Clear Cell Renal Cell Carcinoma: A Comprehensive Review of its Histopathology, Genetics, and Differential Diagnosis.

Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal epithelial tumor, accounting for roughly 2% of all malignancies. Clinically, it often presents in the sixth to seventh decade of life, predominantly in men. Pathologically, these tumors exhibit a distinctive golden yellow cut surface, usually arising from the renal cortex. Their microscopic features are characterized by solid and nested architectures of cells with clear or eosinophilic granular cytoplasm and a prominent vascular network. A hallmark genetic feature is the inactivation of the VHL gene situated on chromosome 3p25. The majority of ccRCCs are sporadic (over 95%), typically presenting as a single mass; and a small percentage have a hereditary basis, often associated with VHL disease, characterized by multiple bilateral tumors with an earlier onset. Immunohistochemically, ccRCC tumors express PAX8, CA9 box like pattern, and CD10 but are generally negative for AMACR (35% positive) and KRT7 (15% positive). The prognosis of ccRCC is largely determined by its TNM stage, ISUP/WHO nucleolar grade, and the presence of specific aggressive features. This review article delves into the detailed gross, microscopic, molecular, and clinical features of ccRCC, offering comprehensive insights into its diagnosis, management, and prognosis.

Multi-scale statistical deformation based co-registration of prostate MRI and post-surgical whole mount histopathology.

BACKGROUND: Accurate delineations of regions of interest (ROIs) on multi-parametric magnetic resonance imaging (mpMRI) are crucial for development of automated, machine learning-based prostate cancer (PCa) detection and segmentation models. However, manual ROI delineations are labor-intensive and susceptible to inter-reader variability. Histopathology images from radical prostatectomy (RP) represent the "gold standard" in terms of the delineation of disease extents, for example, PCa, prostatitis, and benign prostatic hyperplasia (BPH). Co-registering digitized histopathology images onto pre-operative mpMRI enables automated mapping of the ground truth disease extents onto mpMRI, thus enabling the development of machine learning tools for PCa detection and risk stratification. Still, MRI-histopathology co-registration is challenging due to various artifacts and large deformation between in vivo MRI and ex vivo whole-mount histopathology images (WMHs). Furthermore, the artifacts on WMHs, such as tissue loss, may introduce unrealistic deformation during co-registration. PURPOSE: This study presents a new registration pipeline, MSERgSDM, a multi-scale feature-based registration (MSERg) with a statistical deformation (SDM) constraint, which aims to improve accuracy of MRI-histopathology co-registration. METHODS: In this study, we collected 85 pairs of MRI and WMHs from 48 patients across three cohorts. Cohort 1 (D1), comprised of a unique set of 3D printed mold data from six patients, facilitated the generation of ground truth deformations between ex vivo WMHs and in vivo MRI. The other two clinically acquired cohorts (D2 and D3) included 42 patients. Affine and nonrigid registrations were employed to minimize the deformation between ex vivo WMH and ex vivo T2-weighted MRI (T2WI) in D1. Subsequently, ground truth deformation between in vivo T2WI and ex vivo WMH was approximated as the deformation between in vivo T2WI and ex vivo T2WI. In D2 and D3, the prostate anatomical annotations, for example, tumor and urethra, were made by a pathologist and a radiologist in collaboration. These annotations included ROI boundary contours and landmark points. Before applying the registration, manual corrections were made for flipping and rotation of WMHs. MSERgSDM comprises two main components: (1) multi-scale representation construction, and (2) SDM construction. For the SDM construction, we collected N = 200 reasonable deformation fields generated using MSERg, verified through visual inspection. Three additional methods, including intensity-based registration, ProsRegNet, and MSERg, were also employed for comparison against MSERgSDM. RESULTS: Our results suggest that MSERgSDM performed comparably to the ground truth (p > 0.05). Additionally, MSERgSDM (ROI Dice ratio = 0.61, landmark distance = 3.26 mm) exhibited significant improvement over MSERg (ROI Dice ratio = 0.59, landmark distance = 3.69 mm) and ProsRegNet (ROI Dice ratio = 0.56, landmark distance = 4.00 mm) in local alignment. CONCLUSIONS: This study presents a novel registration method, MSERgSDM, for mapping ex vivo WMH onto in vivo prostate MRI. Our preliminary results demonstrate that MSERgSDM can serve as a valuable tool to map ground truth disease annotations from histopathology images onto MRI, thereby assisting in the development of machine learning models for PCa detection on MRI.

Frequent Telomerase Reverse Transcriptase Promoter and Fibroblast Growth Factor Receptor 3 Mutations Support the Precursor Nature of Papillary Urothelial Hyperplasia of the Urinary Bladder.

The precursor nature of papillary urothelial hyperplasia of the urinary bladder is uncertain. In this study, we investigated the telomerase reverse transcriptase (TERT) promoter and fibroblast growth factor receptor 3 (FGFR3) mutations in 82 patients with papillary urothelial hyperplasia lesions. Thirty-eight patients presented with papillary urothelial hyperplasia and concurrent noninvasive papillary urothelial carcinoma, and 44 patients presented with de novo papillary urothelial hyperplasia. The prevalence of the TERT promoter and FGFR3 mutations is compared between de novo papillary urothelial hyperplasia and those with concurrent papillary urothelial carcinoma. Mutational concordance between papillary urothelial hyperplasia and concurrent carcinoma was also compared. The TERT promoter mutations were detected in 44% (36/82) of papillary urothelial hyperplasia, including 23 (23/38, 61%) papillary urothelial hyperplasia with urothelial carcinoma and 13 (13/44, 29%) de novo papillary urothelial hyperplasia. The overall concordance of TERT promoter mutation status between papillary urothelial hyperplasia and concurrent urothelial carcinoma was 76%. The overall FGFR3 mutation rate of papillary urothelial hyperplasia was 23% (19/82). FGFR3 mutations were detected in 11 patients with papillary urothelial hyperplasia and concurrent urothelial carcinoma (11/38, 29%) and 8 patients with de novo papillary urothelial hyperplasia (8/44, 18%). Identical FGFR3 mutation status was detected in both papillary urothelial hyperplasia and urothelial carcinoma components in all 11 patients with FGFR3 mutations. Our findings provide strong evidence of a genetic association between papillary urothelial hyperplasia and urothelial carcinoma. High frequency of TERT promoter and FGFR3 mutations suggests the precursor role of papillary urothelial hyperplasia in urothelial carcinogenesis.

Comparison of Morphological and Histological Characteristics of Human and Sheep: Sheep as a Potential Model for Testing Midurethral Slings in vivo.

INTRODUCTION: The sheep was evaluated as a potential model for preclinical evaluation of urethral slings in vivo based on: (1) anatomical measurements of the sheep vagina and (2) histological tissue integration and host response to polypropylene (PP) slings. METHODS: Eight female, multiparous sheep were utilized. Three of 8 animals underwent surgery mimicking human tension-free vaginal tape protocols for midurethral slings and were euthanized at 6 months. The following measurements were obtained: vaginal length, maximum vaginal width with retraction, symphysis pubis length, and distance from the pubic bone to incision. Explanted sling samples from sheep and human were stained with hematoxylin and eosin for host reaction assessment. RESULTS: Geometric measurements were similar between humans and sheep. Sheep vaginal anatomy allowed sling placement similar to procedures in human surgeries, and all sheep recovered without problems. Comparative histology between the sheep and human indicated similar host reaction and collagen deposition around implants, confirming suitability of the sheep model for biomaterial response assessment. CONCLUSION: Sheep vaginal length is comparable to humans. Tissue integration and host response to PP slings showed chronic inflammation with rich collagen deposition around the material in both sheep and human specimens, highlighting the sheep as a potential animal model for preclinical testing of midurethral slings.

GATA3 expression in clear cell adenocarcinoma of the lower urinary tract: a potential diagnostic pitfall.

BACKGROUND: Clear cell adenocarcinoma of the lower urinary tract (CCACLUT) is a rare primary malignant neoplasm with heterogenous morphology. There is a paucity of data in the literature regarding its immunohistochemical profile. METHODS: The immunohistochemical features (extent and intensity) of a multinational cohort of CCACLUT were evaluated with comparison between clear cell adenocarcinoma of the female genital tract (CCACFGT, tissue microarray) and nephrogenic adenoma (NA). RESULTS: 33 CCACLUT (24 female, 9 male; mean age 59 years) were collected. CCACLUT most commonly arose from the urinary bladder (26/33, 78%), particularly from the trigone (10/33, 30.3%) followed by the urethra (8/33, 22%). All 12 NA cases were located at the urinary bladder, whereas the most common CCACFGT location was the ovary (29/56, 52%). None of the CCACLUT patients had, intestinal metaplasia, NA, or urothelial carcinoma. One patient had concurrent endometriosis of the sigmoid colon. Most frequently observed morphology in CCACLUT was papillary/tubulocystic (9/3; 27.3%), followed by papillary/tubular (6/33; 18.2%) and papillary/solid (5/33; 15.2%). GATA3 expression was significantly higher in CCACLUT (18/33, 54.5%) and NA (6/12, 50%), when compared to CCACFGT cases 6/56, 11.7%)(p = 0.001 and p = 0.022, respectively). The extent of GATA3 was significantly higher in CCACLUT group (19.2 ± 16.6%) than the other groups (9.6 ± 22.5% in NA and 2.6 ± 9% in CCACFGT group) (p = 0.001). 4/33 patients (12.1) had weak, 10/33 patients (30.3%) had moderate, and 4/33 patients (12.1%) had strong GATA3 intensity in CCACLUT group. In NA group, one patient (8.3%, 1/12) had weak, one patient (8.3%, 1/12) had moderate and 4 patients (33.3%, 4/12) had strong GATA3 intensity. Most cases (CCACLUT 29/33, 88%; NA 11/12, 92%; CCACFGT 46/56, 82.1%) had positive Napsin A expression, by which CCACLUT had significantly more cases with Napsin A expression (p = 0.034). p63 was consistently negative in all cases (30/33 (91.9%) CCACLUT; 12/12 (100%) NA; 42/56 (75%) CCACFGT. Ki67 (MIB) proliferation index was significantly higher in CCACLUT group (54.6 ± 21%) when compared to NA group (4.5 ± 2.7%) and CCACFGT group (35.5 ± 25.8%) (p = 0.001). CONCLUSION: CCACLUT has consistent GATA3 expression, which may cause challenge in the diagnosis of urothelial carcinoma but can be used to distinguish CCACLUT from CCACFGT.

Racial disparities in biochemical recurrence of prostate cancer.

BACKGROUND: The aim of this study was to determine the biochemical recurrence among Black and White American men with grade group 2-5 prostate cancer managed primarily by radical prostatectomy (RP). METHODS: This was a single-institution, retrospective study evaluating biochemical recurrence by self-identified race. 163 patients who underwent RP at the University Hospitals Cleveland Medical Center between 2015-2021 were analyzed for racial differences in age at diagnosis, clinical stage, and preoperative serum prostate-specific antigen (PSA). Patients were followed for PSA recurrence (PSA ≥ 0.2 ng/ml). Multivariate analysis was used to determine clinical and pathologic variables that were significant in predicting biochemical recurrence after RP and to determine whether race was an independent predictor of biochemical recurrence-free survival (BCRFS). RESULTS: Of 163 patients, 82 (50.3%) were Black Americans and 81 (49.7%) were White Americans with a median age of 62.7 ranging between 38.7 to 76.3 years. The grade-specific distribution of cancer 3+4 was 54.9% versus 65.4%; 4+3 was 25.6% versus 30.9%; 4+4 was 7.3% versus 2.5%; 4+5 was 12.2% versus 1.2% in Black American and White American men. Univariate analysis of BCRFS using Kaplan-Meier method demonstrated a significant difference among levels of Gleason score between Black Americans and White Americans (P = 0.041). Multivariable analysis after controlling the effects of age, Gleason score exhibited no significant difference of BCRFS comparing Black and White American men (P = 0.145). Specifically, the hazard of biochemical recurrence among Black Americans was 1.6 times (95% CI: 0.85-3.02) compared to White Americans (P = 0.145). CONCLUSION: Our study demonstrated a significant difference in BCRFS between Black and White American patients. Additional studies with larger sample size underlying this clinical disparity are warranted.

A preliminary evaluation of in vivo response to a filament-wound macroporous collagen midurethral sling in an ovine model.

Stress urinary incontinence (SUI) impacts ~1/3 of women over age 50. Negative publicity around PP meshes used in pelvic prolapse repair drives the need for identifying alternative biomaterials for SUI repair. Our study evaluated in vivo response to collagen sling implanted in an ovine model. Electrocompacted collagen threads were filament wound as slings and crosslinked in genipin. Collagen slings were implanted suburethrally mimicking the transvaginal tape technique. Main study groups were: Collagen sling (n = 3, 6 months) and PP sling (n = 3, 6 months). Collagen sling was also tested at 3-weeks (n = 1) to observe early-stage tissue response and 1-year (n = 2) to assess biomaterial longevity in a preliminary capacity. Collagen slings healed to a fibrous ligament texture at 6 months and maintained such texture to 1 year. Histological scoring indicated biocompatible responses to collagen slings with no adverse events. All study groups exhibited complete tissue ingrowth and interstitial de novo collagen deposition at all time points. Collagen threads induced orderly de novo collagen deposition that was aligned along long axes of threads. Tissue infiltrated collagen slings that were explanted at 6 and 12 months presented similar structural strength with native tissues such as vagina and fascia, and PP (Lynx) slings (p > .05). With the limitation of low number of animals per time point in hindsight, this preliminary study justifies evaluation of collagen slings in a larger sample size of animals, particularly to assess persistence of ligamentous tissue response over longer durations than 1-year.

Development of a novel castration-resistant orthotopic prostate cancer model in New Zealand White rabbit.

BACKGROUND: Prostate cancer (PCa) models in mice and rats are limited by their size and lack of a clearly delineated or easily accessible prostate gland. The canine PCa model is currently the only large animal model which can be used to test new preclinical interventions but is costly and availability is sparse. As an alternative, we developed an orthotopic human prostate tumor model in an immunosuppressed New Zealand White rabbit. Rabbits are phylogenetically closer to humans, their prostate gland is anatomically similar, and its size allows for clinically-relevant testing of interventions. METHODS: Rabbits were immunosuppressed via injection of cyclosporine. Human PC3pipGFP PCa cells were injected into the prostate via either (a) laparotomy or (b) transabdominal ultrasound (US) guided injection. Tumor growth was monitored using US and magnetic resonance imaging (MRI). Contrast-enhanced ultrasound (CEUS) imaging using nanobubbles and Lumason microbubbles was also performed to examine imaging features and determine the optimal contrast dose required for enhanced visualization of the tumor. Ex vivo fluorescence imaging, histopathology, and immunohistochemistry analyses of the collected tissues were performed to validate tumor morphology and prostate-specific membrane antigen (PSMA) expression. RESULTS: Immunosuppression and tumor growth were, in general, well-tolerated by the rabbits. Fourteen out of 20 rabbits, with an average age of 8 months, successfully grew detectable tumors from Day 14 onwards after cell injection. The tumor growth rate was 39 ± 25 mm2 per week. CEUS and MRI of tumors appear hypoechoic and T2 hypointense, respectively, relative to normal prostate tissue. Minimally invasive US-guided tumor cell injection proved to be a better method compared to laparotomy due to the shorter recovery time required for the rabbits following injection. Among the rabbits that grew tumors, seven had tumors both inside and outside the prostate, three had tumors only inside the prostate, and four had tumors exclusively outside of the prostate. All tumors expressed the PSMA receptor. CONCLUSIONS: We have established, for the first time, an orthotopic PCa rabbit model via percutaneous US-guided tumor cell inoculation. This animal model is an attractive, clinically relevant intermediate step to assess preclinical diagnostic and therapeutic compounds.

Identification of Key Genes Associated with Progression and Prognosis of Bladder Cancer through Integrated Bioinformatics Analysis.

Bladder cancer prognosis remains dismal due to lack of appropriate biomarkers that can predict its progression. The study aims to identify novel prognostic biomarkers associated with the progression of bladder cancer by utilizing three Gene Expression Omnibus (GEO) datasets to screen differentially expressed genes (DEGs). A total of 1516 DEGs were identified between non-muscle invasive and muscle invasive bladder cancer specimens. To identify genes of prognostic value, we performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. A total of seven genes, including CDKN2A, CDC20, CTSV, FOXM1, MAGEA6, KRT23, and S100A9 were confirmed with strong prognostic values in bladder cancer and validated by qRT-PCR conducted in various human bladder cancer cells representing stage-specific disease progression. ULCAN, human protein atlas and The Cancer Genome Atlas datasets were used to confirm the predictive value of these genes in bladder cancer progression. Moreover, Kaplan-Meier analysis and Cox hazard ratio analysis were performed to determine the prognostic role of these genes. Univariate analysis performed on a validation set identified a 3-panel gene set viz. CDKN2A, CTSV and FOXM1 with 95.5% sensitivity and 100% specificity in predicting bladder cancer progression. In summary, our study screened and confirmed a 3-panel biomarker that could accurately predict the progression and prognosis of bladder cancer.

Presence of Specific Periodontal Pathogens in Prostate Gland Diagnosed With Chronic Inflammation and Adenocarcinoma.

Background Intraprostatic inflammation is frequently observed in the prostate and linked to prostatic diseases, including prostatitis, benign prostatic hyperplasia (BPH), and cancer. The etiology of prostate diseases is unclear. Periodontal diseases are associated with an increased risk of prostate diseases. In men, chronic prostatitis and moderate/severe periodontitis have significantly elevated serum prostate-specific antigen (PSA) levels. Treatment of periodontal disease reduced PSA levels in men. The presence of periodontal pathogens deoxyribonucleic acid (DNA) was identified in the prostate fluid of prostatitis patients. These pathogenic bacteria might have the potential to trigger prostatitis progressing to prostatic adenocarcinoma. The mechanism(s) explaining the etiology of association between periodontal disease and prostate cancer remains unclear. However, the presence of periodontal pathogens has not been analyzed in the prostate gland. Objective To identify and compare the presence of specific periodontal pathogens in the areas of BPH, inflammation, and cancer of the prostate glands diagnosed with malignancy. Materials and methods Whole-mount radical prostatectomy sections from men (n=30) were identified for BPH, inflammation, and cancer areas and marked for tissue procurement. The tissues were subjected to DNA isolation and analysis of microbial DNA and total bacterial load for the following pathogens, including Porphyromonas gingivalis strain ATCC 33277, Prevotella intermedia strain B422, Treponema denticola strain 35405, Fusobacterium nucleatum subsp. fusiform strain, Tannerella forsythia strain ATCC 43037, and Campylobacter​​​​​​​ rectus strain ATCC 33238performed real-time PCR. The universal bacterial primer pairs were used to detect genomic DNA (gDNA) from the total bacteria present in the samples. All species-specific primers were designed to target the variable regions of the 16S ribosomal RNA (rRNA). Data were analyzed using the 2-ΔΔCT method, statistically validated using unpaired t-test and ANOVA test. Results A total of 90 samples of prostate tissue specimens were analyzed for periodontal pathogens; only one pathogen (F. nucleatum subsp. fusiform strain ATCC 51190) showed a significant difference compared to the expression of S. epidermidis (internal control). In particular, F. nucleatum expression was 9, 11.9, and 10.3-fold higher in BPH, inflammation, and cancer, respectively, at p-value <0.05. Moreover, the bacterial load abundance/expression was almost similar in BPH (46.8-fold), inflammation (40.9 fold), and cancer (41.5 fold) higher. There was no significant difference in bacterial load (folder change) among the three areas of BPH, inflammation, and cancer (p-valve>0.05). Similarly, there was no significant difference between F. nucleatum (folder change) among the three areas (p-valve>0.05). Conclusion  Fusobacterium nucleatum is identified in the prostates that harbor cancer, chronic inflammation, and BPH.

Focal Prostate Stereotactic Body Radiation Therapy With Correlative Pathological and Radiographic-Based Treatment Planning.

INTRODUCTION: Advances in multiparametric MRI (mpMRI) combining anatomic and functional imaging can accurately identify foci of adenocarcinoma within the prostate, offering the possibility of partial gland therapy. We performed tandem prospective pilot trials to investigate the feasibility of focal prostate SBRT (f-SBRT) based on correlating diagnostic mpMRI and biopsies with confirmatory pathology in treatment planning. MATERIALS AND METHODS: Patients with pathologic focal Gleason 6-7 disease and a corresponding PIRADS 4-5 lesion on mpMRI underwent targeted and comprehensive biopsies using MRI/ultrasound fusion under electromagnetic sensor navigation. After rigorous analysis for imaging biopsy concordance, five of 18 patients were eligible to proceed to f-SBRT. Chi-squared test was used for differences from expected outcomes, and concordance was estimated with binomial distribution theory and Wilson's method. RESULTS: Six patients had Gleason 6 and 12 had Gleason 3 + 4 disease (mean PSA: 5.8 ng/ml, range: 2.2-8.4). Absolute concordance was 43.8% (95% CI: 0.20, 0.64). Patterns of discordance included additional sites of ipsilateral disease, bilateral disease, and negative target. Five were upstaged to a new NCCN risk category necessitating treatment escalation. The five patients with concordant pathology completed three-fraction f-SBRT with sparing of the surrounding normal structures (including contralateral neurovascular bundle), with no reported grade 2+ toxicities and favorable PSA responses (mean: 41% decrease). CONCLUSIONS: On our pilot trials of f-SBRT planning using rigorous imaging and pathology concordance, image-guided confirmatory biopsies frequently revealed additional disease, suggesting the need for caution in partial-gland therapy. For truly focal disease, f-SBRT provided excellent dosimetry, minimal toxicity, and encouraging biochemical response. Clinical Trial Registration: www.clinicaltrials.gov, NCT02681614; NCT02163317.

T1 and T2 MR fingerprinting measurements of prostate cancer and prostatitis correlate with deep learning-derived estimates of epithelium, lumen, and stromal composition on corresponding whole mount histopathology.

OBJECTIVES: To explore the associations between T1 and T2 magnetic resonance fingerprinting (MRF) measurements and corresponding tissue compartment ratios (TCRs) on whole mount histopathology of prostate cancer (PCa) and prostatitis. MATERIALS AND METHODS: A retrospective, IRB-approved, HIPAA-compliant cohort consisting of 14 PCa patients who underwent 3 T multiparametric MRI along with T1 and T2 MRF maps prior to radical prostatectomy was used. Correspondences between whole mount specimens and MRI and MRF were manually established. Prostatitis, PCa, and normal peripheral zone (PZ) regions of interest (ROIs) on pathology were segmented for TCRs of epithelium, lumen, and stroma using two U-net deep learning models. Corresponding ROIs were mapped to T2-weighted MRI (T2w), apparent diffusion coefficient (ADC), and T1 and T2 MRF maps. Their correlations with TCRs were computed using Pearson's correlation coefficient (R). Statistically significant differences in means were assessed using one-way ANOVA. RESULTS: Statistically significant differences (p < 0.01) in means of TCRs and T1 and T2 MRF were observed between PCa, prostatitis, and normal PZ. A negative correlation was observed between T1 and T2 MRF and epithelium (R = - 0.38, - 0.44, p < 0.05) of PCa. T1 MRF was correlated in opposite directions with stroma of PCa and prostatitis (R = 0.35, - 0.44, p < 0.05). T2 MRF was positively correlated with lumen of PCa and prostatitis (R = 0.57, 0.46, p < 0.01). Mean T2 MRF showed significant differences (p < 0.01) between PCa and prostatitis across both transition zone (TZ) and PZ, while mean T1 MRF was significant (p = 0.02) in TZ. CONCLUSION: Significant associations between MRF (T1 in the TZ and T2 in the PZ) and tissue compartments on corresponding histopathology were observed. KEY POINTS: • Mean T2 MRF measurements and ADC within cancerous regions of interest dropped with increasing ISUP prognostic groups (IPG). • Mean T1 and T2 MRF measurements were significantly different (p < 0.001) across IPGs, prostatitis, and normal peripheral zone (NPZ). • T2 MRF showed stronger correlations in the peripheral zone, while T1 MRF showed stronger correlations in the transition zone with histopathology for prostate cancer.

Gender Disparities in Bladder Cancer-Specific Survival in High Poverty Areas Utilizing Ohio Cancer Incidence Surveillance System (OCISS).

OBJECTIVE: To better understand the interplay of socioeconomic and demographic traits on bladder cancer outcomes utilizing the Ohio state cancer registry, Ohio Cancer Incidence Surveillance System (OCISS). METHODS: We obtained demographic, clinical and outcome data on 47,182 bladder cancer cases diagnosed from 1996 to 2016 from OCISS. Multivariable Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between sex, race and poverty and survival, adjusting age, stage, and primary treatment. RESULTS: Within the OCISS database, there were 47,182 patients with a diagnosis of bladder cancer identified, with females representing 12,056 (26%) of the population. There were a total of 9255(35.2%) deaths due to bladder cancer, with median follow-up time of 4.4 years. After adjusting for confounding variables, women were statistically significantly less likely to die from any cause (HR: 0.94, 95% CI: 0.91-0.96), compared with men, but more likely to die from bladder cancer (HR: 1.21, 95% CI: 1.15-1.27). We also found that after adjusting for confounding variables, including sex and poverty, black race was statistically significantly associated with a higher risk of overall (HR: 1.12, 95% CI: 1.06-1.18) and bladder cancer-specific mortality (HR: 1.25, 95% CI: 1.15-1.36). CONCLUSION: Using the OCISS database, female gender, self-reported black race, and neighborhood poverty level were associated with worse bladder cancer-specific survival. By recognizing these disparities, we can prospectively address risk factors in efforts to improve survival among these patient populations.

Final results of a dose escalation protocol of stereotactic body radiotherapy for poor surgical candidates with localized renal cell carcinoma.

BACKGROUND AND PURPOSE: We previously demonstrated the safety of doses up to 48 Gy in 4 fractions with stereotactic body radiotherapy (SBRT) in poor surgical candidates with localized renal cell carcinoma (RCC). In an additional expansion cohort, we aimed to assess the safety of further dose escalation to 48-60 Gy in 3 fractions. MATERIAL AND METHODS: Patients were required to have localized RCC and be poor surgical candidates due to medical comorbidities. Dose-limiting toxicity (DLT) was defined as acute (<180 days) grade ≥3 gastrointestinal/genitourinary toxicity by CTCAEv4. Tumor response was assessed using RECIST 1.1 criteria measurements every 6 months for 3 years and optional percutaneous biopsy. RESULTS: Groups of 4, 4, and 3 patients received 48, 54, and 60 Gy in 3 fractions, respectively from 2012 to 2016. Median follow-up was 34.3 months. Zero DLTs were observed. Acute toxicities were limited to grade 1 fatigue and nausea in 45.5% and 18.1%. Late grade 2+ and grade 3+ possibly treatment-related events occurred in 18.1% and 9.1%, respectively. Three-year local control was 90% by RECIST 1.1 criteria. Five of 5 post-treatment biopsies in the expansion cohort were positive by Hematoxylin and Eosin staining. Three of the 5 patients with positive biopsies have been observed for 1.2-3.9 years without evidence of progression. CONCLUSION: Dose escalation to 60 Gy in 3 fractions was achieved without DLTs. Favorable local control rates were observed, and the interpretation of post-SBRT biopsies remains uncertain. Further studies comparing SBRT to percutaneous ablation for poor surgical candidates with RCC are warranted.

"Robotic fatigue?" - The impact of case order on positive surgical margins in robotic-assisted laparoscopic prostatectomy.

PURPOSE: Multiple robotic-assisted surgeries are often performed within a single operating day; however, the impact of this practice on patient outcomes has not been examined. We aim to determine whether outcomes for robotic-assisted laparoscopic prostatectomy (RALP) differed when performed sequentially. MATERIALS AND METHODS: A multi-institutional, retrospective cohort study was conducted involving a total of 8 academic centers between years 2015 and 2018. Participants were adult males undergoing RALP for localized prostate cancer on operative days in which 2 RALP cases were performed sequentially by the same resident-attending team. The primary outcome of the study was presence of positive surgical margin (PSM). Secondary outcomes were lymph node yield, operative time, and estimated blood loss. The primary analysis was a random effects meta-analysis model for PSM. RESULTS: Overall, 898 RALP cases (449 sequential pairs) were included in the study. There was no significant difference in PSM rate (27.2% vs. 30.3%, P= 0.338) between first and second case groups, respectively. Utilizing random effects meta-analysis, the second case cohort had no increased risk of PSM (OR 0.761.231.97, P= 0.40). Higher blood loss was noted in the second case cohort (186.7 ml vs. 221.7 ml, P = 0.002). Additionally, factors associated with PSM were increasing prostate specific antigen, higher percent tumor involvement, extraprostatic extension, and seminal vesicle invasion. CONCLUSION: Case sequence was not associated with PSM, lymph node yield, or operative time for RALP. Disease specific factors and institutional experience are associated with increased risk for positive surgical margin which can aid providers in scheduling of patients.

Early Bone Metastases are Associated with Worse Outcomes in Metastatic Urothelial Carcinoma.

BACKGROUND: Outcomes of patients with metastatic urothelial carcinoma (mUC) with early bone metastases (eBM) vs no early bone metastases (nBM) have not thoroughly been described in the age of immuno-oncology. OBJECTIVE: To compare survival and other clinical outcomes in patients with eBM and nBM. METHODS: We used a multi-institutional database of patients with mUC treated with systemic therapy. Demographic, metastatic site, treatment patterns, and clinical outcomes were recorded. Wilcoxon rank-sum, chi-square tests were performed. Survival was estimated by Kaplan-Meier method; multivariable Cox analysis was performed. RESULTS: We identified 270 pts, 67% men, mean age 69±11 years. At metastatic diagnosis, 27% had≥1 eBM and were more likely to have de novo vs. recurrent metastases (42% vs 19%, p < 0.001). Patients with eBM had shorter overall survival (OS) vs. those with nBM, (6.1 vs 13.7 months, p < 0.0001). On multivariable analysis, eBM independently associated with higher risk of death, HR = 2.52 (95% CI: 1.75-3.63, p < 0.0001). OS was shorter for patients with eBM who received initial immune checkpoint inhibitor vs platinum-based chemotherapy, (1.6 vs 9.1 months, p = 0.02). Patients with eBM received higher opioid analgesic doses compared to patients with nBM and received quantitatively more palliative radiation. CONCLUSIONS: Patients with mUC and eBM have poorer outcomes, may benefit less from anti-PD-1/PD-L1 therapy and represent an unmet need for novel therapeutic interventions. Dedicated clinical trials, biomarker validation to assist in patient selection, as well as consensus on reporting of non-measurable disease are required.

Androgen Deprivation Induces Transcriptional Reprogramming in Prostate Cancer Cells to Develop Stem Cell-Like Characteristics.

Enzalutamide, an antiandrogen, is approved for therapy of castration resistant prostate cancer. Clinical applications have shown that approximately 30% of patients acquire resistance after a short period of treatment. However, the molecular mechanisms underlying this resistance is not completely understood. To identify transcriptomic signatures associated with acquisition of drug resistance we profiled gene expression of paired enzalutamide sensitive and resistant human prostate cancer LNCaP (lymph node carcinoma of the prostate) and C4-2B cells. Overlapping genes differentially regulated in the enzalutamide resistant cells were ranked by Ingenuity Pathway Analysis and their functional validation was performed using ingenuity knowledge database followed by confirmation to correlate transcript with protein expression. Analysis revealed that genes associated with cancer stem cells, such as POU5F1 (OCT4), SOX2, NANOG, BMI1, BMP2, CD44, SOX9, and ALDH1 were markedly upregulated in enzalutamide resistant cells. Amongst the pathways enriched in the enzalutamide-resistant cells were those associated with RUNX2, hedgehog, integrin signaling, and molecules associated with elastic fibers. Further examination of a patient cohort undergoing ADT and its comparison with no-ADT group demonstrated high expression of POU5F1 (OCT4), ALDH1, and SOX2 in ADT specimens, suggesting that they may be clinically relevant therapeutic targets. Altogether, our approach exhibits the potential of integrative transcriptomic analyses to identify critical genes and pathways of antiandrogen resistance as a promising approach for designing novel therapeutic strategies to circumvent drug resistance.

Granular necrosis: a distinctive form of cell death in malignant tumours.

Foci of necrosis are frequently seen in malignant tumours and may be due to a variety of causes. Different types of necrosis are given various names based upon their morphological features and presumed pathogenesis, such as coagulative, liquefactive and fibrinoid necrosis. Here, we propose the term 'granular necrosis' (GN) for a specific form of tumour necrosis characterised by the presence of well-defined necrotic foci being sharply demarcated from adjacent viable tumour. A constant feature is loss of architecture resulting in an amorphous necrotic mass containing granular nuclear and cytoplasmic debris, without an associated neutrophilic infiltrate. There is usually extensive karyorrhexis, which in larger tumours is more prominent at the periphery. These foci are often microscopic but may range up to several millimetres or larger in size. This distinctive form of necrosis has been erroneously given a variety of names in the literature including coagulative necrosis and microscopic necrosis, which on the basis of the aforementioned gross and microscopic findings is inappropriate. It is apparent that this is a specific form of necrosis, hence the descriptive term 'granular necrosis' that differentiates this form of necrosis from other types. The presence of GN is recognised as occurring in a variety of tumour types, being commonly seen in renal cell carcinoma, where it has been shown to have independent prognostic significance. In some epithelial and stromal tumours of the uterus, the presence of GN also has prognostic significance and is a defining feature for the differentiation of uterine leiomyoma and leiomyosarcoma. The pathogenesis of GN is unresolved. It does not show the features of apoptosis and in recent studies has been shown to have some of the molecular changes associated with necroptosis.