ULK1-regulated AMP sensing by AMPK and its application for the treatment of chronic kidney disease.

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a central kinase involved in energy homeostasis. Increased intracellular AMP levels result in AMPK activation through the binding of AMP to the γ-subunit of AMPK. Recently, we reported that AMP-induced AMPK activation is impaired in the kidneys in chronic kidney disease (CKD) despite an increase in the AMP/ATP ratio. However, the mechanisms by which AMP sensing is disrupted in CKD are unclear. Here, we identified mechanisms of energy homeostasis in which Unc-51-like kinase 1 (ULK1)-dependent phosphorylation of AMPKγ1 at Ser260/Thr262 promoting AMP sensitivity of AMPK. AMPK activation by AMP was impaired in Ulk1 knockout mice despite an increased AMP/ATP ratio. ULK1 expression is markedly downregulated in CKD kidneys, leading to AMP sensing failure. Additionally, MK8722, an allosteric AMPK activator, stimulated AMPK in the kidneys of a CKD mouse model (5/6th nephrectomy) via a pathway that is independent of AMP sensing. Thus, our study shows that MK8722 treatment significantly attenuates the deterioration of kidney function in CKD and may be a potential therapeutic option in CKD therapeutics.

Prognostic Impact and Genomic Backgrounds of Renal Parenchymal Infiltration or Micronodular Spread in Nonmetastatic Clear Cell Renal Cell Carcinoma.

A subset of clear cell renal cell carcinomas (ccRCCs) exhibits various growth patterns that infiltrate the normal renal parenchyma; however, our understanding of its association with cancer aggressiveness is incomplete. Here, we show that the morphology of the tumor interface with normal renal parenchyma is robustly associated with cancer recurrence after surgery, even when compared with the TNM staging system or the World Health Organization/International Society of Urological Pathology (WHO/ISUP) nuclear grade in nonmetastatic ccRCC. Hematoxylin and eosin-stained slides of whole tissue sections from surgical specimens were analyzed using a cohort of 331 patients with nonmetastatic ccRCC treated with radical nephrectomy. The patients were classified into 10 subgroups based on our classification algorithms for assessing the tumor interface with normal renal parenchyma. Among the 10 subgroups, 4 subgroups consisting of 40 patients (12%) were identified to have aggressive forms of nonmetastatic ccRCC associated with poor prognosis and unified as renal parenchymal infiltration or micronodular spread (RPI/MNS) phenotypes. Multivariable analyses showed that RPI/MNS phenotypes were robustly associated with shorter disease-free survival, independently of existing pathological factors including the TNM staging system and WHO/ISUP nuclear grade. The hazard ratio was highest for RPI/MNS (4.62), followed by WHO/ISUP grades 3 to 4 (2.11) and ≥pT3a stage (2.05). In addition, we conducted genomic analyses using next-generation sequencing of infiltrative lesions in 18 patients with RPI/MNS and tumor lesions in 33 patients without RPI/MNS. Results showed that alterations in SETD2 and TSC1 might be associated with RPI/MNS phenotypes, whereas alterations in PBRM1 might be associated with non-RPI/MNS phenotypes. These data suggest that RPI/MNS may be associated with aggressive genomic backgrounds of ccRCC, although more comprehensive analyses with a larger sample size are required. Future studies may further elucidate the clinical implications of RPI/MNS, particularly for deciding the indication of adjuvant treatment after nephrectomy.

Phase I/IIa trial of 18F-prostate specific membrane antigen (PSMA) 1007 PET/CT in healthy volunteers and prostate cancer patients.

OBJECTIVE: 18F-PSMA 1007 is a promising PET tracer for prostate cancer. We aimed to examine the safety, biodistribution, radiation dosimetry, and clinical effectiveness in Japanese healthy volunteers and patients with prostate cancer. METHODS: Part A evaluated the pharmacokinetics and exposure doses in three healthy volunteers. Part B evaluated the diagnostic accuracy in patients with untreated preoperative prostate cancer (Cohort 1, n = 7) and patients with biochemical recurrence (Cohort 2, n = 3). All subjects received a single dose of 3.7 MBq/kg 18F-PSMA 1007. Results: 18F-PSMA 1007 was found to be safe and well tolerated in all subjects. No serous AEs or drug-related AEs were identified during the present study. The average blood radioactivity concentration reached a maximum of 47.87 ± 1.05 (percentage of injected dose [%ID]/ml) at 5 min and then decreased to 1.60 ± 0.78 in 6 h. The systemic radioactivity reached a maximum of 211.05 ± 6.77 (%ID$\times$103) at 5 min and decreased to 7.18 ± 3.91 in 6 h. The sensitivity and positive predictive value were 100% and 100% based on both pathologic and imaging confirmation as gold standard. In Cohort 1, 15 primary foci (11.9%) were >5 mm in the largest diameter and identified in 39 of 126 segments (30.1%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for 60 min uptake time acquisition were 80.0, 96.5, 91.4, 91.2 and 91.3%, respectively. CONCLUSIONS: Our study revealed that 18F-PSMA 1007 was safe, well tolerated and showed high accuracy in the diagnosis of prostate cancer.

Comparisons of in-hospital fee and surgical outcomes between robot-assisted, laparoscopic, and open radical cystectomy: a Japanese nationwide study.

OBJECTIVE: To evaluate in-hospital fees and surgical outcomes of robot-assisted radical cystectomy (RARC), laparoscopic radical cystectomy (LRC) and open radical cystectomy (ORC) using a Japanese nationwide database. METHODS: All data were obtained from the Diagnosis Procedure Combination database between April 2020 and March 2022. Basic characteristics and perioperative indicators, including in-hospital fees, were compared among the RARC, LRC and ORC groups. Propensity score-matched comparisons were performed to assess the differences between RARC and ORC. RESULTS: During the study period, 2931, 1311 and 2435 cases of RARC, LRC and ORC were identified, respectively. The RARC group had the lowest in-hospital fee (median: 2.38 million yen), the shortest hospital stay (26 days) and the lowest blood transfusion rate (29.5%), as well as the lowest complication rate (20.9%), despite having the longest anesthesia time (569 min) among the three groups (all P < 0.01). The outcomes of LRC were comparable with those of RARC, and the differences in these indicators between the RARC and ORC groups were greater than those between the RARC and LRC groups. In propensity score-matched comparisons between the RARC and ORC groups, the differences in the indicators remained significant (all P < 0.01), with an ~50 000 yen difference in in-hospital fees. CONCLUSIONS: RARC and LRC were considered to be more cost-effective surgeries than ORC due to their superior surgical outcomes and comparable surgical fees in Japan. The widespread adoption of RARC and LRC is expected to bring economic benefits to Japanese society.

Gustave Roussy Immune score as a prognostic biomarker in patients with platinum-refractory metastatic urothelial carcinoma treated with pembrolizumab: YUSHIMA study.

BACKGROUND: This study aimed to investigate the prognostic value of the Gustave Roussy Immune score (GRIm-score) in platinum-refractory metastatic urothelial carcinoma (UC) treated with pembrolizumab. METHODS: This multicenter retrospective study (YUSHIMA study) evaluated 331 patients with metastatic UC treated with pembrolizumab after platinum-based chemotherapy between January 2018 and June 2023 at 13 institutions. We collected pretreatment variables, including the GRIm-score based on serum albumin, lactate dehydrogenase, and neutrophil-to-lymphocyte ratio. The patients were divided into low and high GRIm-score groups. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were determined using the multivariate Cox proportional hazard model. RESULTS: During the median follow-up period of 7.3 months, 278 (84%) patients showed disease progression, and 223 (67%) died from any cause. Multivariate analysis revealed that the high GRIm-score group was an independent and significant adverse prognostic factor of both OS and PFS (hazard ratio, 1.65 and 1.82, respectively; both p < 0.001) along with Eastern Cooperative Oncology Group Performance Status of ≥ 2 (both p < 0.001), presence of visceral metastasis (both p < 0.001), and hemoglobin of < 9.2 g/dL (p = 0.030 and p = 0.038). C-reactive protein of > 42 mg/L was a significant prognostic factor for OS (p = 0.001). CONCLUSION: The GRIm-score is an independent prognostic marker for survival outcomes in patients with platinum-refractory metastatic UC treated with pembrolizumab.

Incidence and predictors of intraoperative hypotension during transurethral bladder tumor resection with oral 5-aminolevulinic acid.

OBJECTIVES: To analyze the incidence and risk factors of intraoperative hypotension related to photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) with oral 5-aminolevulinic acid (5-ALA). METHODS: We retrospectively analyzed 487 patients with bladder tumors who underwent PDD-TURBT (n = 184) or conventional TURBT (conv-TURBT) (n = 303) between 2018 and 2021. Intraoperative hypotension was defined as hypotension requiring vasopressors during TURBT, and its incidence was compared between the two groups. Potential risk factors of intraoperative hypotension, including preoperative change in mean arterial pressure (MAP), were further investigated in patients receiving PDD-TURBT. RESULTS: The median age was 72 years, 392 patients (81%) were male, and 203 (42%) had hypertension. TURBT was performed under general and spinal anesthesia in 76 (16%) and 411 (84%) patients, respectively. The incidence of intraoperative hypotension was significantly higher in PDD-TURBT compared to conv-TURBT (43% vs. 17%, respectively). The median change in MAP until the induction of anesthesia was +6.5 mmHg (range: -29.0 to +46.3) in the PDD-TURBT group and +14.7 mmHg (range: -35.3 to +67.7) in the conv-TURBT group, showing a significantly smaller increase in the PDD-TURBT group (p < 0.001). In the multivariable analysis for PDD-TURBT patients, advanced age, general anesthesia, and lower MAP change (<+6.5 mmHg) until anesthesia induction were significantly associated with intraoperative hypotension (p = 0.0104, <0.001, and <0.001, respectively). CONCLUSIONS: Intraoperative hypotension occurred more frequently in patients who underwent PDD-TURBT than in those who underwent conv-TURBT. Using oral 5-ALA decreases preoperative blood pressure elevation and may be responsible for intraoperative hypotension.

Incidence, risk factors, and significance of 20% decrease from new baseline estimated glomerular filtration rate after radical and partial nephrectomy within 2 years.

OBJECTIVES: To evaluate the incidence and risk factors of a 20% decrease from new baseline (NB)-estimated glomerular filtration rate (eGFR) within 2 years after radical nephrectomy (RN) and partial nephrectomy (PN) and to examine the difference in the incidence of end-stage renal disease (ESRD) with or without the 20% decrease. METHODS: This retrospective study included 238 patients undergoing RN and 369 undergoing PN for cT1a-cT3a renal cancer. The incidence of a 20% decrease from NB-eGFR within 2 years after RN/PN was examined and its potential risk factors including surgery type were assessed by multivariate logistic regression analysis. The development of ESRD was analyzed as an endpoint and its incidence was compared according to the presence or absence of the 20% decrease from NB-eGFR within 2 years. RESULTS: Overall, the 20% decrease from NB-eGFR within 2 years was observed in 37 patients (6.1%), including 10 (4.2%) and 27 (7.3%) after RN and PN, respectively (p = 0.117). Diabetes mellitus, proteinuria, and perioperative complications were shown to be independent risk factors for the 20% decrease from NB-eGFR, while surgery type was not. During the median follow-up of 65 months, the ESRD-free survival rate at 6 years was 75.5% and 99.6% in patients with and without the 20% decrease from NB-eGFR, respectively (p < 0.001), while no significant difference was observed between patients undergoing RN and PN (98.1% and 98.7%, p = 0.561). CONCLUSIONS: Because the incidence of ESRD after the 20% decrease from NB-eGFR within 2 years was as high as 24.5% at 6 years, these patients should be followed with utmost care.

Utility of positive core number on MRI-ultrasound fusion targeted biopsy in combination with PI-RADS scores for predicting unexpected extracapsular extension of clinically localized prostate cancer.

OBJECTIVES: To evaluate the utility of magnetic resonance imaging (MRI) and MRI-ultrasound fusion targeted biopsy (TB) for predicting unexpected extracapsular extension (ECE) in clinically localized prostate cancer (CLPC). METHODS: This study enrolled 89 prostate cancer patients with one or more lesions showing a Prostate Imaging-Reporting and Data System (PI-RADS) score ≥3 but without morphological abnormality in the prostatic capsule on pre-biopsy MRI. All patients underwent TB and systematic biopsy followed by radical prostatectomy (RP). Each lesion was examined by 3-core TB, taking cores from each third of the lesion. The preoperative variables predictive of ECE were explored by referring to RP specimens in the lesion-based analysis. RESULTS: Overall, 186 lesions, including 81 (43.5%), 73 (39.2%), and 32 (17.2%) with PI-RADS 3, 4, and 5, respectively, were analyzed. One hundred and twenty-two lesions (65.6%) were diagnosed as cancer on TB, and ECE was identified in 33 (17.7%) on the RP specimens. The positive TB core number was ≤2 in 129 lesions (69.4%) and three in 57 lesions (30.6%). On the multivariate analysis, PI-RADS ≥4 (p = 0.049, odds ratio [OR] = 2.39) and three positive cores on TB (p = 0.005, OR = 3.07) were independent predictors of ECE. Lesions with PI-RADS ≥4 and a positive TB core number of 3 had a significantly higher rate of ECE than those with PI-RADS 3 and a positive TB core number ≤2 (37.5% vs. 7.8%, p < 0.001). CONCLUSIONS: Positive TB core number in combination with PI-RADS scores is helpful to predict unexpected ECE in CLPC.

Location-specific diagnostic efficiency of photodynamic diagnosis-guided biopsy in bladder mapping biopsies.

BACKGROUND: Photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumors (TURBT) has emerged as a promising complementary tool to white light (WL) cystoscopy, potentially improving cancer detection and replacing conventional mapping biopsies. This study aimed to investigate the diagnostic accuracy of PDD by anatomical locations in mapping biopsies through lesion-based analysis. METHODS: PDD and WL findings were prospectively recorded in 102 patients undergoing mapping biopsies and PDD-assisted TURBT using oral 5-aminolevulinic acid. We evaluated 673 specimens collected from flat tumor or normal-looking lesions on WL cystoscopy, after excluding 98 specimens collected from papillary or nodular tumors. RESULTS: Among the 673 lesions, cancer was detected in 110 (16%) by lesion-based analysis. PDD demonstrated significantly higher sensitivity (65.5% vs. 46.4%, p < 0.001) and negative predictive value (92.5% vs. 89.5%, p < 0.001) compared to WL. The sensitivity of PDD findings varied by location: posterior (100%), right (78.6%), dome (73.3%), left (70.6%), trigone (58.8%), bladder neck (41.7%), anterior (40.0%), and prostatic urethra (25.0%). Incorporating targeted biopsies of specific locations (bladder neck, anterior, and prostatic urethra) into the PDD-guided biopsies, regardless of PDD findings, significantly increased the overall sensitivity from 65.5% to 82.7% (p = 0.001). CONCLUSIONS: This study first demonstrated the detection rate of location-specific mapping biopsies using PDD, revealing difficulties in accuracy assessment in areas susceptible to tangential fluorescence. While PDD-guided biopsy improves cancer detection compared to WL cystoscopy even for flat tumors or normal-looking lesions, more careful decisions, including mapping biopsies, may be beneficial for an assessment in these tangential areas.

Stepwise algorithm using computed tomography and magnetic resonance imaging for differential diagnosis of fat-poor angiomyolipoma in small renal masses: A prospective validation study.

OBJECTIVES: To validate the diagnostic accuracy of a stepwise algorithm to differentiate fat-poor angiomyolipoma (fp-AML) from renal cancer in small renal masses (SRMs). METHODS: We prospectively enrolled 223 patients with solid renal masses <4 cm and no visible fat on unenhanced computed tomography (CT). Patients were assessed using an algorithm that utilized the dynamic CT and MRI findings in a stepwise manner. The diagnostic accuracy of the algorithm was evaluated in patients whose histology was confirmed through surgery or biopsy. The clinical course of the patients was further analyzed. RESULTS: The algorithm classified 151 (68%)/42 (19%)/30 (13%) patients into low/intermediate/high AML probability groups, respectively. Pathological diagnosis was made for 183 patients, including 10 (5.5%) with fp-AML. Of these, 135 (74%)/36 (20%)/12 (6.6%) were classified into the low/intermediate/high AML probability groups, and each group included 1 (0.7%)/3 (8.3%)/6 (50%) fp-AMLs, respectively, leading to the area under the curve for predicting AML of 0.889. Surgery was commonly opted in the low and intermediate AML probability groups (84% and 64%, respectively) for initial management, while surveillance was selected in the high AML probability group (63%). During the 56-month follow-up, 36 (82%) of 44 patients initially surveyed, including 13 of 18 (72%), 6 of 7 (86%), and 17 of 19 (89%) in the low/intermediate/high AML probability groups, respectively, continued surveillance without any progression. CONCLUSIONS: This study confirmed the high diagnostic accuracy for differentiating fp-AMLs. These findings may help in the management of patients with SRMs.

Outcomes and prognostic factors in patients with synchronous and metachronous oligometastatic urothelial carcinoma with visceral metastases.

OBJECTIVES: To evaluate the clinical characteristics of oligometastatic disease (OMD) in metastatic urothelial carcinoma (mUC) with visceral metastases when classified into synchronous and metachronous metastases. METHODS: Of 957 cases of de novo mUC treated between 2008 and 2023, 374 with visceral metastases were analyzed. Cases were classified into OMD with up to three metastatic lesions and polymetastatic disease (PMD), and into synchronous and metachronous metastases. The clinical characteristics and overall survival (OS) for each group were analyzed. RESULTS: Overall, 196 (52.4%) had synchronous metastasis and 178 (47.6%) had metachronous metastasis. Median OS for synchronous metastases was significantly shorter than for metachronous metastases (12.1 months vs. 15.3 months, p = 0.011). Among the synchronous metastases, 48 (24.5%) were OMD and 148 (75.6%) were PMD. There was no significant difference in OS between the OMDs and PMDs (median 14.9 months vs. 11.7 months, p = 0.32), and only decreased albumin level was identified as a significant predictor of poor OS. Among the metachronous metastases, 64 (36.0%) were OMD and 114 (64.0%) were PMD. There was no significant difference in OS between the OMD and PMD (median 21.2 months vs. 15.0 months, p = 0.35), and no significant predictors of poor OS were identified. CONCLUSIONS: For mUC with visceral metastases, the timing of metastasis appearance was associated with prognosis, with synchronous metastases being a poorer prognostic factor compared to metachronous metastases. There was no prognostic difference between OMD and PMD with visceral metastases when classified into synchronous or metachronous metastases.

Clinical questions in the Japanese Urological Association's 2024 clinical practice guidelines for urethral strictures.

Transurethral procedures such as direct vision internal urethrotomy and urethral dilation have been the traditional treatments for urethral strictures. However, transurethral procedures are associated with high recurrence rates, resulting in many uncured cases and prompting major international urological societies to recommend urethroplasty as the standard treatment owing to its high success rate. In contrast, many Japanese general urologists have little doubts about treating urethral strictures with transurethral treatment. Therefore, urethral stricture treatments in Japan are not in line with those used in other countries. To address this, the Trauma, Emergency Medicine, and Reconstruction Subcommittee of the Japanese Urological Association has developed guidelines to offer standardized treatment protocols for urethral stricture, based on international evidence and tailored to Japan's medical landscape. These guidelines target patients with a clinically suspected urethral stricture and are intended for urologists and general practitioners involved in its diagnosis and treatment. Following the Minds Clinical Practice Guideline Development Manual 2020, the committee identified eight critical clinical issues and formulated eight clinical questions using the "patient, intervention, comparison, and outcome" format. A comprehensive literature search was conducted. For six clinical questions addressed by the existing guidelines or systematic reviews, the level of evidence was determined by qualitative systematic reviews. Quantitative systematic reviews and meta-analyses were performed for the two unique clinical questions. The recommendation grades were determined using the Delphi method and consensus by the committee. These guidelines will be useful to clinicians in daily practice, especially those involved in the care of urethral strictures.

Summary of the Clinical Practice Guidelines for Upper Tract Urothelial Carcinoma 2023 by the Japanese Urological Association.

This article is an English translation of the Clinical Practice Guidelines for Upper Tract Urothelial Carcinoma (2nd edition) published in June 2023. The Japanese Urological Association's (JUA) Guidelines Committee on Upper Tract Urothelial Carcinoma (UTUC) created a 2023 update guideline to support clinicians' current evidence-based management of UTUC and to incorporate its recommendations into clinical practice. The new guideline adhered as closely as possible to the Minds Manual for Guideline Development 2020 ver. 3.0. Findings related to epidemiological, pathological, diagnosis, treatment, and follow-up were reviewed. In addition, seven clinical questions (CQs) were set to determine the grade of recommendation and level of evidence. Preconceptions and biases were removed from the preparation process, the overall evidence was evaluated appropriately, and recommendations were made after fully considering the balance between benefits and harms. Although the evidence is still insufficient to be taken up as a CQ, the latest important information is described in seven columns, and clinical issues that should be resolved in the future related to the CQ are described as recommendations for tomorrow. We hope that these guidelines will help medical professionals, patients, and their families involved in the treatment of UTUC in their decision-making, and hope that a critical review of these guidelines will lead to further refinements in the next edition.

Long-term effects of primary aldosteronism treatment on patients with primary aldosteronism and chronic kidney disease.

OBJECTIVE: Primary aldosteronism (PA) is a major cause of secondary hypertension and is associated with chronic renal injury. The glomerular filtration rate (GFR) in PA rapidly decreases after the removal of glomerular hyperfiltration due to aldosterone excess by adrenalectomy (ADX) or mineralocorticoid receptor antagonist (MRA) treatment and is stable in the long term. However, the effects of these treatments on the long-term renal function of PA patients with chronic kidney disease (CKD) is not well understood. DESIGN AND PATIENTS: In this single-center, retrospective study, acute and chronic changes in the estimated GFR (eGFR) were examined in 107 patients with PA, including 49 patients with post-treatment CKD　defined as eGFR < 60 ml/min/1.73 m2 . RESULTS: The reduction in eGFR observed 1 month after ADX in the CKD group (N = 31) was -20.1 ± 8.2 ml/min/1.73 m2 . Multivariate analysis showed that pre-treatment eGFR and plasma aldosterone concentration were independent predictive factors of the acute reduction in eGFR after ADX. The reduction of eGFR observed 1 month after MRA administration in the post-treatment CKD group (N = 18) was -9.2 ± 5.9 ml/min/1.73 m2 . Multivariate analysis showed that the duration of hypertension and pre-treatment eGFR were independent predictive factors of the acute reduction in eGFR after ADX administration. In 20 patients with CKD (N = 12 ADX and N = 8 MRA) followed for more than 5 years post-treatment, there was no further significant decline in eGFR over a follow-up period of 7 (6, 8) years nor any difference between the two treatment modalities. CONCLUSIONS: Our study suggests that treatment of PA in stage 3 CKD is safe and useful in preventing renal injury.

Impact of worsening surgically induced chronic kidney disease (CKD-S) in preoperative CKD-naïve patients on survival in renal cell carcinoma.

OBJECTIVES: To evaluate effects of worsening surgically induced chronic kidney disease (CKD-S) on oncological and non-oncological survival outcomes in renal cell carcinoma (RCC). PATIENTS AND METHODS: We performed a retrospective analysis of patients who underwent partial (PN) or radical nephrectomy (RN) and were free of preoperative CKD (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2 ). Patients were stratified by CKD stage at last follow-up: no CKD-S (eGFR ≥60 mL/min/1.73 m2 ), de novo CKD-S 3a (eGFR 45-59 mL/min/1.73 m2 ), CKD-S 3b (eGFR <45 and ≥30 mL/min/1.73 m2 ) and CKD-S 4 (eGFR <30 and ≥15 mL/min/1.73 m2 ). The primary outcome was all-cause mortality (ACM). Secondary outcomes included non-cancer mortality (NCM), cancer-specific mortality (CSM) and de novo CKD-S Stage 3/4. Multivariable analysis (MVA) was utilised to identify risk factors for outcomes. Kaplan-Meier analysis (KMA) was utilised to evaluate overall (OS), non-cancer (NCS), and cancer-specific survival with respect to CKD-S categories. RESULTS: We analysed 3239 patients. The mean preoperative and last-follow-up eGFRs were 87.4 and 69.5 mL/min/1.73 m2 , respectively. On last follow-up, 57.9% (n = 1876) had no CKD-S, 18.7% (n = 606) had CKD-S 3a, 15.1% (n = 489) had CKD-S 3b and 8.3% (n = 268) had CKD-S 4. On MVA, de novo CKD-S 3b and 4 were independently associated with ACM (hazard ratios [HRs] 1.3-2.1, P = 0.003-0.001) and NCM (HRs 1.5-2.8, P = 0.021-0.001), but not CSM (P = 0.219-0.909); de novo CKD-S 3a was not predictive for any mortality outcomes (P = 0.102-0.81). RN was independently associated with CKD-S 3-4 (HRs 1.78-1.99, P < 0.001-0.035). Comparing no CKD-S, CKD-S 3a, CKD-S 3b and CKD-S 4, KMA demonstrated worsening outcomes with progressive CKD-S stage: 5-year OS 84% vs 78% vs 71% vs 60% (P < 0.001) and 5-year NCS 93% vs 87% vs 83% vs 72% (P < 0.001). CONCLUSION: Development of CKD-S Stage 3b and 4, but not 3a, was associated with worsened ACM and NCM. The decision to proceed with nephron preservation via PN should be individualised based on oncological risk and risk of functional decline to CKD-S 3b or 4, and not CKD-S 3a.

Novel utility of Vesical Imaging-Reporting and Data System in multimodal treatment for muscle-invasive bladder cancer.

OBJECTIVES: To examine the clinical significance of the Vesical Imaging-Reporting and Data System (VI-RADS) in predicting outcome of multimodal treatment (MMT) in muscle-invasive bladder cancer (MIBC) patients. METHODS: We reviewed 78 pathologically proven MIBC patients who underwent MMT including transurethral resection and chemoradiotherapy, followed by partial or radical cystectomy. Treatment response was assessed through histologic evaluation of cystectomy specimens. Two radiologists categorized the index lesions of pretherapeutic MRI according to the 5-point VI-RADS score. The associations of VI-RADS score with the therapeutic effect of MMT were analyzed. The diagnostic performance of VI-RADS scores with a cut-off VI-RADS scores ≤ 2 or ≤ 3 for predicting pathologic complete response to MMT (MMT-CR) was evaluated. RESULTS: MMT-CR was achieved in 2 (100%) of VI-RADS score 1 (n = 2), 16 (84%) of score 2 (n = 19), 12 (86%) of score 3 (n = 14), 7 (64%) of score 4 (n = 11), and 14 (44%) of score 5 (n = 32). VI-RADS score was inversely associated with the incidence of MMT-CR (p = 0.00049). The cut-off VI-RADS score ≤ 2 and ≤ 3 could predict the favorable therapeutic outcome of MMT with high specificity (0.89 with 95% confidence interval [CI]: 0.71-0.98 and 0.82 with 95% CI: 0.62-0.94, respectively) and high positive predictive value (0.86 with 95% CI: 0.64-0.97 and 0.86 with 95% CI: 0.70-0.95, respectively). CONCLUSION: VI-RADS score may serve as an imaging marker in MIBC patients for predicting the therapeutic outcome of MMT. CLINICAL RELEVANCE STATEMENT: Muscle-invasive bladder cancer patients with a lower Vesical Imaging-Reporting and Data System score can be a good candidate for bladder-sparing treatment incorporating multimodal treatment. KEY POINTS: • Vesical Imaging-Reporting and Data System (VI-RADS) score was potentially valuable for classifying pathologic tumor response in patients with muscle-invasive bladder cancer. • The likelihood of achieving complete response of multimodal treatment (MMT) decreased with increasing VI-RADS score. • VI-RADS score could serve as an imaging marker that optimizes patient selection for MMT.

The role of multimodal salvage therapy in the management of recurrent adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma is an aggressive tumor which often recurs despite apparent complete resection. This study assessed the long-term outcomes for patients with recurrent adrenocortical carcinoma after multimodal salvage therapy with chemotherapy, chemoradiotherapy and surgery. METHODS: We retrospectively reviewed medical records of patients who had a pathological diagnosis of adrenocortical carcinoma between 1996 and 2017. Kaplan-Meier curves were used to assess progression-free and cancer-specific survivals among all patients and cancer-specific survival among patients with tumor recurrence. Log-rank test was used to compare patient survivals by modality of salvage therapy (chemotherapy, chemoradiotherapy and chemotherapy/chemoradiotherapy plus surgery). RESULTS: Of 20 patients who underwent initial surgery, recurrence occurred in 14 (70%) with a median interval of 7.5 (range 1.0-12.6) months. Salvage therapy provided was chemotherapy only (n = 7), chemoradiotherapy (n = 2) and chemotherapy/chemoradiotherapy plus surgery (n = 5). Of the five patients who received salvage surgery, three underwent repeated resections. The potential benefit of multimodal salvage therapy was suggested in five patients (4 with chemotherapy/chemoradiotherapy plus surgery and 1 with chemoradiotherapy) who achieved durable disease control (cancer-specific survival from initial recurrence, 22-258 months). With a median follow-up of 25 months from recurrence, the 5-year cancer-specific survival rate was 58%. cancer-specific survival after recurrence was prolonged in patients with ≤ stage 3 disease, positive response to chemotherapy/chemoradiotherapy and salvage surgery. CONCLUSIONS: Long-term disease control and survival could be achieved in highly selected patients with recurrent adrenocortical carcinoma using a multidisciplinary approach. Patients who had relatively limited recurrent sites and responded well to chemotherapy/chemoradiotherapy may be considered for salvage surgery on a case-by-case basis.

Renal function outcome after selective bladder-preserving tetramodality therapy consisting of maximal transurethral resection, induction chemoradiotherapy and consolidative partial cystectomy in comparison with radical cystectomy for patients with muscle-invasive bladder cancer: a two-centre retrospective study.

OBJECTIVE: To compare renal function (RF) outcomes after bladder-preserving tetramodal therapy against muscle-invasive bladder cancer (MIBC) to those after radical cystectomy (RC). METHODS: This study included 95 patients treated with tetramodal therapy consisting of transurethral bladder tumour resection, chemoradiotherapy and partial cystectomy (PC) and 300 patients treated with RC. The annual change in the estimated glomerular filtration rate (eGFR) was compared using the linear mixed model. Renal impairment was defined as a >25% decrease from the pretreatment eGFR, and renal impairment-free survival (RIFS) was calculated. The association between treatment type and renal impairment was assessed. RESULTS: The number of patients who received neoadjuvant chemotherapy was 8 (8.4%) in the tetramodal therapy group and 75 (25.0%) in the RC group. After the inverse probability of treatment weighting adjustments, the baseline characteristics were balanced between the treatment groups. The mean eGFR before treatment in tetramodal therapy and RC groups was 69.4 and 69.6 mL/min/1.73 m2 and declined with a slope of -0.7 and -1.5 mL/min/1.73 m2/year, respectively. The annual deterioration rate of post-treatment eGFR in the tetramodal therapy group was milder than in the RC group. The 5-year RIFS rate in the tetramodal therapy and the RC groups was 91.2 and 85.2%, respectively. Tetramodal therapy was an independent factor of better RIFS compared with RC. CONCLUSIONS: RF was better preserved after tetramodal therapy than after radical therapy; however, even after tetramodal therapy, the eGFR decreased, and a non-negligible proportion of patients developed renal impairment.

A phase II randomized trial of metastasis-directed therapy with alpha emitter radium-223 in men with oligometastatic castration-resistant prostate cancer (MEDAL).

BACKGROUND: The significance of metastasis-directed therapy for oligometastatic prostate cancer has been widely discussed, and targeted therapy for progressive sites is a feasible option as a multidisciplinary treatment for castration-resistant prostate cancer (CRPC). When oligometastatic CRPC with only bone metastases progresses after targeted therapy, it tends to progress as multiple bone metastases. The progression of oligometastatic CRPC after targeted therapy may be due in part to the presence of micrometastatic lesions that, though undetected on imaging, were present prior to targeted therapy. Thus the systemic treatment of micrometastases in combination with targeted therapy for progressive sites is expected to enhance the therapeutic effect. Radium-223 dichloride (radium-223) is a radiopharmaceutical that selectively binds to sites of increased bone turnover and inhibits the growth of adjacent tumor cells by emitting alpha rays. Therefore, for oligometastatic CRPC with only bone metastases, radium-223 may enhance the therapeutic effect of radiotherapy for active metastases. METHODS: This phase II, randomized trial of Metastasis-Directed therapy with ALpha emitter radium-223 in men with oligometastatic CRPC (MEDAL) is designed to assess the utility of radium-223 in combination with metastasis-directed radiotherapy in patients with oligometastatic CRPC confined to bone. In this trial, patients with oligometastatic CRPC with three or fewer bone metastases on whole-body MRI with diffusion-weighted MRI (WB-DWI) will be randomized in a 1:1 ratio to receive radiotherapy for active metastases plus radium-223 or radiotherapy for active metastases alone. The prior use of androgen receptor axis-targeted therapy and prostate-specific antigen doubling time will be used as allocation factors. The primary endpoint will be radiological progression-free survival against progression of bone metastases on WB-DWI. DISCUSSION: This will be the first randomized trial to evaluate the effect of radium-223 in combination with targeted therapy in oligometastatic CRPC patients. The combination of targeted therapy for macroscopic metastases with radiopharmaceuticals targeting micrometastasis is expected to be a promising new therapeutic strategy for patients with oligometastatic CRPC confined to bone. Trial registration Japan Registry of Clinical Trials (jRCT) (jRCTs031200358); Registered on March 1, 2021, https://jrct.niph.go.jp/latest-detail/jRCTs031200358.

Trends of radical cystectomy and comparisons of surgical outcomes among surgical approaches focusing on robot-assisted radical cystectomy: A Japanese nationwide database study.

OBJECTIVE: To clarify the trends in radical cystectomy and to compare surgical outcomes among surgical approaches focusing on robot-assisted radical cystectomy based on a Japanese nationwide database. METHODS: The Diagnosis Procedure Combination database was used to extract data on radical cystectomy cases. Trends in open radical cystectomy, laparoscopic radical cystectomy, minimum incision endoscopic radical cystectomy, and robot-assisted radical cystectomy between April 2012 and March 2021 were evaluated. Basic characteristics and peri-operative indicators were compared among the four groups. Propensity score matching was applied to assess the differences between open radical cystectomy and robot-assisted radical cystectomy. RESULTS: During the study period, a decreasing number of open radical cystectomies and an increasing number of minimally invasive radical cystectomies were shown in the total cohort of 28 345 cases. The number of robot-assisted radical cystectomies rapidly increased after government approval in 2018. Minimally invasive radical cystectomies, including robot-assisted radical cystectomies, had a significantly lower complication rate, a shorter length of stay, and a lower blood transfusion rate, but a longer anesthesia time than open radical cystectomies. In the propensity score matching analysis comparing the surgical outcomes of robot-assisted radical cystectomy and open radical cystectomy, similar results were demonstrated, and blood transfusion rates were equivalent. CONCLUSION: For the past decade, the number of minimally invasive radical cystectomies has steadily increased without compromised surgical outcomes, except for anesthesia time. Robot-assisted radical cystectomies in particular rapidly became widespread in Japan after government approval in 2018 and became a standard surgery within the first 3 years.