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BackgroundTolvaptan is a vasopressin type 2 receptor antagonist and has been used to treat autosomal dominant polycystic kidney disease (ADPKD) since 2014. There has been limited real-world data on the safety and efficacy of tolvaptan.MethodsThis post-marketing surveillance was conducted to evaluate the long-term safety and the efficacy of tolvaptan in Japanese patients with ADPKD in real-world clinical settings. The baseline characteristics of 1630 patients treated with tolvaptan are reported. Safety analysis comprises evaluation of adverse drug reactions (ADRs). The efficacy evaluation includes percent change in total kidney volume (TKV) and change in estimated glomerular filtration rate (eGFR) before and after tolvaptan treatment.ResultsMean age was 49.7 ± 11.2 years and 843 (51.7%) patients were male. Baseline TKV was 2158 ± 1346 mL and eGFR was 44.4 ± 21.7 mL/min/1.73 m2. The majority of CKD patients were stage G3b (27.0%) and G4 (30.1%). Frequently reported ADRs were hepatic function abnormal (8.3%), thirst (8.2%), and hyperuricaemia (6.9%). The frequency of ALT elevation (> 30 and > 90 IU/L) was slightly high (32.9 and 8.3%) to previous studies. After tolvaptan treatment, the annual rate of percentage change in TKV reduced from 11.68%/year to 2.73%/year (P < 0.0001). Similar results were also obtained for the effect on change in eGFR from − 3.31 to − 2.28 mL/min/1.73 m2/year after initiation of tolvaptan treatment (P = 0.0403).ConclusionThere were no major problems with safety of tolvaptan treatment and comparable efficacy for TKV and eGFR was observed in relation to the previous pivotal two randomized control trials in this post-marketing surveillance.

Machine learning (ML) is a valuable tool in healthcare, enabling the prediction of disease progression through data-driven regression and nonlinear modeling. Unlike traditional statistical methods, ML can identify complex interactions among explanatory variables. Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of chronic kidney disease (CKD), often progressing to end-stage renal failure. Accurately predicting CKD progression in ADPKD patients is essential for personalized treatment strategies. This study analyzed data from 2,737 patients with ADPKD enrolled in the Japanese Nationwide Cohort. Using this dataset, we developed ML models to predict CKD stages. Feature importance analysis was performed to identify key predictive variables. Three ML models—random forest, support vector machine, and naïve Bayes—were evaluated for their predictive accuracy. Random forest exhibited the highest predictive accuracy among the models tested. Feature importance analysis identified estimated glomerular filtration rate (eGFR), serum creatinine, CKD heat map, urinary protein, and total kidney volume as the most significant predictors of CKD stage. As a nonlinear model, random forest effectively captured complex interactions between variables, outperforming the linear support vector machine. The naïve Bayes model, despite assuming independence among variables, surpassed the linear model, indicating limited interdependence among some predictors. ML, particularly random forest, provides a robust approach for predicting CKD stages in patients with ADPKD by accounting for nonlinear variable relationships. These findings emphasize ML’s potential in personalized CKD management and highlight the need for individualized treatment approaches.

Intratumoral androgen biosynthesis has been recognized as an essential factor of castration‐resistant prostate cancer. The present study investigated the effects of curcumin on the inhibition of intracrine androgen synthesis in prostate cancer. Human prostate cancer cell lines, LNCaP and 22Rv1 cells were incubated with or without curcumin after which cell proliferation was measured at 0, 24, 48 and 72 hours, respectively. Prostate tissues from the transgenic adenocarcinoma of the mouse prostate (TRAMP) model were obtained after 1‐month oral administration of 200 mg/kg/d curcumin. Testosterone and dihydrotestosterone concentrations in LNCaP prostate cancer cells were determined through LC‐MS/MS assay. Curcumin inhibited cell proliferation and induced apoptosis of prostate cancer cells in a dose‐dependent manner. Curcumin decreased the expression of steroidogenic acute regulatory proteins, CYP11A1 and HSD3B2 in prostate cancer cell lines, supporting the decrease of testosterone production. After 1‐month oral administration of curcumin, Aldo‐Keto reductase 1C2 (AKR1C2) expression was elevated. Simultaneously, decreased testosterone levels in the prostate tissues were observed in the TRAMP mice. Meanwhile, curcumin treatments considerably increased the expression of AKR1C2 in prostate cancer cell lines, supporting the decrease of dihydrotestosterone. Taken together, these results suggest that curcumin's natural bioactive compounds could have potent anticancer properties due to suppression of androgen production, and this could have therapeutic effects on prostate cancer. The present study demonstrates significant effects of curcumin on the inhibition of intracrine androgen synthesis in prostate cancer.

BackgroundTolvaptan slowed the rates of total kidney volume (TKV) growth and renal function decline over a 3-year period in patients with autosomal dominant polycystic kidney disease (ADPKD) enrolled in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial (NCT00428948). In this post hoc analysis of Japanese patients from TEMPO 3:4, we evaluated whether the effects of tolvaptan on TKV and on renal function are interrelated.MethodsOne hundred and forty-seven Japanese patients from TEMPO 3:4 were included in this analysis (placebo, n = 55; tolvaptan, n = 92). Tolvaptan-treated patients were stratified into the responder group (n = 37), defined as tolvaptan-treated patients with a net decrease in TKV from baseline to year 3, and the non-responder group (n = 55), defined as tolvaptan-treated patients with a net increase in TKV.ResultsMean changes during follow-up in the placebo, responder, and non-responder groups were 16.99%, − 8.33%, and 13.95%, respectively, for TKV and − 12.61, − 8.47, and − 8.58 mL/min/1.73 m2, respectively, for estimated glomerular filtration rate (eGFR). Compared with the placebo group, eGFR decline was significantly slowed in both the responder and non-responder groups (P < 0.05).ConclusionTolvaptan was effective in slowing eGFR decline, regardless of TKV response, over 3 years in patients with ADPKD in Japan. Treatment with tolvaptan may have beneficial effects on slowing of renal function decline even in patients who have not experienced a reduction in the rate of TKV growth by treatment with tolvaptan.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a progressive condition that eventually leads to end-stage renal disease. A phase 3 trial of tolvaptan (TEMPO 3:4; NCT00428948) and its open-label extension (TEMPO Extension Japan: TEMPO-EXTJ; NCT01280721) were conducted in patients with ADPKD. In this post hoc analysis, effects on renal function and the safety profile of tolvaptan were assessed over a long-term period that included the 3-year TEMPO 3:4 and the approximately 3-year TEMPO-EXTJ trials.MethodsPatients from Japanese trial sites who completed TEMPO 3:4 were offered participation in TEMPO-EXTJ. Patients whose efficacy parameters were measured at year 2 in TEMPO-EXTJ for efficacy evaluation were included. The annual slope of the estimated glomerular filtration rate (eGFR) and growth in total kidney volume (TKV) were analyzed.ResultsIn patients who received tolvaptan in TEMPO 3:4 and TEMPO-EXTJ, the annual slope of eGFR (mL/min/1.73 m2) was − 3.480 in TEMPO 3:4 and − 3.417 in TEMPO-EXTJ, with no apparent effect of an approximately 3.6-month off-treatment interval between the two trials. In patients who received a placebo in TEMPO 3:4 before initiating tolvaptan in TEMPO-EXTJ, the slope of eGFR was significantly less steep from TEMPO 3:4 (− 4.287) to TEMPO-EXTJ (− 3.364), a difference of 0.923 (P = 0.0441).ConclusionThe TEMPO-EXTJ trial supports a sustained beneficial effect of tolvaptan on eGFR. In patients who received a placebo in TEMPO 3:4, initiation of tolvaptan in TEMPO-EXTJ was associated with a significant slowing of eGFR decline.

Tolvaptan, an oral vasopressin V2 receptor antagonist, reduces renal volume expansion and loss of renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Data for predictive factors indicating patients more likely to benefit from long-term tolvaptan are lacking. Data were retrospectively collected from 55 patients on tolvaptan for 6 years. Changes in renal function, progression of renal dysfunction (estimated glomerular filtration rate [eGFR], 1-year change in eGFR [ΔeGFR/year]), and renal volume (total kidney volume [TKV], percentage 1-year change in TKV [ΔTKV%/year]) were evaluated at 3-years pre-tolvaptan, at baseline, and at 6 years. In 76.4% of patients, ΔeGFR/year improved at 6 years. The average 6-year ΔeGFR/year (range) minus baseline ΔeGFR/year: 3.024 (−8.77–20.58 mL/min/1.73 m2). The increase in TKV was reduced for the first 3 years. A higher BMI was associated with less of an improvement in ΔeGFR (p = 0.027), and family history was associated with more of an improvement in ΔeGFR (p = 0.044). Hypernatremia was generally mild; 3 patients had moderate-to-severe hyponatremia due to prolonged, excessive water intake in response to water diuresis—a side effect of tolvaptan. Family history of ADPKD and baseline BMI were contributing factors for ΔeGFR/year improvement on tolvaptan. Hyponatremia should be monitored with long-term tolvaptan administration.

IntroductionLong-term outcomes from large cohorts are not yet available upon which to base recommended follow-up protocols after prostate focal therapy. This is an updated summary of a 2015 SIU-ICUD review of the best available current evidence and expert consensus on guidelines for surveillance after prostate focal therapy.MethodsWe performed a systematic search of the PubMed, Cochrane and Embase databases to identify studies where primary prostate focal therapy was performed to treat prostate cancer.ResultsMultiparametric magnetic resonance imaging (mpMRI) should be performed at 3–6 months, 12–24 months and at 5 years after focal therapy. Targeted biopsy of the treated zone should be performed at 3–6 months and fusion biopsy of any suspicious lesion seen on mpMRI. Additionally, a systematic biopsy should be performed at 12–24 months and again at 5 years. In histological diagnosis, characteristic changes of each treatment modality should be noted and in indeterminate situations various immunohistochemical molecular markers can be helpful. Small volume 3 + 3 (Prognostic grade group [PGG] 1) or very small volume (< 0.2 cc or < 7 mm diameter) 3 + 4 (PGG 2) are acceptable in the treated zone at longitudinal follow-up. Significant volumes of 3 + 4 (PGG 2) or more within the treated zone should be treated. Any clinically significant cancer subsequently arising within the non-treated zone should be treated and handled in the same way as any de novo prostate cancer. Patients should be counseled regarding whole-gland and focal approaches to treating these new foci where appropriate. One or two well-delineated foci of significant cancer can be ablated to keep the patient in the ‘active surveillance pool’. More extensive disease should be treated with traditional whole-gland techniques.ConclusionFocal therapy remains a nascent field largely comprising single center cohorts with little long-term data. Our current post-focal therapy surveillance consensus recommendations represent the synthesis of the best available evidence as well as expert opinion. Further work is necessary to define the most oncologically safe and cost-effective way of following patients after focal therapy.

The aim of this study is to elucidate the clinical significance of prostate-specific membrane antigen (PSMA) expression in circulating tumor cells (CTCs) from castration-resistant prostate cancer (CRPC) patients. We analyzed a total of 203 CTC samples from 79 CRPC patients to investigate the proportion of positive mRNA expressions at different treatment phases. Among them, we elected to focus on specimens from 56 CRPC patients who progressed on therapy and were subsequently provided a new treatment (treatment-switch cohort). In this cohort, we investigated the association between PSMA expression in CTCs and treatment response. CTCs were detected in 55/79 patients and median serum PSA in CTC-positive patients was 67.0 ng/ml. In the treatment-switch cohort of 56 patients, 20 patients were positive for PSMA in CTCs. PSMA expression was inversely associated with percentage of change in prostate-specific antigen (PSA). The median PSA progression-free survival and overall survival were significantly shorter in the PSMA-positive cohort. Furthermore, PSMA expression was predictive of poorer treatment response, shorter PSA progression-free survival and overall survival. PSMA expression in circulating tumor cells may be a novel poor prognostic marker for CRPC.

Background Tolvaptan, a vasopressin type 2 receptor antagonist, has been used to treat autosomal dominant polycystic kidney disease in Japan since 2014. Methods This long-term, real-world, post-marketing surveillance (PMS) was conducted in Japan from March 2014 to March 2022. Safety was assessed based on adverse drug reactions (ADRs). For efficacy, changes in the slope of total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) were assessed before and during the administration of tolvaptan. Results A total of 1676 patients were enrolled, with mean TKV (n = 1000) of 2149 ± 1339 mL and eGFR (n = 1641) of 44.4 ± 21.7 mL/min/1.73 m 2 . Frequent ADRs were hepatic function abnormal (9.6%), hyperuricaemia (8.3%), and thirst (8.1%). Most of the increased alanine aminotransferase exceeding 3 times the upper limit of the reference level occurred from 3  to  14 months after the start of treatment, but about 20% was observed after 15 months. There was no increase in ADRs over 36 months, suggesting that no other safety concerns need to be monitored during administration over 3–7 years. The mean slope of the estimated TKV increase before and during tolvaptan treatment was 6.58 and 3.71%/year, respectively ( P  = 0.0020). The mean slope of eGFR decline was − 3.63 and − 3.26 mL/min/1.73 m 2 /year, respectively ( P  = 0.2728). Conclusion There were no major problems with the safety of tolvaptan treatment, and efficacy in limiting TKV increase in this PMS was comparable to the previous, pivotal randomized control trials. Trial registration ClinicalTrials.gov; NCT02847624.