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Background: Alterations in the PIK3/Akt/mTOR pathway are commonly seen in metastatic castration-sensitive prostate cancer (mCSPC), however their role in outcomes is unknown. We aim to evaluate the prognostic significance as well as the genetic landscape of PIK3/Akt/mTOR pathway alteration in mCSPC., Methods: Fourhundred and seventy-two patients with mCSPC were included who underwent next generation sequencing. PIK3/Akt/mTor pathway alterations were defined as mutations in Akt1, mTOR, PIK3CA, PIK3CB, PIK3R1, PTEN, TSC1, and TSC2. Endpoints of interests were radiographic progression-free survival (rPFS), time to development of castration resistant prostate cancer (tdCRPC), and overall survival (OS). Kaplan-Meier analysis was performed and Cox regression hazard ratios (HR) were calculated., Results: One hundred and fifty-two (31.9%) patients harbored a PIK3/Akt/mTOR pathway alteration. Median rPFS and tdCRPC were 23.7 and 21.0 months in PIK3/Akt/mTOR altered compared to 32.8 (p = 0.08) and 32.1 months (p = 0.002) in wildtype tumors. On multivariable analysis PIK3/Akt/mTOR pathway alterations were associated with tdCRPC (HR 1.43, 95% CI, 1.05-1.94, p = 0.02), but not rPFS [Hazard ratio (HR) 1.20, 95% confidence interval (CI), 0.90-1.60, p = 0.21]. PIK3/Akt/mTOR pathway alterations were more likely to be associated with concurrent mutations in TP53 (40% vs. 28%, p = 0.01) and TMPRSS2-ERG (37% vs. 26%, p = 0.02) than tumors without PIK3/Akt/mTOR pathway alterations. Concurrent mutations were typically associated with shorter median times to rPFS and tdCRPC. DAVID analysis showed p53 signaling and angiogenesis pathways were enriched in PIK3/Akt/mTOR pathway altered tumors while beta-catenin binding and altered BRCA pathway were enriched in PIK3/Akt/mTOR pathway wildtype tumors., Conclusions: PIK3/Akt/mTOR pathway alterations were common in mCSPC and associated with poorer prognosis. The genetic landscape of PIK3/Akt/mTOR pathway altered tumors differed from wildtype tumors. Additional studies are needed to better understand and target the PIK3/Akt/mTOR pathway in mCSPC., (© 2024 The Author(s). The Prostate published by Wiley Periodicals LLC.)

Introduction & Objective: The role of the microbiome in the development and treatment of genitourinary malignancies is just starting to be appreciated. Accumulating evidence suggests that the microbiome can modulate immunotherapy through signaling in the highly dynamic tumor microenvironment. Nevertheless, much is still unknown about the immuno-oncology-microbiome axis, especially in urologic oncology. The objective of this review is to synthesize our current understanding of the microbiome's role in modulating and predicting immunotherapy response to genitourinary malignancies., Methods: A literature search for peer-reviewed publications about the microbiome and immunotherapy response in bladder, kidney, and prostate cancer was conducted. All research available in PubMed, Google Scholar, clinicaltrials.gov, and bioRxiv up to September 2023 was analyzed., Results: Significant differences in urinary microbiota composition have been found in patients with genitourinary cancers compared to healthy controls. Lactic acid-producing bacteria, such as Bifidobacterium and Lactobacillus genera, may have value in augmenting BCG responsiveness to bladder cancer. BCG may also be a dynamic regulator of PD-L1. Thus, the combination of BCG and immune checkpoint inhibitors may be an effective strategy for bladder cancer management. In advanced renal cell carcinoma, studies show that recent antibiotic administration negatively impacts survival outcomes in patients undergoing immunotherapy, while administration of CBM588, a live bacterial product, is associated with improved progression-free survival. Specific bacterial taxa, such as Streptococcus salivarius , have been linked with response to pembrolizumab in metastatic castrate-resistant prostate cancer. Fecal microbiota transplant has been shown to overcome resistance and reduce toxicity to immunotherapy; it is currently being investigated for both kidney and prostate cancers., Conclusions: Although the exact mechanism is unclear, several studies identify a symbiotic relationship between microbiota-centered interventions and immunotherapy efficacy. It is possible to improve immunotherapy responsiveness in genitourinary malignancies using the microbiome, but further research with more standardized methodology is warranted., Competing Interests: Conflict of Interests The authors declare that they have no conflicts of interest.

Background & Objectives: No definite treatment is known for COVID-19 till date. The objective of this study is to assess the efficacy of customized Homoeopathic medicines, when used as an add-on treatment to Standard of Care (SOC), in patients suffering from moderate to severe COVID-19 infection., Methods: This was a randomized, controlled, single-blind, parallel-group trial where 214 COVID19-positive patients were screened for moderate and severe cases of COVID-19. Adjuvant homoeopathic medicines were given in the treatment group and SOC was given to both groups. The duration of oxygen support was compared as the primary outcome. Subjects were followed for 28 days or till the end-point of mechanical ventilation/ death., Results: Of 129 subjects included, 57 and 55 were severe; and 8 and 9 were moderate cases in Homoeopathy and SOC arms, respectively. In all, 9 (15.2%) participants in Homoeopathy and 20 (32.2%) participants in SOC arms eventually expired (p<0.05). Oxygen support was required for 9.84±7.00 and 14.92±7.549 days in Homoeopathy and SOC arms, respectively (p<0.005). Subjects receiving Homoeopathy (12.9±6.days) had a shorter hospitalization stay than in SOC (14.9±7.5 days). Homoeopathy arm (10.6±5.7 days) also showed statistically significant mean conversion time of of Realtime-Polymerase Chain Reaction (RT-PCR) from positive to negative than the SOC arm (12.9±5.6 days). The mean score of Clinical Outcome Ordinal Scale (COOS) was lower in the Homoeopathy arm. Laboratory markers [Interleukins (IL)-6, C-reactive protein (CRP), Neutrophils-Lymphocytes ratio (NLR)]were normalized earlier in Homoeopathy arm., Conclusion: Homoeopathy, as add-on therapy with SOC for COVID-19 management, demonstrates a reduction in mortality and morbidity, by reduced requirement of oxygen and hospitalization. Some laboratory markers are normalized at an earlier time. Hence, there is overall control over the disease. Registry: The study was registered on the http://ctri.nic.in/Clinicaltrials website under identifier number: CTRI/2020/12/029668 on 9th December 2020., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kaur et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Diagnostic ureteroscopic biopsy for upper tract urothelial carcinoma (UTUC) has been hypothesized to increase intravesical recurrence of urothelial carcinoma after radical nephroureterectomy (RNU). Moreover, the impact of ureteroscopy without biopsy or percutaneous biopsy on intravesical recurrence remains unknown. Herein, we compared post-RNU intravesical recurrences across UTUC diagnostic modalities., Materials and Methods: Patients undergoing RNU at our institution between 1995 and 2019 were categorized by UTUC diagnostic modality: 1) no ureteroscopy or percutaneous biopsy; 2) percutaneous biopsy; 3) ureteroscopy without biopsy; 4) ureteroscopic biopsy. Intravesical recurrences were compared using Kaplan-Meier analyses and Cox-proportional hazard models. Results of group 4 vs 1 were pooled with the literature using a fixed effects meta-analysis., Results: In a cohort of 834 RNU patients, 210 (25.2%) had undergone no ureteroscopy, 57 (6.6%) percutaneous biopsy, 125 (15.0%) ureteroscopy without biopsy, and 442 (53.0%) ureteroscopic biopsy. Two-year intravesical recurrence rates were 15.0%, 12.7%, 18.4%, and 21.9% for groups 1 through 4, respectively (p=0.09). Multivariable analysis found that group 4 had increased intravesical recurrences (HR 1.40, p=0.04) relative to group 1 while group 2 (HR 1.07, p=0.87) and group 3 (HR 1.15, p=0.54) did not. Group 4 remained associated with intravesical recurrence on subset analyses accounting for post-RNU surveillance cystoscopy frequency. On meta-analysis including 11 other series, ureteroscopic biopsy was associated with intravesical recurrence (HR 1.47, p <0.01)., Conclusions: Ureteroscopic biopsy before RNU, but not percutaneous biopsy or ureteroscopy without biopsy, was associated with increased intravesical recurrence. Clinical trials of intravesical chemotherapy after ureteroscopic biopsy are warranted to reduce intravesical recurrences.

Background: Clinical and pathological factors alone have limited prognostic ability in patients with metastatic clear cell renal cell carcinoma (ccRCC). Bim, a downstream pro-apoptotic molecule in the PD-1 signaling pathway, has recently been associated with survival in other malignancies. We sought to determine if tissue biomarkers including Bim, added to a previously reported clinical metastases score, improved prediction of cancer-specific survival (CSS) for patients with metastatic ccRCC., Methods: Patients with metastatic ccRCC who underwent nephrectomy between 1990 and 2004 were identified using our institutional registry. Sections from paraffin-embedded primary tumor tissue blocks were used for immunohistochemistry staining for Bim, PD-1, B7-H1 (PD-L1), B7-H3, CA-IX, IMP3, Ki67, and survivin. Biomarkers that were significantly associated with CSS after adjusting for the metastases score were used to develop a biomarker-specific multivariable model using a bootstrap resampling approach and forward selection. Predictive ability was summarized using a bootstrap-corrected c-index., Results: The cohort included 602 patients: 192 (32%) with metastases at diagnosis and 410 (68%) who developed metastases after nephrectomy. Median follow-up was 9.6 years (IQR 4.2-12.8), during which 504 patients died of RCC. Bim, IMP3, Ki67, and survivin expression were significantly associated with CSS after adjusting for the metastases score, and were eligible for biomarker-specific model inclusion. After variable selection, high Bim (hazard ratio [HR] = 1.44; 95% confidence interval [CI] 1.16-1.78; P <0.001), high survivin (HR = 1.35; 95% CI 1.08-1.68; P = 0.008), and the metastases score (HR = 1.13 per 1 point; 95% CI 1.10-1.16; P <0.001) were retained in the final multivariable model (c-index = 0.69)., Conclusion: We created a prognostic model combining the clinical metastases score and 2 primary tumor tissue expression biomarkers, Bim and survivin, for patients with metastatic renal cell carcinoma who underwent nephrectomy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To better understand the safety and diagnostic yield of percutaneous core-needle biopsy (PCNB) for upper tract urothelial carcinoma (UTUC)., Methods: Of 444 patients undergoing radical nephroureterectomy (RNU) for UTUC between 2009 and 2017 at our institution, 42 who had PCNB prior to RNU were identified for analysis. Endpoints included safety, diagnostic yield, and concordance with RNU pathology. PCNB specimens were deemed histologically concordant with RNU specimens for cases when cytologic evaluation of biopsy specimen and corresponding pathologic evaluation of RNU specimen both made a histologic diagnosis of urothelial carcinoma., Results: Median tumor size was 3.8 cm (1.2-10.2 cm). All lesions arose from the pelvicalyceal system. CT-guidance was utilized in 52% (n = 22), and ultrasound-guidance in 48% (n = 20). Relative to RNU pathology, 95% of PCNBs demonstrated histologic concordance. Histologic grade was provided in 69% (n = 29) of PCNBs, with a 90% (n = 26) concordance with surgical pathology. Grades 1-2 and 3 complications occurred in 14.3% (n = 6) and 2.4% (n = 1), respectively. At a median follow-up of 28.2 months (range, 1.2-97.1 months) after biopsy, no cases of radiographic tract seeding were identified., Conclusion: In our cohort of 42 patients undergoing RNU for UTUC, PCNB appeared a safe diagnostic tool with high histologic yield and grade concordance. With greater than 2 years of follow-up, no cases of tract seeding were identified., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The performance of prostate health index (phi) in predicting prostate biopsy outcomes has been well established for patients with prostate-specific antigen (PSA) values between 2 and 10 ng/mL. However, the performance of phi remains unknown in patients with PSA >10 ng/mL, the vast majority in Chinese biopsy patients. We aimed to assess the ability of phi to predict prostate cancer (PCa) and high-grade disease (Gleason Score ≥7) on biopsy in a Chinese population., Methods: This is a prospective, observational, multi-center study of consecutive patients who underwent a transrectal ultrasound guided prostate biopsy at four hospitals in Shanghai, China from August 2013 to December 2014., Results: In the cohort of 1538 patients, the detection rate of PCa was 40.2%. phi had a significantly better predictive performance for PCa than total PSA (tPSA). The areas under the receiver operating characteristic curve (AUC) were 0.90 and 0.79 for phi and tPSA, respectively, P < 0.0001. A considerable proportion of patients in the cohort had PSAs >10 ng/mL (N = 838, 54.5%). The detection rates of PCa were 35.9% and 57.7% in patients with tPSA 10.1-20 and 20.1-50 ng/mL, respectively. The AUCs of phi (0.79 and 0.89, for these two groups, respectively) were also significantly higher than tPSA (0.57 and 0.63, respectively), both P < 0.0001. If a phi ≤35 was used as the cutoff, 599/1538 (39%) biopsies could have been avoided at a cost of missing small numbers of PCa patients: 49 (7.93%) PCa patients, including 18 (3.69%) high-grade tumors., Conclusions: Results from this study suggest that phi can be used to predict PCa and high-grade disease in Chinese men with high PSA levels (>10 ng/mL)., (© 2017 Wiley Periodicals, Inc.)

Purpose: To determine patient and pathologic characteristics as well as outcomes for patients with clinically localized, nonurothelial histology bladder cancer., Materials and Methods: Using the National Cancer Data Base, we identified patients between 2000 and 2010 diagnosed with bladder cancer as their only malignancy undergoing definitive surgical management. Patients were characterized as urothelial (n = 13,442), squamous (n = 789), small cell (n = 124), adenocarcinoma (n = 789), or other histology (n = 499). Patient and pathologic characteristics were compared across histologic subtypes. We also evaluated for incidence of T and N upstaging. Survival analysis was performed using the Kaplan-Meier method. Multivariate survival analysis was performed to identify predictors of adverse overall survival., Results: Patients with nonurothelial histology were more likely to be African-American, treated at academic medical centers, and of younger age (all P<0.05). Among those with nonurothelial histology, 55.4% of patients presenting with clinical stage T1 or less had their tumor upstaged during definitive surgical treatment compared to 42.7% of those with urothelial carcinoma. Squamous histology incurred the highest upgrading rate of 61.8%. Five-year survival varied by subtype, with universally decreased survival for those upstaged. Among nonurothelial histology, overall 5-year survival was 32.4% (95% CI: 28.8%-36.2%) vs. 46.0% (95% CI: 42.3%-49.6%) for those upstaged and not upstaged, respectively. Neoadjuvant therapy is used infrequently in this population., Conclusion: We present the largest survival analysis of various rare subtypes of bladder cancer to date. Patients with nonurothelial bladder cancer have significantly higher rate of upstaging at cystectomy and with this a worsened overall survival. Aggressive treatment should be strongly considered for nonurothelial cancers when identified., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To assess the training of medical students and their confidence in urethral catheter placement, given growing evidence of unnecessary urology consults and iatrogenic injury., Subjects and Methods: A third-year medical school class was queried about their attitudes and knowledge of catheter placement before and after the Clinical Biennium. The Clinical Biennium introduces hands-on skills prior to clinical clerkships. Urethral catheterisation is one of the skill stations that students rotate through, and urology residents provide a didactic session and supervised simulation. Confidence was self-rated regarding catheter technique, knowledge, troubleshooting, and comfort with placement in the same and opposite gender. Factual questions were posed about proper insertion and malfunctioning catheters., Results: In all, 92 students participated in the initial survey, 41% female and 59% male, and 87% of the students had never placed a catheter. Students desired high confidence in catheter skills (4.4/5). There were no significant differences in responses for those with a desire to pursue urology vs other specialties, or procedural fields compared with non-procedural fields. Prior independent learning was reported by 38% of students and was a predictor for increased confidence across all domains (P < 0.05). In all, 16.7% of students initially identified proper male urethral insertion distance, which improved to 95.6% after the session. Student interest in urology modestly increased after the educational session (P = 0.028). At 3-6 months follow-up, students had performed a median (interquartile range) of 4 (2-7) urethral catheter placements, and 74.2% of students rated training useful or extremely useful. Indeed, 54.8% desired more instruction. Knowledge assessment indicated that 93% of students retained comprehension of proper male urethral insertion distance. Clinical Foley training rarely contradicted instruction from the Clinical Biennium (6.5%). At all time-points, medical student knowledge for troubleshooting catheters was low., Conclusions: Medical students strive for high confidence in urethral catheter placement. Prior targeted education improves confidence and knowledge. Together with clinical experience, these effects are durable up to 6 months., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

Objectives: This study aimed to compare survival outcomes after hepatic resection (HR) and radiofrequency ablation (RFA) in early-stage hepatocellular carcinoma (HCC) at a Western hepatobiliary centre., Methods: Demographic details, clinicopathologic tumour characteristics and survival outcomes were compared among non-transplant candidate patients undergoing HR (n= 50) and RFA (n= 60) for early-stage HCC during 2001-2011., Results: Patients who underwent HR had larger tumours, a longer length of stay and a higher rate of postoperative complications. After a median follow-up of 29 months, there were no significant differences between the treatment groups in 1-, 3- and 5-year overall survival (OS) [RFA group: 86%, 50%, 35%, respectively; HR group: 88%, 68%, 47%, respectively (P= 0.222)] or disease-free survival (DFS) [RFA group: 68%, 42%, 28%, respectively; HR group: 66%, 42%, 34%, respectively (P= 0.823)]. The 58 patients who underwent RFA demonstrated ablation success on follow-up computed tomography at 3 months. Of these, 96.5% of patients showed sustained ablation success over the entire follow-up period. In a subgroup analysis of patients with tumours measuring 2-5 cm, no differences in OS or DFS emerged between the HR and RFA groups. Similarly, no significant differences in outcomes in patients with Child-Pugh class A cirrhosis were seen between the RFA and HR groups., Conclusions:   Radiofrequency ablation is comparable with HR in terms of OS and DFS. It is a reasonable alternative as a first-line treatment for HCC in well-selected patients who are not candidates for transplant., (© 2012 International Hepato-Pancreato-Biliary Association.)

Background: The purpose of this study was to compare the clinical and economic outcomes of robotic versus laparoscopic left lateral sectionectomy (LLS)., Methods: A retrospective analysis was made comparing robotic (n = 11) and laparoscopic (n = 18) LLS performed at the University of Pittsburgh Medical Center between January 2009 and July 2011. Demographic data, operative, and postoperative outcomes were collected., Results: Demographic and tumor characteristics of robotic and laparoscopic LLS were similar. There were also no significant differences in operative outcomes including estimated blood loss and operating room time. Patients undergoing robotic LLS had more admissions to the ICU (46 versus 6 %), increased rate of minor complications (27 versus 0 %), and longer lengths of stay (4 versus 3 days). There were no significant differences in major complication rates or 90-day mortality. The cost of robotic and laparoscopic LLS was not significantly different when only considering direct costs ($5,130 versus $4,408, p = 0.401). However, robotic LLS costs were significantly greater when including indirect costs, which were estimated to be $1,423 per robotic case ($6,553 versus $4,408, p = 0.021)., Discussion: Robotic LLS yields slightly inferior clinical outcomes and increased cost compared to the laparoscopic approach.

Background: The present study examines the presentation and outcomes of hepatocellular carcinoma (HCC) at a Western centre over the last decade., Methods: Between January 2000 and September 2009, 1010 patients with HCC were evaluated at the University of Pittsburgh Medical Center (UPMC). Retrospectively, four treatment groups were classified: no treatment (NT), systemic therapy (ST), hepatic artery-based therapy (HAT) and surgical intervention (SI) including radiofrequency ablation, hepatic resection and transplantation. Kaplan-Meier analysis assessed survival between groups. Cox regression analysis identified factors predicting survival., Results: Patients evaluated were 75% male, 87% Caucasian, 84% cirrhotic, and predominantly diagnosed with hepatitis C. In all, 169 patients (16.5%) received NT, 25 (2.4%) received ST, 529 (51.6%) received HAT and 302 (29.5%) received SI. Median survival was 3.6, 5.6, 8.8, and 83.5 months with NT, ST, HAT and SI, respectively (P= 0.001). Transplantation increased from 9.5% to 14.2% after the model for end-stage liver disease (MELD) criteria granted HCC patients priority points. Survival was unaffected by bridging transplantation with HAT or SI (P= 0.111). On multivariate analysis, treatment modality was a robust predictor of survival after adjusting for age, gender, AFP, Child-Pugh classification and cirrhosis (P < 0.001, χ(2) = 460)., Discussion:   Most patients were not surgical candidates and received HAT alone. Surgical intervention, especially transplantation, yields the best survival., (© 2011 International Hepato-Pancreato-Biliary Association.)

Laparoscopic liver surgery has evolved significantly over the past decade. Increasing understanding of hepatic anatomy and advancements in technology have extended the scope of the minimally invasive approach. Robotic-assisted technology offers solutions to the fundamental limitations of conventional laparoscopic liver resection. Several centers have begun to utilize robotic technology to perform complex liver surgeries. The purpose of this review is to provide a comprehensive analysis of published literature about the role of robotic-assisted laparoscopic technology in liver surgery. A literature search of Pubmed was used to identify all English publications about robotic liver surgery. Publications were selected to examine all unique patient series. Outcomes analyzed included operative time, estimated blood loss, length of stay, complication rate, conversion rate to open, cost, and oncologic outcomes. A total of eight series containing 134 unique patients were selected for review. Sixty-nine percent of patients had malignant lesions resected, while 31% had benign lesions. Segmentectomy/wedge (36%) was the most common resection performed, followed by left lateral sectionectomy (28%) right hepatectomy (16%) and left hepatectomy (9%). A meta-analysis of the remaining data was not possible due to heterogeneity in methods for reporting. Outcomes varied widely between studies. Based on analysis of early published series, robotic liver surgery is a feasible and safe tool for the minimally invasive resection of hepatic lesions. Further evaluation is required to assess for improvement in outcomes, and long-term oncologic outcomes are still pending.

Freshly isolated hepatic dendritic cells (DC) are comparatively immature, relatively resistant to maturation, and can downmodulate effector T cell responses. Molecular mechanisms that underlie these properties are ill defined. DNAX-activating protein of 12 kDa (DAP12) is an ITAM-bearing transmembrane adaptor protein that integrates signals through several receptors, including triggering receptor expressed on myeloid cells-1, -2, and CD200R. Notably, DC propagated from DAP12-deficient mice exhibit enhanced maturation in response to TLR ligation. Given the constitutive exposure of liver DC to endotoxin draining from the gut, we hypothesized that DAP12 might regulate liver DC maturation. We show that DAP12 is expressed by freshly isolated liver, spleen, kidney, and lung myeloid DC. Moreover, inhibition of DAP12 expression by liver DC using small interfering RNA promotes their phenotypic and functional maturation, resulting in enhanced TNF-α, IL-6, and IL-12p70 production, reduced secretion of IL-10, and enhanced CD4(+) and CD8(+) T cell proliferation. Furthermore, DAP12 silencing correlates with decreased STAT3 phosphorylation in mature liver DC and with diminished expression of the IL-1R-associated kinase-M, a negative regulator of TLR signaling. These findings highlight a regulatory role for DAP12 in hepatic DC maturation, and suggest a mechanism whereby this function may be induced/maintained.