 068 000 in spending on aRT in 2019. Strategies to reduce PSMs could be associated with a reduction in the overall health costs of surgically treated PCa.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.1913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109597PMC
March 2020

Bioptic intraprostatic chronic inflammation predicts adverse pathology at radical prostatectomy in patients with low-grade prostate cancer.

Urol Oncol 2020 10 25;38(10):793.e19-793.e25. Epub 2020 Mar 25.

Department of Urology and Organ Transplantation, University of Foggia, Foggia, Italy.

Purpose: To determine the potential role of bioptic inflammation (Irani score) in predicting adverse pathology (AP) at radical prostatectomy (RP) in patients with low-grade (ISUP Gleason Group [ISUP GG] 1 and 2) prostate cancer (CaP).

Methods: After institutional review board-approval, we identified patients who underwent prostate biopsy, had bioptic Irani score assessment, were diagnosed with low-grade CaP (ISUP GG 1-2, prostate-specific antigen [PSA] <20 ng/ml), and underwent RP. The impact of standard clinicopathological variables and bioptic Irani Score (G = grade and A = aggressiveness) on AP at RP, defined as stage ≥T3 and/or ISUP GG ≥3, was assessed by univariate and multivariate logistic regression analysis.

Results: A total of 282 patients were eligible for this study. AP at RP occurred in 37 of 214 (17.3%) patients with ISUP GG 1, and 26 of 68 (38.2%) with ISUP GG 2. At univariate analysis, serum PSA, PSA density, bioptic ISUP GG, number of positive cores, total percentage of core involvement and Irani G score emerged as significant risk factors of AP. At multivariate analysis, however, only PSA density, bioptic ISUP GG, total percentage of core, and Irani G score kept statistical significance. The area under the curve for the resulting model was 0.75.

Conclusions: This is the first study demonstrating that low-grade inflammation is associated with a significantly increased risk of AP at RP. These findings would support the concept of prostatic inflammation being inversely correlated with presence and aggressiveness of CaP. Further studies are needed to externally validate the role of this readily available parameter in the decision-making process of patients with low-grade CaP.
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http://dx.doi.org/10.1016/j.urolonc.2020.02.025DOI Listing
October 2020

Performance of prostate multiparametric MRI for prediction of prostate cancer extra-prostatic extension according to NCCN risk categories: implication for surgical planning.

Minerva Urol Nefrol 2020 Dec 16;72(6):746-754. Epub 2020 Mar 16.

Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Prediction of extra-prostatic extension (EPE) in men undergoing radical prostatectomy (RP) is of utmost importance. Great variability in the performance of multiparametric magnetic resonance imaging (mpMRI) has been reported for prediction of EPE. The present study aimed to determine the diagnostic performance of mpMRI for predicting EPE in different National Comprehensive Cancer Network (NCCN) risk categories.

Methods: Overall 664 patients who underwent radical prostatectomy with a staging mpMRI were enrolled in this single-center, retrospective study. Patients with mpMRI report non-compliant with PI-RADSv2.0, were excluded. Patients were stratified according to NCCN criteria: very low/low (VLR-LR) to High Risk (HR) in order to assess final pathology EPE rates (focal and established). Sensitivity, specificity, positive and negative predictive values of staging mpMRI were computed in each group. Univariable and multivariable analysis were used to evaluate predictors of positive surgical margins.

Results: Pathological evaluation demonstrated established and focal EPE in 60 (9%) and 106 (16%) patients, respectively, while mpMRI suspicion for EPE was present in 180 (27%) patients. Age, preoperative PSA, PSA density, number of positive cores, NCCN groups, prostate volume, mpMRI suspicion for EPE, PIRADSv2.0 and lesion size differed significantly between the patients with any EPE and without EPE (all P≤0.05). The sensitivity of mpMRI in detecting any EPE varied from 12% (95% CI: 0.6-53%) in VLR-LR to 83% (66-93%) in HR while the corresponding values for the specificity were 92% (85-96%) and 63% (45-78%), respectively. Patients with false-negative mpMRI EPE prediction were more likely to have positive surgical margins in univariable (OR: 2.14; CI: 1.18, 3.87) as well as multivariable analysis adjusting for NCCN risk categories (OR: 1.97; CI: 1.08, 3.60).

Conclusions: The performance of mpMRI for prediction of EPE varies greatly between different NCCN risk categories with a low positive predicting value in patients at low to favorable intermediate risk and a low negative predictive value in patients at Unfavorable intermediate to high risk PCa. Given that mpMRI EPE misdiagnosis could have a negative impact on oncological and functional outcomes, NCCN risk categories should be considered when interpreting mpMRI findings in PCa patients.
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http://dx.doi.org/10.23736/S0393-2249.20.03688-7DOI Listing
December 2020