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Gleason grading, a risk stratification method for prostate cancer, is subjective and dependent on experience and expertise of the reporting pathologist. Deep Learning (DL) systems have shown promise in enhancing the objectivity and efficiency of Gleason grading. However, DL networks exhibit domain shift and reduced performance on Whole Slide Images (WSI) from a source other than training data. We propose a DL approach for segmenting and grading epithelial tissue using a novel training methodology that learns domain agnostic features. In this retrospective study, we analyzed WSI from three cohorts of prostate cancer patients. 3741 core needle biopsies (CNBs) received from two centers were used for training. The κquad (quadratic-weighted kappa) and AUC were measured for grade group comparison and core-level detection accuracy, respectively. Accuracy of 89.4% and κquad of 0.92 on the internal test set of 425 CNB WSI and accuracy of 85.3% and κquad of 0.96 on an external set of 1201 images, was observed. The system showed an accuracy of 83.1% and κquad of 0.93 on 1303 WSI from the third institution (blind evaluation). Our DL system, used as an assistive tool for CNB review, can potentially improve the consistency and accuracy of grading, resulting in better patient outcomes.

Several newly approved therapies have substantially altered the treatment paradigm for multiple genitourinary cancers. Considering the existence of numerous possible treatment approaches, understanding which treatment attributes are most valued by each patient is crucial to physicians to recommend a cancer-directed treatment.

The purpose of this study was to assess the predictive value of prostate specific antigen density (PSAD) for detection of clinically significant prostate cancer in men undergoing systematic transrectal ultrasound (TRUS)-guided prostate biopsy. We retrospectively analyzed data of men who underwent TRUS-guided prostate biopsy because of elevated PSA (≤ 20 ng/ml) or abnormal digital rectal examination. Receiver operating characteristic curve analysis to compare PSA and PSAD performance and chi-square automatic interaction detector methodologies were used to identify predictors of clinically significant cancer (Gleason score ≥ 7 or international society of urological pathology grade group ≥ 2). Nine-hundred and ninety-two consecutive men with a median age of 66 years (IQR 61–71) were included in the study. Median PSAD was 0.10 ng/ml 2 (IQR 0.10–0.22). Prostate adenocarcinoma was diagnosed in 338 men (34%). Clinically significant prostate adenocarcinoma was diagnosed in 167 patients (50% of all cancers and 17% of the whole cohort). The AUC to predict clinically significant prostate cancer was 0.64 for PSA and 0.78 for PSAD (P < 0.001). The highest Youden's index for PSAD was at 0.20 ng/ml 2 with 70% sensitivity and 79% specificity for the diagnosis of clinically significant cancer. Men with PSAD < 0.09 ng/ml 2 had only 4% chance of having clinically significant disease. The detection rate of clinically significant prostate cancer in patients with PSAD between 0.09 and 0.19 ng/ml 2 was significantly higher when prostate volume was less than 33 ml. In conclusion, PSAD was a better predictor than PSA alone of clinically significant prostate cancer in patients undergoing TRUS-guided biopsy. Patients with PSAD below 0.09 ng/ml 2 were unlikely to harbor clinically significant prostate cancer. Combining PSAD in the gray zone (0.09–0.19) with prostate volume below 33 ml adds diagnostic value of clinically significant prostate cancer.

While the antiandrogen enzalutamide (Enz) extends the castration resistant prostate cancer (CRPC) patients’ survival an extra 4.8 months, it might also result in some adverse effects via inducing the neuroendocrine differentiation (NED). Here we found that lncRNA-p21 is highly expressed in the NEPC patients derived xenograft tissues (NEPC-PDX). Results from cell lines and human clinical sample surveys also revealed that lncRNA-p21 expression is up-regulated in NEPC and Enz treatment could increase the lncRNA-p21 to induce the NED. Mechanism dissection revealed that Enz could promote the lncRNA-p21 transcription via altering the androgen receptor (AR) binding to different androgen-response-elements, which switch the EZH2 function from histone-methyltransferase to non-histone methyltransferase, consequently methylating the STAT3 to promote the NED. Preclinical studies using the PDX mouse model proved that EZH2 inhibitor could block the Enz-induced NED. Together, these results suggest targeting the Enz/AR/lncRNA-p21/EZH2/STAT3 signaling may help urologists to develop a treatment for better suppression of the human CRPC progression. The induction of neuroendocrine differentiation occurs in enzalutamide treated castration resistant prostate cancer. Here, the authors show that lncRNA-21 mediates enzalutamide induced neuroendocrine differentiation through EZH2/STAT axis and EZH2 inhibition suppresses this differentiation.

Non-muscle-invasive bladder cancer (NMIBC) is an early-stage cancer without invasion into the detrusor muscle layer. Transurethral resection of bladder tumour (TURBT) is a diagnostic and potentially curative procedure for NMIBC, but has some limitations, including difficulties in ascertaining complete tumour removal upon piecemeal resection and the possibility of tumour re-implantation after the procedure. The oncological control of NMIBC is far from satisfactory, with a 1-year recurrence rate of 15–61%, and a 5-year recurrence rate of 31–78%. Various recurrence mechanisms have been described for NMIBC, such as undetected tumours upon cystoscopy, incomplete resection during TURBT, tumour re-implantation after TURBT, drop metastasis from upper tract urothelial carcinoma and field change cancerization. Understanding the recurrence mechanisms from a clinical perspective has strong implications for the optimization of NMIBC oncological outcomes, as a cure for patients with NMIBC can only be achieved by tackling all possible recurrence mechanisms in a comprehensive manner.In this Review, Teoh et al. describe different mechanisms of early and late disease recurrence in non-muscle-invasive bladder cancer and discuss potential treatment options. In addition, the authors discuss the potential of molecular classification and treatment with immunotherapy and novel therapeutic agents in the future management of bladder cancer.

The molecular features that define clear cell renal cell carcinoma (ccRCC) initiation and progression are being increasingly defined. The TRACERx Renal studies and others that have described the interaction between tumour genomics and remodelling of the tumour microenvironment provide important new insights into the molecular drivers underlying ccRCC ontogeny and progression. Our understanding of common genomic and chromosomal copy number abnormalities in ccRCC, including chromosome 3p loss, provides a mechanistic framework with which to organize these abnormalities into those that drive tumour initiation events, those that drive tumour progression and those that confer lethality. Truncal mutations in ccRCC, including those in VHL, SET2, PBRM1 and BAP1, may engender genomic instability and promote defects in DNA repair pathways. The molecular features that arise from these defects enable categorization of ccRCC into clinically and therapeutically relevant subtypes. Consideration of the interaction of these subtypes with the tumour microenvironment reveals that specific mutations seem to modulate immune cell populations in ccRCC tumours. These findings present opportunities for disease prevention, early detection, prognostication and treatment.The molecular features that define the initiation and progression of clear cell renal cell carcinoma (ccRCC) are being increasingly defined. This Review summarizes common genomic and chromosomal copy number abnormalities in ccRCC, providing a mechanistic framework with which to organize these features into initiating events, drivers of progression and factors that confer lethality.

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients. However, most patients eventually develop Enz resistance that may involve inducing the androgen receptor (AR) splicing variant 7 (ARv7). Here we report that high expression of monoamine oxidase-A (MAO-A) is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC. Castration resistant prostate cancer patients treated with enzalutamide may develop resistance to the drug. Here, the authors report that monoamine oxidase-A expression is increased in these resistant tumors and that the antidepressants phenelzine/clorgyline can reverse such resistance to further suppress tumor growth

In the pre-PSA-detection era, a large proportion of men were diagnosed with metastatic prostate cancer and died of the disease; after the introduction of the serum PSA test, randomized controlled prostate cancer screening trials in the USA and Europe were conducted to assess the effect of PSA screening on prostate cancer mortality. Contradictory outcomes of the trials and the accompanying overdiagnosis resulted in recommendations against prostate cancer screening by organizations such as the United States Preventive Services Task Force. These recommendations were followed by a decline in PSA testing and a rise in late-stage diagnosis and prostate cancer mortality. Re-evaluation of the randomized trials, which accounted for contamination, showed that PSA-based screening does indeed reduce prostate cancer mortality; however, the debate about whether to screen or not to screen continues because of the considerable overdiagnosis that occurs using PSA-based screening. Meanwhile, awareness among the population of prostate cancer as a potentially lethal disease stimulates opportunistic screening practices that further increase overdiagnosis without the benefit of mortality reduction. However, in the past decade, new screening tools have been developed that make the classic PSA-only-based screening an outdated strategy. With improved use of PSA, in combination with age, prostate volume and with the application of prostate cancer risk calculators, a risk-adapted strategy enables improved stratification of men with prostate cancer and avoidance of unnecessary diagnostic procedures. This combination used with advanced detection techniques (such as MRI and targeted biopsy), can reduce overdiagnosis. Moreover, new biomarkers are becoming available and will enable further improvements in risk stratification.In this Perspective, the authors discuss the past, present and future of PSA screening for the early detection of aggressive prostate cancer and propose a way forward for the rational use of PSA testing as part of a risk-adapted screening strategy.

Bladder cancer is a global health issue with sex differences in incidence and prognosis. Bladder cancer has distinct molecular subtypes with multiple pathogenic pathways depending on whether the disease is non-muscle invasive or muscle invasive. The mutational burden is higher in muscle-invasive than in non-muscle-invasive disease. Commonly mutated genes include TERT , FGFR3 , TP53 , PIK3CA , STAG2 and genes involved in chromatin modification. Subtyping of both forms of bladder cancer is likely to change considerably with the advent of single-cell analysis methods. Early detection signifies a better disease prognosis; thus, minimally invasive diagnostic options are needed to improve patient outcomes. Urine-based tests are available for disease diagnosis and surveillance, and analysis of blood-based cell-free DNA is a promising tool for the detection of minimal residual disease and metastatic relapse. Transurethral resection is the cornerstone treatment for non-muscle-invasive bladder cancer and intravesical therapy can further improve oncological outcomes. For muscle-invasive bladder cancer, radical cystectomy with neoadjuvant chemotherapy is the standard of care with evidence supporting trimodality therapy. Immune-checkpoint inhibitors have demonstrated benefit in non-muscle-invasive, muscle-invasive and metastatic bladder cancer. Effective management requires a multidisciplinary approach that considers patient characteristics and molecular disease characteristics. Urothelial bladder cancer has various pathogenic pathways and comprises distinct molecular subtypes. This Primer reviews the epidemiology of the disease with a focus on risk factors, discusses mechanisms of pathogenesis, diagnosis and management at different disease stages, and highlights patient quality of life and open research questions.

Prostate cancer is a global health problem, but incidence varies considerably across different continents. Asia is traditionally considered a low-incidence area, but the incidence and mortality of prostate cancer have rapidly increased across the continent. Substantial differences in epidemiological features have been observed among different Asian regions, and incidence, as well as mortality-to-incidence ratio, is associated with the human development index. Prostate cancer mortality decreased in Japan and Israel from 2007 to 2016, but mortality has increased in Thailand, Kyrgyzstan and Uzbekistan over the same period. Genomic analyses have shown a low prevalence of ERG oncoprotein in the East Asian population, alongside a low rate of PTEN loss, high CHD1 enrichments and high FOXA1 alterations. Contributions from single-nucleotide polymorphisms to prostate cancer risk vary with ethnicity, but germline mutation rates of DNA damage repair genes in metastatic prostate cancer are comparable in Chinese and white patients from the USA and UK. Pharmacogenomic features of testosterone metabolism might contribute to disparities seen in the response to androgen deprivation between East Asian men and white American and European men. Overall, considerable diversity in epidemiology and genomics of prostate cancer across Asia defines disease characteristics in these populations, but studies in this area are under-represented in the literature. Taking into account this intracontinental and intercontinental heterogeneity, translational studies are required in order to develop ethnicity-specific treatment strategies.Asia is traditionally considered to have a low incidence of prostate cancer, but the incidence and mortality of prostate cancer have rapidly increased across the continent. Taking into account this intracontinental and intercontinental heterogeneity, translational studies are required in order to develop ethnicity-specific treatment strategies.