DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs.

Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, whose contribution to tumorigenesis is uncertain. Through high-resolution genome-wide single-cell DNA methylation sequencing, we identify 40 core domains that are uniformly hypomethylated from the earliest detectable stages of prostate malignancy through metastatic circulating tumor cells (CTCs). Nested among these repressive domains are smaller loci with preserved methylation that escape silencing and are enriched for cell proliferation genes. Transcriptionally silenced genes within the core hypomethylated domains are enriched for immune-related genes; prominent among these is a single gene cluster harboring all five CD1 genes that present lipid antigens to NKT cells and four IFI16-related interferon-inducible genes implicated in innate immunity. The re-expression of CD1 or IFI16 murine orthologs in immuno-competent mice abrogates tumorigenesis, accompanied by the activation of anti-tumor immunity. Thus, early epigenetic changes may shape tumorigenesis, targeting co-located genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for CTCs.

Pathology of hereditary renal cell carcinoma syndromes: Tuberous sclerosis complex (TSC).

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomatous tumors involving multiple organs such as the brain, skin, heart, lung and kidney. TSC is caused by inactivating mutations in TSC1/TSC2, which encodes hamartin and tuberin, respectively, and forms a complex that regulates mechanistic target of rapamycin complex 1 (mTORC1), resulting in cell overgrowth and oncogenesis. Since a leading cause of morbidity and mortality in TSC relates to chronic kidney disease and the ability to preserve renal function, this review describes the important pathologic findings in TSC-associated renal neoplasms and their correlating sporadic counterparts. The most common renal tumor in TSC patients are AMLs, followed by a heterogeneous spectrum of renal epithelial tumors, which may provide clues to establishing a diagnosis of TSC.

Birt-Hogg-Dubé syndrome in an overall view: Focus on the clinicopathological prospects in renal tumors.

Birt-Hogg-Dubé syndrome (BHD) represents a rare autosomal dominant tumor predisposition syndrome characterized by skin lesions, lung cysts, and renal tumors. The predominant histological subtypes of BHD-related renal tumors include hybrid oncocytoma-chromophobe tumors, oncocytomas, and chromophobe renal cell carcinomas, all exhibiting eosinophilic/oncocytic features. Immunohistochemistry staining for KIT (CD117) and CK7 exhibits variability in these tumor types. Germline mutations in FLCN have been consistently identified. Generally, patients with BHD demonstrate a favorable prognosis with minimal metastatic potential. Nonetheless, the comprehensive elucidation of pathological characteristics of BHD remains incomplete, particularly in BHD-associated renal tumors that deviate from the previously identified subtypes, thereby complicating the differential diagnosis. In this review, we provide a comprehensive overview of BHD encompassing epidemiology, clinical manifestations, genetic and molecular pathogenesis, as well as clinical diagnostic modalities. Emphasis is placed on clinicopathological features, specifically focusing on BHD-associated renal tumors. Collectively, this review aims to present the latest insights into BHD which benefits in the early detection, therapeutic decision-making, and prognosis prediction in BHD cases, and deepen the understanding of sporadic renal tumors.

Estimated Prostate Volume by Semiautomatic Segmentation of MRI Is More Accurately Correlated with Radical Prostatectomy Specimen Weight than the Volume Calculated by Ellipsoid Formula.

INTRODUCTION: Accurate in vivo prostate volume (PV) estimation is important for obtaining prostate-specific antigen density (PSAD) and further predicting clinically significant prostate cancer (csPCa). We aimed to evaluate the accuracy of multiparametric magnetic resonance imaging (mpMRI)-estimated PV compared to both volume and weight of radical prostatectomy (RP). METHODS: We identified 310 PCa patients who underwent RP following combined targeted and systematic biopsy in our institution from September 2019 to February 2021. The MRI PV was determined using a semiautomated segmentation algorithm. RP PV was calculated using the prolate ellipsoid formula (length × width × height × π/6). Formula (prostate weight = [actual weight-3.8 g]/1.05 g/mL) was applied, and the resulting volume was used in further analysis. RESULTS: The median PV from MRI, RP, and RP weight were 39 mL, 38 mL, and 44 mL, respectively. Spearman's rank correlation coefficients (ρ) were 0.841 (MRI PV vs. RP weight), 0.758 (RP PV vs. RP weight), and 0.707 (MRI PV vs. RP PV) (all p < 0.001). Decreased correlation between the MRI PV and RP PV was observed in the larger (more than 55 mL) prostate. The PSAD derived from MRI PV showed most efficient to detect csPCa in RP specimen (57.9% vs. 57.6% vs. 45.4%). CONCLUSION: MRI PV is correlated better with RP weight than calculated RP PV, especially in larger prostate. The high csPCa detection rate in final pathology suggested that PSAD derived from MRI PV can be confidently used in clinical practice.

Dynamic viral integration patterns actively participate in the progression of BK polyomavirus-associated diseases after renal transplantation.

The classical lytic infection theory along with large T antigen-mediated oncogenesis cannot explain the BK polyomavirus (BKPyV)-associated tumor secondary to BKPyV-associated nephropathy (BKVAN), viremia/DNAemia, and viruria after renal transplantation. This study performed virome capture sequencing and pathological examination on regularly collected urine sediment and peripheral blood samples, and BKVAN and tumor biopsy tissues of 20 patients with BKPyV-associated diseases of different stages. In the early noncancerous stages, well-amplified integration sites were visualized by in situ polymerase chain reaction, simultaneously with BKPyV inclusion bodies and capsid protein expression. The integration intensity, the proportion of microhomology-mediated end-joining integration, and host PARP-1 and POLQ gene expression levels increased with disease progression. Furthermore, multiomics analysis was performed on BKPyV-associated urothelial carcinoma tissues, identifying tandem-like structures of BKPyV integration using long-read genome sequencing. The carcinogenicity of BKPyV integration was proven to disturb host gene expression and increase viral oncoprotein expression. Fallible DNA double-strand break repair pathways were significantly activated in the parenchyma of BKPyV-associated tumors. Olaparib showed an antitumor activity dose-response effect in the tumor organoids without BRCA1/2 genes mutation. In conclusion, the dynamic viral integration patterns actively participate in the progression of BKPyV-associated diseases and thus could be a potential target for disease monitoring and intervention.

Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer.

PURPOSE: Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes. MATERIALS AND METHODS: Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression. RESULTS: Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome. Family history of prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history suggestive of a hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. CONCLUSIONS: An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression.

TSC2 inactivation, low mutation burden and high macrophage infiltration characterise hepatic angiomyolipomas.

AIMS: Although TSC1 or TSC2 inactivating mutations that lead to mTORC1 hyperactivation have been reported in hepatic angiomyolipomas (hAML), the role of other somatic genetic events that may contribute to hAML development is unknown. There are also limited data regarding the tumour microenvironment (TME) of hAML. The aim of the present study was to identify other somatic events in genomic level and changes in TME that contribute to tumorigenesis in hAML. METHODS AND RESULTS: In this study, we performed exome sequencing in nine sporadic hAML tumours and deep-coverage targeted sequencing for TSC2 in three additional hAML. Immunohistochemistry and multiplex immunofluorescence were carried out for 15 proteins to characterise the tumour microenvironment and assess immune cell infiltration. Inactivating somatic variants in TSC2 were identified in 10 of 12 (83%) cases, with a median allele frequency of 13.6%. Five to 18 somatic variants (median number: nine, median allele frequency 21%) not in TSC1 or TSC2 were also identified, mostly of uncertain clinical significance. Copy number changes were rare, but detection was impaired by low tumour purity. Immunohistochemistry demonstrated numerous CD68+ macrophages of distinct appearance from Küpffer cells. Multiplex immunofluorescence revealed low numbers of exhausted PD-1+/PD-L1+, FOXP3+ and CD8+ T cells. CONCLUSION: hAML tumours have consistent inactivating mutations in TSC2 and have a low somatic mutation rate, similar to other TSC-associated tumours. Careful histological review, standard IHC and multiplex immunofluorescence demonstrated marked infiltration by non-neoplastic inflammatory cells, mostly macrophages.

Implementation of a prostate cancer-specific targeted sequencing panel for credentialing of patient-derived cell lines and genomic characterization of patient samples.

BACKGROUND: Primary and metastatic prostate cancers have low mutation rates and recurrent alterations in a small set of genes, enabling targeted sequencing of prostate cancer-associated genes as an efficient approach to characterizing patient samples (compared to whole-exome and whole-genome sequencing). For example, targeted sequencing provides a flexible, rapid, and cost-effective method for genomic assessment of patient-derived cell lines to evaluate fidelity to initial patient tumor samples. METHODS: We developed a prostate cancer-specific targeted next-generation sequencing (NGS) panel to detect alterations in 62 prostate cancer-associated genes as well as recurring gene fusions with ETS family members, representing the majority of common alterations in prostate cancer. We tested this panel on primary prostate cancer tissues and blood biopsies from patients with metastatic prostate cancer. We generated patient-derived cell lines from primary prostate cancers using conditional reprogramming methods and applied targeted sequencing to evaluate the fidelity of these cell lines to the original patient tumors. RESULTS: The prostate cancer-specific panel identified biologically and clinically relevant alterations, including point mutations in driver oncogenes and ETS family fusion genes, in tumor tissues from 29 radical prostatectomy samples. The targeted panel also identified genomic alterations in cell-free DNA and circulating tumor cells (CTCs) from patients with metastatic prostate cancer, and in standard prostate cancer cell lines. We used the targeted panel to sequence our set of patient-derived cell lines; however, no prostate cancer-specific mutations were identified in the tumor-derived cell lines, suggesting preferential outgrowth of normal prostate epithelial cells. CONCLUSIONS: We evaluated a prostate cancer-specific targeted NGS panel to detect common and clinically relevant alterations (including ETS family gene fusions) in prostate cancer. The panel detected driver mutations in a diverse set of clinical samples of prostate cancer, including fresh-frozen tumors, cell-free DNA, CTCs, and cell lines. Targeted sequencing of patient-derived cell lines highlights the challenge of deriving cell lines from primary prostate cancers and the importance of genomic characterization to credential candidate cell lines. Our study supports that a prostate cancer-specific targeted sequencing panel provides an efficient, clinically feasible approach to identify genetic alterations across a spectrum of prostate cancer samples and cell lines.

Implementation and Clinical Adoption of Precision Oncology Workflows Across a Healthcare Network.

BACKGROUND: Precision oncology relies on molecular diagnostics, and the value-proposition of modern healthcare networks promises a higher standard of care across partner sites. We present the results of a clinical pilot to standardize precision oncology workflows. METHODS: Workflows are defined as the development, roll-out, and updating of disease-specific molecular order sets. We tracked the timeline, composition, and effort of consensus meetings to define the combination of molecular tests. To assess clinical impact, we examined order set adoption over a two-year period (before and after roll-out) across all gastrointestinal and hepatopancreatobiliary (GI) malignancies, and by provider location within the network. RESULTS: Development of 12 disease center-specific order sets took ~9 months, and the average number of tests per indication changed from 2.9 to 2.8 (P = .74). After roll-out, we identified significant increases in requests for GI patients (17%; P < .001), compliance with testing recommendations (9%; P < .001), and the fraction of "abnormal" results (6%; P < .001). Of 1088 GI patients, only 3 received targeted agents based on findings derived from non-recommended orders (1 before and 2 after roll-out); indicating that our practice did not negatively affect patient treatments. Preliminary analysis showed 99% compliance by providers in network sites, confirming the adoption of the order sets across the network. CONCLUSION: Our study details the effort of establishing precision oncology workflows, the adoption pattern, and the absence of harm from the reduction of non-recommended orders. Establishing a modifiable communication tool for molecular testing is an essential component to optimize patient care via precision oncology.

Prediction of non-muscle invasive bladder cancer recurrence using machine learning of quantitative nuclear features.

Non-muscle invasive bladder cancer (NMIBC) generally has a good prognosis; however, recurrence after transurethral resection (TUR), the standard primary treatment, is a major problem. Clinical management after TUR has been based on risk classification using clinicopathological factors, but these classifications are not complete. In this study, we attempted to predict early recurrence of NMIBC based on machine learning of quantitative morphological features. In general, structural, cellular, and nuclear atypia are evaluated to determine cancer atypia. However, since it is difficult to accurately quantify structural atypia from TUR specimens, in this study, we used only nuclear atypia and analyzed it using feature extraction followed by classification using Support Vector Machine and Random Forest machine learning algorithms. For the analysis, 125 patients diagnosed with NMIBC were used; data from 95 patients were randomly selected for the training set, and data from 30 patients were randomly selected for the test set. The results showed that the support vector machine-based model predicted recurrence within 2 years after TUR with a probability of 90% and the random forest-based model with probability of 86.7%. In the future, the system can be used to objectively predict NMIBC recurrence after TUR.

Transperineal Multiparametric Magnetic Resonance Imaging-Ultrasound Fusion Targeted Prostate Biopsy Combined with Standard Template Improves Prostate Cancer Detection.

PURPOSE: Transperineal (TP) prostate biopsy provides an effective approach to prostate cancer (PCa) detection. Although transrectal targeted biopsy has been well described, the specific advantage of the standard TP template or TP targeted biopsy using multiparametric (mp) magnetic resonance imaging (MRI)-ultrasound (US) fusion remains less understood and without consensus. MATERIALS AND METHODS: We identified all men who underwent a transperineal standard 20-core template in addition to a targeted biopsy with mpMRI-US fusion-guided software from September 2019 to February 2021. We assessed and compared clinical, MRI and biopsy characteristics between standard TP template and fusion targeted biopsies. RESULTS: A total of 301 men underwent TP fusion biopsy during the study period. Target lesions on MRI were sampled with 3 targeted cores per patient (IQR 3-4). The overall cancer detection rate was 74.1% and 63.5% by standard template and targeted biopsy, respectively, of which 52.5% and 59.7% were clinically significant (cs) PCa. Combined csPCa detection rate was 62.2%. Of 176 cases with a cancer diagnosis by both biopsy methods, 18.8% were upgraded with targeted biopsies while 18.2% were upgraded with template biopsies. CONCLUSIONS: In men with suspicious lesions on mpMRI, TP MRI fusion-guided biopsies combined with standard template provide a higher overall cancer detection rate and higher detection rate of csPCa than the standard template or targeted biopsy alone. In the setting of a suspicious mpMRI prostate lesion, targeted plus standard template should be included as part of the TP biopsy procedure.

COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis.

Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single-cell RNA sequencing in an orthotopic mouse prostate cancer model, we find up-regulation of prolactin receptor as cancer cells that have disseminated to the lungs expand into micrometastases. Secretion of the ligand prolactin by adjacent lung stromal cells is induced by tumor cell production of the COX-2 synthetic product prostaglandin E2 (PGE2). PGE2 treatment of fibroblasts activates the orphan nuclear receptor NR4A (Nur77), with prolactin as a major transcriptional target for the NR4A-retinoid X receptor (RXR) heterodimer. Ectopic expression of prolactin receptor in mouse cancer cells enhances micrometastasis, while treatment with the COX-2 inhibitor celecoxib abrogates prolactin secretion by fibroblasts and reduces tumor initiation. Across multiple human cancers, COX-2, prolactin, and prolactin receptor show consistent differential expression in tumor and stromal compartments. Such paracrine cross-talk may thus contribute to the documented efficacy of COX-2 inhibitors in cancer suppression.

Novel immune-related signature for risk stratification and prognosis in prostatic adenocarcinoma.

A substantial proportion of prostatic adenocarcinoma (PRAD) patients experience biochemical failure (BCF) after radical prostatectomy (RP). The immune microenvironment plays a vital role in carcinogenesis and the development of PRAD. This study aimed to identify a novel immune-related gene (IRG)-based signature for risk stratification and prognosis of BCF in PRAD. Weighted gene coexpression network analysis was carried out to identify a BCF-related module in a discovery cohort of patients who underwent RP at the Massachusetts General Hospital. The median follow-up time was 70.32 months. Random forest and multivariate stepwise Cox regression analyses were used to identify an IRG-based signature from the specific module. Risk plot analyses, Kaplan-Meier curves, receiver operating characteristic curves, univariate and multivariate Cox regression analyses, stratified analysis, and Harrell's concordance index were used to assess the prognostic value and predictive accuracy of the IRG-based signature in the internal discovery cohort; The Cancer Genome Atlas database was used as a validation cohort. Tumor immune estimation resource database analysis and CIBERSORT algorithm were used to assess the immunophenotype of PRAD. A novel IRG-based signature was identified from the specific module. Five IRGs (BUB1B, NDN, NID1, COL4A6, and FLRT2) were verified as components of the risk signature. The IRG-based signature showed good prognostic value and predictive accuracy in both the discovery and validation cohorts. Infiltrations of various immune cells were significantly different between low-risk and high-risk groups in PRAD. We identified a novel IRG-based signature that could function as an index for assessing tumor immune status and risk stratification in PRAD.

To stage or not to stage: determining the true clinical significance of the biopsy tract through perinephric fat in assessing renal cell carcinoma.

AIMS: Perinephric fat invasion (PFI) is a key component of renal cell carcinoma (RCC) staging, but there are limited data pertaining to biopsy tract seeding (BTS) resulting in perirenal tissue involvement [BTS with perinephric fat invasion (BTS-P)].The aim is to correlate clinical outcomes with pathologic stage to determine whether the presence of BTS-P should be considered a criterion to stage RCC as part of the pT3a category in the absence of any other upstaging variables. MATERIALS AND RESULTS: We identified 304 renal biopsies from patients with subsequent nephrectomies for RCC; 33 of the tumours contained PFI. Each case was reviewed to determine the presence of BTS-P and other forms of invasion [e.g. non-BTS-P PFI, sinus fat invasion (SFI), and/or renal vein invasion (RVI)], and these findings were compared with survival outcomes. Ten (30%) of 33 tumours with PFI showed BTS-P as the only finding, and were otherwise pT1 tumours; six (60%) patients were alive without disease (AWOD) (mean, 77.5 months), three were lost to follow-up (LTF), and one died of other disease (DOOD). Two patients showed true PFI plus BTS-P; one was LTF and one is AWOD at 107 months. Ten (43%) of 23 patients with tumours with true invasion (PFI ± SFI and/or RVI) are AWOD (mean, 97.7 months), eight (35%) died of disease (DOD), four were LTF, and one DOOD. Kaplan-Meier survival curves showed that the cancer-specific survival was significantly worse in patients with true invasion (P = 0.044) than in those with BTS-P as the sole finding. CONCLUSION: Patients with tumours showing BTS-P only appear to have better outcomes than those with other non-PFI invasion, suggesting that this finding should not be upstaged to pT3a. Additional studies are needed to corroborate the significance of our observations.

Impairment of gamma-glutamyl transferase 1 activity in the metabolic pathogenesis of chromophobe renal cell carcinoma.

Chromophobe renal cell carcinoma (ChRCC) accounts for 5% of all sporadic renal cancers and can also occur in genetic syndromes including Birt-Hogg-Dube (BHD) and tuberous sclerosis complex (TSC). ChRCC has a distinct accumulation of abnormal mitochondria, accompanied by characteristic chromosomal imbalances and relatively few "driver" mutations. Metabolomic profiling of ChRCC and oncocytomas (benign renal tumors that share pathological features with ChRCC) revealed both similarities and differences between these tumor types, with principal component analysis (PCA) showing a distinct separation. ChRCC have a striking decrease in intermediates of the glutathione salvage pathway (also known as the gamma-glutamyl cycle) compared with adjacent normal kidney, as well as significant changes in glycolytic and pentose phosphate pathway intermediates. We also found that gamma glutamyl transferase 1 (GGT1), the key enzyme of the gamma-glutamyl cycle, is expressed at ∼100-fold lower levels in ChRCC compared with normal kidney, while no change in GGT1 expression was found in clear cell RCC (ccRCC). Significant differences in specific metabolite abundance were found in ChRCC vs. ccRCC, including the oxidative stress marker ophthalmate. Down-regulation of GGT1 enhanced the sensitivity to oxidative stress and treatment with buthionine sulfoximine (BSO), which was associated with changes in glutathione-pathway metabolites. These data indicate that impairment of the glutathione salvage pathway, associated with enhanced oxidative stress, may have key therapeutic implications for this rare tumor type for which there are currently no specific targeted therapies.

A novel mouse model of hemangiopericytoma due to loss of Tsc2.

Hemangiopericytoma (HPC) is a rare vascular tumor, which is thought to originate from pericytes. However, no direct evidence for the cell of origin has been found, and the mechanism of HPC tumorigenesis is poorly understood. Here we report that loss of the tumor suppressor gene Tsc2 in pericytes using a FoxD1 promoter driven cre allele (Foxd1tm1(GFP/cre) Amc, FoxD1GC) leads to the formation of HPC in multiple sites. Tsc2ffFoxD1GC mice had stunted growth with seizures and tail and hind limb tremor with a median survival of 110 days. They also showed recombination in brain, spinal cord, tongue, liver, intestine and skeletal muscle. Distinctive perivascular tumors consisting of cells with oval nuclei and scant cytoplasm were identified in multiple sites in all Tsc2ffFoxD1GC mice. Immunohistochemistry staining showed a high expression of phospho-S6-S240/244, a hallmark of activated mTORC1, as well as pericyte markers NG2 and vimentin in these tumors. In summary, we demonstrate that loss of Tsc2 in pericytes generates HPC, the first mouse model of HPC reported.

ARNT-dependent CCR8 reprogrammed LDH isoform expression correlates with poor clinical outcomes of prostate cancer.

Lactate dehydrogenase isozyme (LDH) is a tetramer constituted of two isoforms, LDHA and LDHB, the expression of which is associated with cell metabolism and cancer progression. Our previous study reveals that CC-chemokine ligand-18 (CCL18) is involved in progression of prostate cancer (PCa).This study aims to investigate how CCL18 regulates LDH isoform expression, and therefore, contributes to PCa progression. The data revealed that the expression of LDHA was upregulated and LDHB was downregulated in PCa cells by CCL18 at both messenger RNA and protein levels. The depletion of CCR8 reduced the ability of CCL18 to promote the proliferation, migration, and lactate production of PCa cells. Depletion of a CCR8 regulated transcription factor, ARNT, significantly reduced the expression of LDHA. In addition, The Cancer Genome Atlas dataset analyses revealed a positive correlation between CCR8 and ARNT expression. Two dimension difference gel electrophoresis revealed that the LDHA/LDHB ratio was increased in the prostatic fluid of patients with PCa and PCa tissues. Furthermore, increased LDHA/LDHB ratio was associated with poor clinical outcomes of patients with PCa. Together, our results indicate that the CCR8 pathway programs LDH isoform expression in an ARNT dependent manner and that the ratio of LDHA/LDHB has the potential to serve as biomarkers for PCa diagnosis and prognosis.

The clinicopathological characteristics and prognostic value of squamous differentiation in patients with bladder urothelial carcinoma: a meta-analysis.

PURPOSE: Urothelial carcinoma with squamous differentiation (UCSD) is the most common histologic variant in bladder cancer (BCa). Previously, some studies have linked the presence of UCSD with the risk of worse survival outcomes in BCa patients. However, such association is still controversial. In this study, we performed a meta-analysis to clarify the clinicopathological characteristics and to further investigate the prognostic value of UCSD in BCa. METHODS: A systematic literature search was performed in electronic databases including PubMed, Embase, Chinese National Knowledge Infrastructure and Wanfang Data until October 2018. Subgroup analyses were performed according to different treatments and study outcomes. RESULTS: Total of 13,284 patients were enrolled in 19 studies which were included in this meta-analysis. The percentage of female patients with UCSD was significantly higher than those with pure urothelial carcinoma. UCSD was correlated with tumor stage T3/T4, tumor grade 3, positive surgical margin, and lymph node involvement. Moreover, the recurrence rate was higher in patients with UCSD after surgery. UCSD was associated with poorer disease-free survival (DFS). No significant difference of cancer-specific survival (CSS) or overall survival (OS) was found on multivariable analysis between the two groups. CONCLUSIONS: Our study demonstrated that UCSD in BCa was associated not only with unfavorable clinicopathological features, but also with high risk of recurrence and poorer prognosis for DFS. However, UCSD is not independently significant for CSS and OS. Well-designed randomized study with larger sample size is warranted to verify the findings and to further explore the role of UCSD in BCa.

Update on Renal Neoplasms: Clinicopathologic-Radiologic Correlation With Case-Based Examples.

OBJECTIVE. This article provides a brief overview of the clinicopathologic and radiologic correlation of 12 renal neoplasms, encompassing the conventional subtypes of renal cell carcinoma and a few of the newly recognized subtypes from the 2016 World Health Organization classification of renal tumors. In addition, we touch upon infrequent neoplasms that may enter the differential diagnosis of a renal mass, with corresponding radiologic and gross images and histologic findings of case-based examples. CONCLUSION. Familiarity with the radiologic and pathologic characteristics of renal cell carcinoma and other renal neoplasms is important to correctly identify and treat these masses.

Prognostic value of a gene signature in clear cell renal cell carcinoma.

Renal cancer is a common urogenital system malignance. Novel biomarkers could provide more and more critical information on tumor features and patients' prognosis. Here, we performed an integrated analysis on the discovery set and established a three-gene signature to predict the prognosis for clear cell renal cell carcinoma (ccRCC). By constructing a LASSO Cox regression model, a 3-messenger RNA (3-mRNA) signature was identified. Based on the 3-mRNA signature, we divided patients into high- and low-risk groups, and validated this by using three other data sets. In the discovery set, this signature could successfully distinguish between the high- and low-risk patients (hazard ratio (HR), 2.152; 95% confidence interval (CI),1.509-3.069; p < 0.0001). Analysis of internal and two external validation sets yielded consistent results (internal: HR, 2.824; 95% CI, 1.601-4.98; p < 0.001; GSE29609: HR, 3.002; 95% CI, 1.113-8.094; p = 0.031; E-MTAB-3267: HR, 2.357; 95% CI, 1.243-4.468; p = 0.006). Time-dependent receiver operating characteristic (ROC) analysis indicated that the area under the ROC curve at 5 years was 0.66 both in the discovery and internal validation set, while the two external validation sets also suggested good performance of the 3-mRNA signature. Besides that, a nomogram was built and the calibration plots and decision curve analysis indicated the good performance and clinical utility of the nomogram. In conclusion, this 3-mRNA classifier proved to be a useful tool for prognostic evaluation and could facilitate personalized management of ccRCC patients.