Quantitative Histomorphometric Features of Prostate Cancer Predict Patients Who Biochemically Recur Following Prostatectomy.

Prostate cancer is the most commonly diagnosed cancer in men, accounting for 27% of the new male cancer diagnoses in 2022. If organ-confined, removal of the prostate through radical prostatectomy is considered curative; however, distant metastases may occur, resulting in a poor patient prognosis. This study sought to determine whether quantitative pathomic features of prostate cancer differ in patients who biochemically experience biological recurrence after surgery. Whole-mount prostate histology from 78 patients was analyzed for this study. In total, 614 slides were hematoxylin and eosin stained and digitized to produce whole slide images (WSI). Regions of differing Gleason patterns were digitally annotated by a genitourinary fellowship-trained pathologist, and high-resolution tiles were extracted from each annotated region of interest for further analysis. Individual glands within the prostate were identified using automated image processing algorithms, and histomorphometric features were calculated on a per-tile basis and across WSI and averaged by patients. Tiles were organized into cancer and benign tissues. Logistic regression models were fit to assess the predictive value of the calculated pathomic features across tile groups and WSI; additionally, models using clinical information were used for comparisons. Logistic regression classified each pathomic feature model at accuracies >80% with areas under the curve of 0.82, 0.76, 0.75, and 0.72 for all tiles, cancer only, noncancer only, and across WSI. This was comparable with standard clinical information, Gleason Grade Groups, and CAPRA score, which achieved similar accuracies but areas under the curve of 0.80, 0.77, and 0.70, respectively. This study demonstrates that the use of quantitative pathomic features calculated from digital histology of prostate cancer may provide clinicians with additional information beyond the traditional qualitative pathologist assessment. Further research is warranted to determine possible inclusion in treatment guidance.

Multi-Site Concordance of Diffusion-Weighted Imaging Quantification for Assessing Prostate Cancer Aggressiveness.

BACKGROUND: Diffusion-weighted imaging (DWI) is commonly used to detect prostate cancer, and a major clinical challenge is differentiating aggressive from indolent disease. PURPOSE: To compare 14 site-specific parametric fitting implementations applied to the same dataset of whole-mount pathologically validated DWI to test the hypothesis that cancer differentiation varies with different fitting algorithms. STUDY TYPE: Prospective. POPULATION: Thirty-three patients prospectively imaged prior to prostatectomy. FIELD STRENGTH/SEQUENCE: 3 T, field-of-view optimized and constrained undistorted single-shot DWI sequence. ASSESSMENT: Datasets, including a noise-free digital reference object (DRO), were distributed to the 14 teams, where locally implemented DWI parameter maps were calculated, including mono-exponential apparent diffusion coefficient (MEADC), kurtosis (K), diffusion kurtosis (DK), bi-exponential diffusion (BID), pseudo-diffusion (BID*), and perfusion fraction (F). The resulting parametric maps were centrally analyzed, where differentiation of benign from cancerous tissue was compared between DWI parameters and the fitting algorithms with a receiver operating characteristic area under the curve (ROC AUC). STATISTICAL TEST: Levene's test, P < 0.05 corrected for multiple comparisons was considered statistically significant. RESULTS: The DRO results indicated minimal discordance between sites. Comparison across sites indicated that K, DK, and MEADC had significantly higher prostate cancer detection capability (AUC range = 0.72-0.76, 0.76-0.81, and 0.76-0.80 respectively) as compared to bi-exponential parameters (BID, BID*, F) which had lower AUC and greater between site variation (AUC range = 0.53-0.80, 0.51-0.81, and 0.52-0.80 respectively). Post-processing parameters also affected the resulting AUC, moving from, for example, 0.75 to 0.87 for MEADC varying cluster size. DATA CONCLUSION: We found that conventional diffusion models had consistent performance at differentiating prostate cancer from benign tissue. Our results also indicated that post-processing decisions on DWI data can affect sensitivity and specificity when applied to radiological-pathological studies in prostate cancer. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

The prognostic value of digital rectal exam for the existence of advanced pathologic features after prostatectomy.

BACKGROUND: Accurate staging at the time of prostate cancer diagnosis is fundamental to risk stratification and management counseling. Digital rectal exam (DRE) is foundational in clinical staging of prostate cancer, even with a known limited interexaminer agreement and poor sensitivity for detecting extraprostatic disease. We sought to evaluate the prognostic value of DRE for the presence of advanced pathologic features (APFs) following radical prostatectomy (RP). METHODS: All patients undergoing RP as primary treatment for clinically localized prostate cancer in the National Cancer Database between 2008 and 2014 were identified. Patients with additional malignancies, prior treatment with radiation or systemic therapy, incongruent clinical staging and DRE findings or without fully evaluable clinical staging were excluded. The primary outcome was the presence of postsurgical APFs, defined as positive surgical margins, nodal disease, or pathologic stage T3 or greater. Multivariable logistic regression analysis was performed to account for prostate-specific antigen (PSA), biopsy grade group, percent of positive biopsy cores, and clinical stage. RESULTS: In total, 91,525 patients consisting of 69,182 cT1, 20,641 cT2, and 1702 cT3-T4 were included. The average age was 61.1 ± 7.0 years, and the average PSA was 8.6 ± 10.3 ng/ml. On multivariable analysis, cT3 and T4 were associated with the presence of APFs (odds ratio [OR] 11.12, p < .01 and 5.28, p = .04), however, cT2 was only slightly associated with the presence of APFs when compared with cT1 (OR 1.15, p < .01). Furthermore, cT2 was associated with more node-positive disease (OR 1.63, p < .01), positive margins (OR 1.06, p < .01), and more than or equal to pT3 disease (OR 1.22, p < .01). CONCLUSIONS: Overall, advanced clinical stage as assessed by DRE was independently associated with an increasing risk of APFs. For individual APFs, the greatest effect is noticed between clinical stage and nodal positivity and less so between clinical stage and positive margins. DRE continues to hold value, particularly for patients with locally advanced disease and potential lymph node disease.

Comparative Outcomes of Salvage Retzius-Sparing versus Standard Robotic Prostatectomy: An International, Multi-Surgeon Series.

PURPOSE: Salvage radical prostatectomy is rare due to the risk of postoperative complications. We compare salvage Retzius-sparing robotic assisted radical prostatectomy (SRS-RARP) with salvage standard robotic assisted radical prostatectomy (SS-RARP). MATERIALS AND METHODS: A total of 72 patients across 9 centers were identified (40 SRS-RARP vs 32 SS-RARP). Demographics, perioperative data, and pathological and functional outcomes were compared using Student's t-test and ANOVA. Cox proportional hazard models and Kaplan-Meier curves were constructed to assess risk of incontinence and time to continence. Linear regression models were constructed to investigate postoperative pad use and console time. RESULTS: Median followup was 23 vs 36 months for SRS-RARP vs SS-RARP. Console time and estimated blood loss favored SRS-RARP. There were no differences in complication rates or oncologic outcomes. SRS-RARP had improved continence (78.4% vs 43.8%, p <0.001 for 0-1 pad, 54.1% vs 6.3%, p <0.001 for 0 pad), lower pads per day (0.57 vs 2.03, p <0.001), and earlier return to continence (median 47 vs 180 days, p=0.008). SRS-RARP was associated with decreased incontinence defined as >0-1 pad (HR 0.28, 95% CI 0.10-0.79, p=0.016), although not when defined as >0 pad (HR 0.56, 95% CI 0.31-1.01, p=0.053). On adjusted analysis SRS-RARP was associated with decreased pads per day. Lymph node dissection and primary treatment with stereotactic body radiation therapy were associated with longer console time. CONCLUSIONS: SRS-RARP is a feasible salvage option with significantly improved urinary function outcomes. This may warrant increased utilization of SRS-RARP to manage men who fail nonsurgical primary treatment for prostate cancer.

Robotic partial nephrectomy vs minimally invasive radical nephrectomy for clinical T2a renal mass: a propensity score-matched comparison from the ROSULA (Robotic Surgery for Large Renal Mass) Collaborative Group.

OBJECTIVE: To compare outcomes of minimally invasive radical nephrectomy (MIS-RN) and robot-assisted partial nephrectomy (RAPN) in clinical T2a renal mass (cT2aRM). PATIENTS AND METHODS: Retrospective, multicentre, propensity score-matched (PSM) comparison of RAPN and MIS-RN for cT2aRM (T2aN0M0). Cohorts were PSM for age, sex, body mass index, American Society of Anesthesiologists (ASA) class, clinical tumour size, and R.E.N.A.L. score using a 2:1 ratio for RN:PN. The primary outcome was disease-free survival (DFS). Secondary outcomes included overall survival (OS), complication rates, and de novo estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 . Multivariable (MVA) and Kaplan-Meier survival analyses (KMSA) were conducted. RESULTS: In all, 648 patients (216 RAPN/432 MIS-RN) were matched. There were no significant differences in intraoperative complications (P = 0.478), Clavien-Dindo Grade ≥III complications (P = 0.063), and re-admissions (P = 0.238). The MVA revealed high ASA class (hazard ratio [HR] 2.7, P = 0.044) and sarcomatoid (HR 5.3, P = 0.001), but not surgery type (P = 0.601) to be associated with all-cause mortality. Increasing R.E.N.A.L. score (HR 1.31, P = 0.037), high tumour grade (HR 2.5, P = 0.043), and sarcomatoid (HR 2.8, P = 0.02) were associated with recurrence, but not surgery (P = 0.555). Increasing age (HR 1.1, P < 0.001) and RN (HR 3.9, P < 0.001) were predictors of de novo eGFR of <45 mL/min/1.73 m2 . Comparing RAPN and MIS-RN, KMSA revealed no significant differences for 5-year OS (76.3% vs 88.0%, P = 0.221) and 5-year DFS (78.6% vs 85.3%, P = 0.630) for pT2 RCC, and no differences for 3-year OS (P = 0.351) and 3-year DFS (P = 0.117) for pT3a upstaged RCC. The 5-year freedom from de novo eGFR of <45 mL/min/1.73 m2 was 91.6% for RAPN vs 68.9% for MIS-RN (P < 0.001). CONCLUSIONS: RAPN had similar oncological outcomes and morbidity profile as MIS-RN, while conferring functional benefit. RAPN may be considered as a first-line option for cT2aRM.

Cystectomy and Urinary Diversion for the Management of a Devastated Lower Urinary Tract Following Prostatic Cryotherapy and/or Radiotherapy.

INTRODUCTION: We investigated the outcomes and quality of life measures in men who underwent cystectomy and urinary diversion for devastating lower urinary tract toxicity after prostatic radiotherapy and/or cryotherapy for the treatment of prostate cancer. METHODS: Records of patients who underwent cystectomy and urinary diversion for the management of a devastated lower urinary tract following prostatic radiotherapy or cryotherapy were reviewed retrospectively. A postoperative, retrospective quality of life (QOL) survey was designed specific to this patient subset and obtained by telephone interview. RESULTS: Extirpative surgery with urinary diversion for management of a devastated lower urinary tract was performed on 15 patients with a mean age of 72 years (range 63-82). Toxicities leading to bladder removal included bladder neck contractures, prostatic necrosis, incontinence, osteomyelitis, bladder calculi, fistulae, urethral strictures, abscesses, necrotizing fasciitis, and radiation/hemorrhagic cystitis. The mean number of failed conservative, minimally invasive interventions per patients prior to cystectomy was 3.7 (range 1-12). The average time period from major complication following radiotherapy/cryotherapy to cystectomy was 29.1 months (range 5-65). The QOL survey showed all of the patients who completed the survey (n = 13) would undergo the procedure again and 11 (85%) would have undergone the procedure an average of 13.2 months sooner (range 5-36). CONCLUSION: Toxicities secondary to prostatic radiotherapy or cryotherapy may be debilitating. Our results demonstrate that cystectomy with urinary diversion can improve QOL in patients with a devastated lower urinary tract.

Is chest imaging needed as part of pT1a renal cell carcinoma surveillance after surgical resection?

INTRODUCTION: Following surgical excision of pT1a renal cell carcinoma (RCC), 2% to 5% will recur, with 50% to 60% being lung metastases. The ideal surveillance strategy to identify recurrences is unclear. Guidelines are mixed, with NCCN and AUA recommending surveillance via chest x-ray (CXR) at least annually for 5 years, while EAU guidelines do not specifically recommend the use of CXR. In an effort to clarify the utility of surveillance CXR, we retrospectively evaluated pT1a patients following surgical treatment at a single institution. METHODS: We performed retrospective analysis of unique patients who underwent surgical excision of pT1 RCC between January 2000 and January 2020. In addition to demographic information, we collected RCC pathology, recurrence details, and most recent chest imaging. We excluded non-RCC pathology, and patients with pulmonary nodules on baseline imaging. RESULTS: We identified 463 unique patients (mean age 58.3 years, range 23-87) that underwent surgical excision of pT1a RCC with mean follow-up of 47.6 months (range 1-201). On the most recent pulmonary surveillance imaging, 72.4% (335/463) had CXR while 27.6% (128/463) had chest CT performed. Regardless of modality, pulmonary recurrence was not detected on any surveillance imaging (0/463). CONCLUSION: In patients without baseline preoperative lung pathology, we found that there is questionable clinical value in surveillance for pulmonary recurrence after resection of pT1a RCC.

Stat5 induces androgen receptor (AR) gene transcription in prostate cancer and offers a druggable pathway to target AR signaling.

Androgen receptor (AR) drives prostate cancer (PC) growth and progression, and targeting AR signaling is the mainstay of pharmacological therapies for PC. Resistance develops relatively fast as a result of refueled AR activity. A major gap in the field is the lack of understanding of targetable mechanisms that induce persistent AR expression in castrate-resistant PC (CRPC). This study uncovers an unexpected function of active Stat5 signaling, a known promoter of PC growth and clinical progression, as a potent inducer of AR gene transcription. Stat5 suppression inhibited AR gene transcription in preclinical PC models and reduced the levels of wild-type, mutated, and truncated AR proteins. Pharmacological Stat5 inhibition by a specific small-molecule Stat5 inhibitor down-regulated Stat5-inducible genes as well as AR and AR-regulated genes and suppressed PC growth. This work introduces the concept of Stat5 as an inducer of AR gene transcription in PC. Pharmacological Stat5 inhibitors may represent a new strategy for suppressing AR and CRPC growth.

Impact of Acetazolamide on Perioperative Pain Control in Robotic Assisted Laparoscopic Prostatectomy.

OBJECTIVE: To evaluate the efficacy of peri-operative acetazolamide for pain control in robotic assisted laparoscopic prostatectomy (RALP). Prior studies have demonstrated that preoperative acetazolamide decreased postoperative referred pain in the postsurgical period for laparoscopic procedures. The proposed mechanism is acetazolamide mediated inhibition of carbonic anhydrase, thereby preventing formation of carbonic acid and subsequent peritoneal acidosis with referred pain. This has yet to be demonstrated in the setting of RALP. METHODS AND MATERIALS: Patients undergoing RALP were randomized to receive either preoperative saline or acetazolamide prior to the procedure. Overall pain scores were recorded at multiple time points post operatively, as well as total morphine equivalents administered for adjunctive pain control. RESULTS: Thirty-one patients were included in the study: 16 patients (51.6%) received perioperative acetazolamide, and 15 patients (48.4%) received perioperative saline as placebo. Overall pain scores were similar for patients receiving acetazolamide compared to placebo at various time points: first responsive (3.5 ± 3.1 vs 4.1 ± 1.7, P = .28), immediately prior to leaving PACU (2.8 ± 2.9 vs 2.9 ± 2.9, P = .48), at 4 hours post-procedure (3.1 ± 3.0 vs 2.9 ± 1.8, P = .362), or at 24 hours post-procedure (2.3 ± 1.7 vs 2.2 ± 1.6, P = .5). Shoulder tip pain was not present in either cohort. No statistically significant difference was observed for total morphine equivalents delivered between acetazolamide and placebo (17.3 vs 20.5, P= .2, respectively). CONCLUSION: Acetazolamide does not appear to impact overall pain or shoulder tip pain in the observed cohort of patients undergoing RALP.

T2-Weighted MRI Radiomic Features Predict Prostate Cancer Presence and Eventual Biochemical Recurrence.

Prostate cancer (PCa) is the most diagnosed non-cutaneous cancer in men. Despite therapies such as radical prostatectomy, which is considered curative, distant metastases may form, resulting in biochemical recurrence (BCR). This study used radiomic features calculated from multi-parametric magnetic resonance imaging (MP-MRI) to evaluate their ability to predict BCR and PCa presence. Data from a total of 279 patients, of which 46 experienced BCR, undergoing MP-MRI prior to surgery were assessed for this study. After surgery, the prostate was sectioned using patient-specific 3D-printed slicing jigs modeled using the T2-weighted imaging (T2WI). Sectioned tissue was stained, digitized, and annotated by a GU-fellowship trained pathologist for cancer presence. Digitized slides and annotations were co-registered to the T2WI and radiomic features were calculated across the whole prostate and cancerous lesions. A tree regression model was fitted to assess the ability of radiomic features to predict BCR, and a tree classification model was fitted with the same radiomic features to classify regions of cancer. We found that 10 radiomic features predicted eventual BCR with an AUC of 0.97 and classified cancer at an accuracy of 89.9%. This study showcases the application of a radiomic feature-based tool to screen for the presence of prostate cancer and assess patient prognosis, as determined by biochemical recurrence.

Systematic review of the impact of a plant-based diet on prostate cancer incidence and outcomes.

BACKGROUND: Plant-based diets are increasingly popular and have many well-established benefits for health and environmental sustainability. Our objective was to perform a systematic review of plant-based diets and prostate cancer. METHODS: We performed a systematic database and citation search in February 2022. Studies were included if they reported primary data on plant-based dietary patterns (i.e., vegan, vegetarian, plant-based) and incidence among at-risk men for prostate cancer, or oncologic, general health/nutrition, or quality of life outcomes among patients with prostate cancer or caregivers. RESULTS: A total of 32 publications were eligible for the qualitative synthesis, representing 5 interventional and 11 observational studies. Interventional studies primarily focused on lifestyle modification including plant-based diets for men on active surveillance for localized prostate cancer or with biochemical recurrence after treatment, showing improvements in short-term oncologic outcomes alongside improvements in general health and nutrition. Observational studies primarily focused on prostate cancer risk, showing either protective or null associations for plant-based dietary patterns. Studies of the vegan diet consistently showed favorable associations with risk and/or outcomes. Gaps in the current literature include impact for long-term disease-specific outcomes. CONCLUSIONS: Interventional studies showed generally favorable results of lifestyle modifications incorporating a plant-based diet with prostate cancer outcomes as well as improvements in nutrition and general health. Observational studies demonstrated either a lower risk of prostate cancer or no significant difference. These results are encouraging in light of the many benefits of plant-based diets for overall health, as well as environmental sustainability and animal welfare.

Diffusion Restriction Comparison between Gleason 4 Fused Glands and Cribriform Glands within Patient Using Whole-Mount Prostate Pathology as Ground Truth.

The presence and extent of cribriform patterned Gleason 4 (G4) glands are associated with poor prognosis following radical prostatectomy. This study used whole-mount prostate histology and multiparametric magnetic resonance imaging (MP-MRI) to evaluate diffusion differences in G4 gland morphology. Fourty-eight patients underwent MP-MRI prior to prostatectomy, of whom 22 patients had regions of both G4 cribriform glands and G4 fused glands (G4CG and G4FG, respectively). After surgery, the prostate was sliced using custom, patient-specific 3D-printed slicing jigs modeled according to the T2-weighted MR image, processed, and embedded in paraffin. Whole-mount hematoxylin and eosin-stained slides were annotated by our urologic pathologist and digitally contoured to differentiate the lumen, epithelium, and stroma. Digitized slides were co-registered to the T2-weighted MRI scan. Linear mixed models were fitted to the MP-MRI data to consider the different hierarchical structures at the patient and slide level. We found that Gleason 4 cribriform glands were more diffusion-restricted than fused glands.

On-Clamp vs. Off-Clamp Robot-Assisted Partial Nephrectomy for cT2 Renal Tumors: Retrospective Propensity-Score-Matched Multicenter Outcome Analysis.

We compared perioperative outcomes after on-clamp versus off-clamp robot-assisted partial nephrectomy (RAPN) for >7 cm renal masses. A multicenter dataset was queried for patients who had undergone RAPN for a cT2cN0cM0 kidney tumor from July 2007 to February 2022. The Trifecta achievement (negative surgical margins, no severe complications, and ≤ 30% postoperative estimated glomerular filtration rate (eGFR) reduction) was considered a surrogate of surgical quality. Overall, 316 cases were included in the analysis, and 58% achieved the Trifecta. A propensity-score-matched analysis generated two cohorts of 89 patients homogeneous for age, ASA score, preoperative eGFR, and RENAL score (all p > 0.21). Compared to the on-clamp approach, OT was significantly shorter in the off-clamp group (80 vs. 190 min; p < 0.001), the incidence of sRFD was lower (22% vs. 40%; p = 0.01), and the Trifecta rate higher (66% vs. 46%; p = 0.01). In a crude analysis, >20 min of hilar clamping was associated with a significantly higher risk of sRFD (OR: 2.30; 95%CI: 1.13−4.64; p = 0.02) and with reduced probabilities of achieving the Trifecta (OR: 0.46; 95%CI: 0.27−0.79; p = 0.004). Purely off-clamp RAPN seems to be a safe and viable option to treat cT2 renal masses and may outperform the on-clamp approach regarding perioperative surgical outcomes.

Pain management following robotic-assisted radical prostatectomy: transitioning to an opioid free regimen.

Few studies demonstrate the safety and efficacy of postoperative pain regimens that exclude opioids altogether in patients undergoing robot-assisted radical prostatectomy (RARP). To reduce opioid use, we sought to develop an opioid-free regimen for RARP and determine perioperative outcomes before and after implementation. A retrospective, pre-post-interventional study was performed at a single institution between 8/2018 and 10/2019. An opioid-free pain regimen was developed and instituted on 3/7/2019, and all patients received preoperative counseling regarding pain expectations and management. Postoperative pain score was the primary outcome. Secondary outcomes included postoperative opioid use, length of stay, adverse events and unplanned health encounters within 30 days of discharge. Pearson's chi-squared and Student's t-tests were performed on categorical and continuous variables, respectively. Multivariable analysis was performed to determine risk factors for postoperative opioid use in the opioid-free cohort. A total of 89 patients were included for analysis; consisting of 47 (53%) pre-intervention and 42 (47%) post-intervention patients. Baseline characteristics were similar between groups. A significantly lower proportion of patients in the post-intervention group were administered opioids postoperatively (5% vs 53%, p < 0.01), despite having similar postoperative pain scores (2.69 vs 3.11, p = 0.19) and length of stay (1.0 days vs 1.2 days, p = 0.07). The post-intervention group had a significantly lower rate of opioid discharge prescriptions (14% vs 96%, p < 0.01). The rate of ED visits (12% vs 15%, p = 0.68), pain-related phone calls (17% vs 19%, p = 0.76) or adverse events (19% vs 13%, p = 0.42) were similar between groups. Among the opioid-free group, older patients were less likely to be administered postoperative opioids (OR 0.84, p = 0.046). A structured opioid-free pain regimen following RARP is non-inferior compared to traditional opioid-based standard of care. Adoption of similar regimens can help address the ongoing opioid epidemic in the United States and future work is needed to apply these principles broadly.

Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?

Androgen deprivation therapy (ADT) for metastatic and high-risk prostate cancer (PC) inhibits growth pathways driven by the androgen receptor (AR). Over time, ADT leads to the emergence of lethal castrate-resistant PC (CRPC), which is consistently caused by an acquired ability of tumors to re-activate AR. This has led to the development of second-generation anti-androgens that more effectively antagonize AR, such as enzalutamide (ENZ). However, the resistance of CRPC to ENZ develops rapidly. Studies utilizing preclinical models of PC have established that inhibition of the Jak2-Stat5 signaling leads to extensive PC cell apoptosis and decreased tumor growth. In large clinical cohorts, Jak2-Stat5 activity predicts PC progression and recurrence. Recently, Jak2-Stat5 signaling was demonstrated to induce ENZ-resistant PC growth in preclinical PC models, further emphasizing the importance of Jak2-Stat5 for therapeutic targeting for advanced PC. The discovery of the Jak2V617F somatic mutation in myeloproliferative disorders triggered the rapid development of Jak1/2-specific inhibitors for a variety of myeloproliferative and auto-immune disorders as well as hematological malignancies. Here, we review Jak2 inhibitors targeting the mutated Jak2V617F vs. wild type (WT)-Jak2 that are currently in the development pipeline. Among these 35 compounds with documented Jak2 inhibitory activity, those with potency against WT-Jak2 hold strong potential for advanced PC therapy.

Outcome prediction following radical nephroureterectomy for upper tract urothelial carcinoma.

OBJECTIVE: To predict overall survival, cancer, and metastasis specific survival in upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy (RNU). MATERIALS AND METHODS: All nonmetastatic UTUC patients who underwent RNU with a curative intent at 1 institution between December 1998 and January 2017 were included.  Detailed data were collected. End points for this study included OS, CCS, and MFS. Univariate and multivariate analysis were conducted. Log Rank tests and Kaplan-Meier curves were generated. Backward elimination and boot strapping was used to identify the most parsimonious model with the smallest number of variables in order to predict the outcomes of interest. A separate second institution data base was used for external validation. RESULTS: There were 218 patients in the development cohort. Mean follow-up was 42 months (±39.6). There was 99 (45.4%) deaths, 28 (12.8%) cancer related deaths, 72 (33%) recurrences, and 54 (24.8%) metastases. The c-index for our model was 0.71 for OS, 0.72 for MFS and 0.74 for CSS. The nomograms did not show significant deviation from actual observations using our calibration plots. We divided the patient into 3 different groups (low, intermediate and high risk) based on their final total score for each outcome and compared them. On external validation our accuracy was 78.4%, 71.4%, and 75.3% for OS, CSS, and MFS survival respectively. CONCLUSION: We designed a predictive model for survival outcomes following RNU in UTUC. This model uses simple, readily available data for patients without the need for expensive or additional testing.

Factors Influencing Patient Selection of Urologists.

OBJECTIVE: To describe the factors affecting patients' selection of a urologist, and the utilization of the Internet and social media. MATERIALS AND METHODS: All new patients presenting to a single-institution for evaluation were invited to complete an anonymous 26-item questionnaire between April 2018 and October 2018, including demographic information, use of Internet and social media resources, and relative importance of factors when selecting a urologist. Descriptive statistics were reported, and a stratified analysis was performed for age, gender, and education. RESULTS: A total of 238 patients responded. More than half (53%) of patients searched their medical condition prior to presentation. When stratified by age, younger patients were 3 times as likely to utilize Internet resources (Group 1 vs Group 2; OR 3.3, 95%CI 1.5-7.2, P <.01). Few patients utilized Facebook (7%) or Twitter (1%). The 3 most important surveyed urologist selection factors included hospital reputation (4.3 ± 1.0), in-network providers (4.0 ± 1.3), and appointment availability (3.9 ± 1.0). The 3 least important included medical school attended (2.7 ± 1.3), urologist on social media (1.9 ± 1.2), and TV, radio, and/or billboard advertisements (1.7 ± 1.3). CONCLUSION: This study suggests a significant proportion of patients search the Internet regarding their medical condition prior to presenting to clinic. Further, younger patients utilize this methodology significantly more than the senior population. Important factors when selecting a urologist may be driven by a hospital's reputation, in addition to scheduling convenience.

Enzalutamide-Induced Feed-Forward Signaling Loop Promotes Therapy-Resistant Prostate Cancer Growth Providing an Exploitable Molecular Target for Jak2 Inhibitors.

The second-generation antiandrogen, enzalutamide, is approved for castrate-resistant prostate cancer (CRPC) and targets androgen receptor (AR) activity in CRPC. Despite initial clinical activity, acquired resistance to enzalutamide arises rapidly and most patients develop terminal disease. Previous work has established Stat5 as a potent inducer of prostate cancer growth. Here, we investigated the significance of Jak2-Stat5 signaling in resistance of prostate cancer to enzalutamide. The levels of Jak2 and Stat5 mRNA, proteins and activation were evaluated in prostate cancer cells, xenograft tumors, and clinical prostate cancers before and after enzalutamide therapy. Jak2 and Stat5 were suppressed by genetic knockdown using lentiviral shRNA or pharmacologic inhibitors. Responsiveness of primary and enzalutamide-resistant prostate cancer to pharmacologic inhibitors of Jak2-Stat5 signaling was assessed in vivo in mice bearing prostate cancer xenograft tumors. Patient-derived prostate cancers were tested for responsiveness to Stat5 blockade as second-line treatment after enzalutamide ex vivo in tumor explant cultures. Enzalutamide-liganded AR induces sustained Jak2-Stat5 phosphorylation in prostate cancer leading to the formation of a positive feed-forward loop, where activated Stat5, in turn, induces Jak2 mRNA and protein levels contributing to further Jak2 activation. Mechanistically, enzalutamide-liganded AR induced Jak2 phosphorylation through a process involving Jak2-specific phosphatases. Stat5 promoted prostate cancer growth during enzalutamide treatment. Jak2-Stat5 inhibition induced death of prostate cancer cells and patient-derived prostate cancers surviving enzalutamide treatment and blocked enzalutamide-resistant tumor growth in mice. This work introduces a novel concept of a pivotal role of hyperactivated Jak2-Stat5 signaling in enzalutamide-resistant prostate cancer, which is readily targetable by Jak2 inhibitors in clinical development.

Accurate segmentation of prostate cancer histomorphometric features using a weakly supervised convolutional neural network.

Purpose: Prostate cancer primarily arises from the glandular epithelium. Histomophometric techniques have been used to assess the glandular epithelium in automated detection and classification pipelines; however, they are often rigid in their implementation, and their performance suffers on large datasets where variation in staining, imaging, and preparation is difficult to control. The purpose of this study is to quantify performance of a pixelwise segmentation algorithm that was trained using different combinations of weak and strong stroma, epithelium, and lumen labels in a prostate histology dataset. Approach: We have combined weakly labeled datasets generated using simple morphometric techniques and high-quality labeled datasets from human observers in prostate biopsy cores to train a convolutional neural network for use in whole mount prostate labeling pipelines. With trained networks, we characterize pixelwise segmentation of stromal, epithelium, and lumen (SEL) regions on both biopsy core and whole-mount H&E-stained tissue. Results: We provide evidence that by simply training a deep learning algorithm on weakly labeled data generated from rigid morphometric methods, we can improve the robustness of classification over the morphometric methods used to train the classifier. Conclusions: We show that not only does our approach of combining weak and strong labels for training the CNN improve qualitative SEL labeling within tissue but also the deep learning generated labels are superior for cancer classification in a higher-order algorithm over the morphometrically derived labels it was trained on.

Radio-pathomic mapping model generated using annotations from five pathologists reliably distinguishes high-grade prostate cancer.

Purpose: Our study predictively maps epithelium density in magnetic resonance imaging (MRI) space while varying the ground truth labels provided by five pathologists to quantify the downstream effects of interobserver variability. Approach: Clinical imaging and postsurgical tissue from 48 recruited prospective patients were used in our study. Tissue was sliced to match the MRI orientation and whole-mount slides were stained and digitized. Data from 28 patients ( n = 33 slides) were sent to five pathologists to be annotated. Slides from the remaining 20 patients ( n = 123 slides) were annotated by one of the five pathologists. Interpathologist variability was measured using Krippendorff's alpha. Pathologist-specific radiopathomic mapping models were trained using a partial least-squares regression using MRI values to predict epithelium density, a known marker for disease severity. An analysis of variance characterized intermodel means difference in epithelium density. A consensus model was created and evaluated using a receiver operator characteristic classifying high grade versus low grade and benign, and was statistically compared to apparent diffusion coefficient (ADC). Results: Interobserver variability ranged from low to acceptable agreement (0.31 to 0.69). There was a statistically significant difference in mean predicted epithelium density values ( p < 0.001 ) between the five models. The consensus model outperformed ADC (areas under the curve = 0.80 and 0.71, respectively, p < 0.05 ). Conclusion: We demonstrate that radiopathomic maps of epithelium density are sensitive to the pathologist annotating the dataset; however, it is unclear if these differences are clinically significant. The consensus model produced the best maps, matched the performance of the best individual model, and outperformed ADC.