Tumor-derived lactic acid promotes acetylation of histone H3K27 and differentiation of IL-10-producing regulatory B cells through direct and indirect signaling pathways.

Tumor cells are known to enhance glycolysis, even under normoxic conditions, via the Warburg effect, producing excess lactic acid in the tumor microenvironment. Lactic acid enhances the IL-23/IL-17 pathway and induces chronic inflammation. The acidic microenvironment formed by lactic acid suppresses immune cell proliferation and activation. In the present study, we clarified that lactic acid had two novel activities for immune cells. First, lactic acid specifically enhanced acetylation at lysine 27 of histone H3 (H3K27ac) in splenic B cells and monocytes/macrophages, and this epigenetically up-regulates the expression of genes. Acetylation and methylation of other residues of histone H3 were rarely induced. Second, lactic acid induced a particularly-marked enhancement of Il10 gene expression in B cells, leading to an increase in IL-10-producing regulatory B (Breg) cells. Furthermore, two pathways should be involved in both the enhancement of H3K27ac and the induction of Breg cells by lactic acid: a direct pathway that enhances the CD40 signal in B cells, and an indirect pathway that affects B cells by activating the exchange protein directly activated by cAMP (EPAC) 1/2 in non-B cells. In tumor-bearing mice, the levels of H3K27ac of tumor-infiltrating B cells were significantly higher than splenic B cells and were suppressed by intraperitoneal injection of the EPAC1/2 inhibitor. In conclusion, tumor-derived lactic acid increases H3K27ac and IL-10-producing Breg cells, causing the suppression of anti-tumor immunity.

Clinicopathological and molecular features of renal cell carcinomas with haemangioblastoma-like features distinct from clear cell renal cell carcinoma.

AIMS: Haemangioblastomas arise in the central nervous system. Rarely, haemangioblastomas may develop in extra-neural sites, such as the kidneys. A few reported cases of renal cell carcinomas (RCCs) with haemangioblastoma-like features have exhibited both clear cell renal cell carcinoma (CCRCC)- and haemangioblastoma-like components. The clinicopathological and molecular characteristics of RCCs with haemangioblastoma-like features were analysed, focusing on VHL alterations, in comparison with CCRCCs partially resembling haemangioblastoma. METHODS AND RESULTS: Four RCCs with haemangioblastoma-like features and five CCRCCs partially resembling haemangioblastoma were included. The RCCs with haemangioblastoma-like features were indolent and lacked adverse prognostic factors. All RCCs with haemangioblastoma-like features had a well-circumscribed appearance and a thick fibromuscular capsule, with fibromuscular bundles extending into the tumour to varying degrees in the three tumours. Each RCC with haemangioblastoma-like features exhibited CCRCC-like areas with indistinct tubular structures and foci of haemangioblastoma-like areas, in which vessels and short spindle cells overwhelmed tumour cells. Whereas haemangioblastoma-like areas in the CCRCCs partially resembling haemangioblastoma exhibited sparse vessels and spindle cells and distinct clear cells. The RCCs with haemangioblastoma-like features exhibited a unique immunohistochemical profile, with positive staining for inhibin-α, S100, carbonic-anhydrase-9, keratin7, and high molecular weight keratin and negative staining for (alpha-methylacyl-CoA racemase) AMACR. RCC with haemangioblastoma-like features did not display any VHL alterations, including VHL mutation, 3p LOH, and methylation of the VHL promoter region, and the two tumours harboured a likely oncogenic missense variant of MTOR (c.7280T>G). CONCLUSION: The histopathological, immunohistochemical, and molecular findings suggest that RCC with haemangioblastoma-like features is a distinct entity from CCRCC.

Association of lung immune prognostic index with survival outcomes in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

OBJECTIVE: Lung immune prognostic index is based on derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase level. Lung immune prognostic index has reported association with survival outcomes in patients with various malignancies undergoing treatment with immune checkpoint inhibitors. However, the prognostic impact of pre-treatment lung immune prognostic index in patients with metastatic renal cell carcinoma receiving nivolumab plus ipilimumab treatment remains unclear. This study examines the association between lung immune prognostic index and outcomes in this setting. METHODS: We retrospectively evaluated 156 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab at eight institutions. We assessed the associations between pre-treatment lung immune prognostic index and survival outcomes including progression-free survival, second progression-free survival (PFS2), cancer-specific survival and overall survival. RESULTS: Patients were classified into good (n = 84, 54%), intermediate (n = 52, 33%) and poor (n = 20, 13%) lung immune prognostic index groups. Progression-free survival did not significantly differ between lung immune prognostic index groups, but there was significant difference in PFS2, cancer-specific survival and overall survival. In multivariable Cox proportional hazard analyses, high pre-treatment lung immune prognostic index was a significant predictor of poor PFS2 (vs. good group, intermediate group: P = 0.01 and poor group: P = 0.04) and poor overall survival (vs. good group, intermediate group: P = 0.01 and poor group: P < 0.01). Moreover, the patients with poor lung immune prognostic index had significantly poorer cancer-specific survival than those with good LIPI (P < 0.01). CONCLUSIONS: High pre-treatment LIPI is suggested by our results to be a significant independent predictor of poor prognosis in patients receiving nivolumab plus ipilimumab for metastatic renal cell carcinoma.

Effect of nephrostomy sheath size on renal pelvic pressure during endoscopic combined intrarenal surgery: artificial kidney model study.

BACKGROUND: This study aimed to evaluate the intrarenal pelvic pressure in endoscopic combined intrarenal surgery using an artificial kidney model. METHODS: An artificial kidney model was created using the Urovac evacuator™. Four sizes of nephrostomy sheaths (MIP-L: 25/26 Fr, MIP-M: 16.5/17.5 Fr, MIP-S: 11/12 Fr, MIP-XS: 8.5/9.5 Fr) and two sizes of ureteral access sheaths (12/14 Fr and 10/12 Fr) were installed into the model. For each combination of nephrostomy and ureteral access sheath, renal pelvic pressure was measured with and without insertion of the retrograde flexible ureteroscope. Irrigation from the nephroscope was adjusted to 40-160 mmHg using an automatic irrigation device, and the irrigation of the ureteroscope was by spontaneous dripping at 80 cmH2O. Conditions were measured six times, and the renal pelvic pressure was compared in different conditions. RESULTS: Without ureteroscope insertion through the ureteral access sheath, the renal pelvic pressure never exceeded 30 mmHg. Meanwhile, when the ureteroscope was inserted, the renal pelvic pressure increased as the nephrostomy sheath and ureteral access sheath became narrower and as the irrigation pressure increased. Intrarenal pelvic pressure exceeded 30 mmHg when the irrigation pressure was increased in 12/14 Fr ureteral access sheath when MIP-XS was used, and in 10/12 Fr ureteral access sheath when MIP-XS and MIP-S were used. CONCLUSIONS: The use of a thin nephrostomy sheath in endoscopic combined intrarenal surgery can lead to increased intrarenal pelvic pressure. Although our results are from an artificial kidney model, special care is suggested to be required when using a retrograde flexible ureteroscope simultaneously in treatment of patients.

Poor performance status is a risk factor for higher detection of Gram positive coccus in stone-related pyelonephritis.

INTRODUCTION: We aimed to investigate the detection rate of causative organisms in stone-related pyelonephritis and to compare their distribution according to patient backgrounds. METHODS: We retrospectively identified patients with stone-related pyelonephritis. Clinical data were collected between November 2012 and August 2020 at Wakayama Medical University Hospital, including on patient backgrounds and causative organisms. Patients were categorized by Eastern Cooperative Oncology Group performance status (PS) as the good PS group (0, 1) and the poor PS group (2-4). Bacteria were divided into Gram-positive cocci (GPC) or non-GPC groups and logistic regression analysis was used to examine factors that predict detection of GPC. RESULTS: Seventy-nine patients had stone-related pyelonephritis, 54 (68.4 %) in the good PS group and 25 (31.6 %) in the poor PS group. In the good PS group, Escherichia coli (67 %) was followed by Klebsiella species (9 %), while in the poor PS group, Escherichia coli (20 %) was followed by Enterococci and Staphylococci (12 %). GPC detection rate was significantly higher in the poor PS group than in the good PS group (40.0 % vs 14.8 %, p = 0.016), and multivariate logistic regression analysis showed that poor PS was an independent factor predicting detection of GPC (OR = 6.54, p = 0.02). CONCLUSIONS: The distribution of the causative organisms in stone pyelonephritis was similar to that in common complicated urinary tract infections. Poor PS may be an independent predictor of GPC detection in patients with stone pyelonephritis.

Local extension findings on MRI compensate for the ability of pathological staging to predict oncological outcome.

BACKGROUND: We investigated whether local extension findings on preoperative MRI and excisional pathology are associated with positive surgical margin and biochemical recurrence after robot-assisted radical prostatectomy. METHODS: We identified 704 of our patients that underwent robot-assisted radical prostatectomy between 2012 and 2020, and extracted the 326 patients who had preoperative MRI scans and a radiologist reading. These patients were classified into groups according to the presence of local extension on MRI and pathological findings: ≤ cT2pT2 (195 cases), ≤ cT2pT3 (55 cases), cT3pT2 (31 cases), and cT3pT3 (45 cases). We compared positive surgical margin and biochemical recurrence between them. RESULTS: Median age was 69 years, positive surgical margin rate was 20.2%, and five-year biochemical recurrence rate was 20.3%. Of the 226 patients without local invasion on excisional pathology, those with local extension on MRI (cT3pT2) had relatively higher positive surgical margin rate (29.0% vs. 14.4%, p = 0.05) and significantly higher five-year biochemical recurrence rate (25.8% vs. 9.3%, p = 0.01) than those without local extension on MRI (≤ cT2pT2). Similarly, among the 100 patients with local extension on excisional pathology, those with cT3pT3 had relatively higher positive surgical margin (37.8% vs. 21.8%, p = 0.08) and significantly higher five-year biochemical recurrence (53.3% vs. 29.3%, p = 0.01) than those with ≤ cT2pT3. In multivariate analysis, local extension on MRI was an independent predictor of biochemical recurrence (OR 2.1, 95%CI 1.1-3.9, p = 0.01). CONCLUSIONS: Local extension on MRI is a prognostic factor independent of pathological stage. The use of MRI may complement the prognostic value of excisional pathology of prostate cancer.

Significance of androgen-deprivation therapy for intermediate- and high-risk prostate cancer treated with high-dose radiotherapy: A literature review.

The real-world benefits of adding androgen-deprivation therapy (ADT) and its optimal duration when combined with current standard high-dose radiation therapy (RT) remain unknown. We aimed to assess the efficacy of and toxicities associated with ADT in the setting of combination with high-dose RT for intermediate-risk (IR) and high-risk (HR) prostate cancer (PCa). This article is a modified and detailed version of the commentary on Clinical Question 8 described in the Japanese Clinical Practice Guidelines for Prostate Cancer (ver. 2023). A qualitative systematic review was performed according to the Minds Guide. All relevant published studies between September 2010 and August 2020, which assessed the outcomes of IR or HR PCa treated with high-dose RT, were screened using two databases (PubMed and ICHUSHI). A total of 41 studies were included in this systematic review, mostly consisting of retrospective studies (N = 34). The evidence basically supports the benefit of adding ADT to high-dose RT to improve tumor control. Regarding IR populations, many studies suggested the existence of a subgroup for which adding ADT had no impact on either overall survival or the BF-free duration. On the other hand, regarding HR populations, several studies suggested the positive impact of adding ADT for ≥1 year on overall survival. Adding ADT increases not only the risk of sexual dysfunction but also that of cardiovascular toxicities or bone fracture. Although the benefit of adding ADT was basically suggested for both IR and HR populations, further investigations are warranted to identify subgroups of patients for whom ADT has no benefit, as well as the appropriate duration of ADT for those who do derive benefit.

Myosteatosis as a novel predictor of new-onset diabetes mellitus after kidney transplantation.

OBJECTIVES: We evaluate the effect of myosteatosis on new-onset diabetes mellitus after kidney transplantation. METHODS: Consecutive patients who had renal transplant between 2006 and 2021 were reviewed, and 219 patients were finally included. Psoas muscle index was used to evaluate sarcopenia and average total psoas density (calculated by computed tomography before surgery) for myosteatosis. We used Cox proportional regression analyses in investigation of whether skeletal muscle depletion before surgery inclusive of sarcopenia and myosteatosis is a new additional predictor of new-onset diabetes mellitus. RESULTS: Median recipient age and body mass index were 45 years and 21.1 kg/m2 , respectively, and 123 patients (56%) were male. Preoperative impaired glucose tolerance was present in 58 patients (27%) and new-onset diabetes mellitus in 30 patients (14%), with median psoas muscle index of 6 cm2 /m2 and average total psoas density of 41 Hounsfield Unit. In multivariate analysis, significant risk factors were body mass index ≥25 kg/m2 (p < 0.01), impaired glucose tolerance (p < 0.01), and average total psoas density < 41.9 Hounsfield Unit (p = 0.03). New-onset diabetes mellitus had incidence rates of 3.7% without risk factors, 10% with a single risk factor, 33% with two, and 60% with three. Patients with new-onset diabetes mellitus were effectively stratified by the number of risk factors (p < 0.01). CONCLUSIONS: Myosteatosis could be a new risk factor used to predict new-onset diabetes mellitus.

In vitro comparison of simulated intrapelvic pressure in an artificial kidney model during retrograde intrarenal surgery among various single-use ureteroscopes.

OBJECTIVES: This study compares intrapelvic pressure (IPP) during retrograde intrarenal surgery with various single-use flexible ureteroscopes (f-URS) in an artificial kidney model. METHODS: We created an artificial kidney model with a pressure sensor using a bladder evacuation device. The model was completely closed and the only backflow was on the side of the ureteroscope inside the ureteral access sheath (UAS). We tested five single-use f-URSs (LithoVue, Wiscope, PU3022A, PU3033A, and AXIS) with six different types of UAS (9.5/11.5-14/16 Fr). Using the automatic irrigation system, 30 s of irrigation was performed at various pressures (40-180 mmHg) and steady-state IPP was recorded. IPP was compared between the five single-use f-URSs. IPP cutoff value was determined at 30 mmHg. The diameter of the endoscope tip and the curved and shaft parts were also measured and recorded. RESULTS: The diameters of all parts were significantly different between single-use f-URSs. The maximum IPP tended to be higher in ureteroscopes with larger diameters of the proximal parts (curved part/shaft part). In LithoVue and Uscope PU3022A f-URSs, the maximum IPP did not exceed 30 mmHg when UAS ≥12/14 Fr was used. In AXIS and Wiscope f-URSs, it did not exceed the cutoff value when the UAS ≥11/13 Fr was used. In Uscope PU3033A f-URS, it did not exceed 30 mmHg when the UAS ≥10/12 Fr was used. CONCLUSIONS: Maximum IPP tended to be higher in f-URSs with larger diameters of the proximal part and the appropriate size of the UAS differed between various single-use f-URSs.

Pharmacotherapy for patients with calcium oxalate stones and abnormal urine chemistry: A systematic review and meta-analysis for the Japanese Clinical Practice Guidelines for the Management of Urinary Stones, Third Edition.

We performed a systematic review and meta-analysis to evaluate the benefits and harms of pharmacotherapies for patients with calcium oxalate stones and abnormal urine chemistry. This article is a modified and detailed version of the commentary on Clinical Question 10 described in the Japanese Clinical Practice Guidelines for the Management of Urinary Stones, Third Edition. PubMed and Ichushi Web were searched through August 2020 for articles on pharmacotherapies for calcium oxalate stones (thiazides, citrate preparations, uric acid production inhibitors, and magnesium preparations). Two reviewers independently selected randomized controlled trials reporting reduction of stone recurrence and adverse drug reactions as outcomes and performed data extraction and quality assessment. Meta-analyses with random effects models and rating of the strength of evidence were performed. Pharmacotherapies were shown to significantly reduce stone recurrence (risk ratio 0.47, 95% confidence interval 0.35-0.63). Meanwhile, the pharmacotherapies increased adverse drug reactions leading to study dropout (risk ratio 2.51, 95% confidence interval 1.09-5.75) and adverse drug reactions/adverse events (risk ratio 1.95, 95% confidence interval 1.07-3.56). The reported adverse drug reactions were, however, mainly minor and did not frequently require discontinuation of medication (2%-16%). The strengths of evidence for both outcomes were rated as moderate, because the risk of bias, indirectness, inconsistency, imprecision, and publication bias were all serious except for one item. The overall strength of evidence across outcomes was therefore determined to be moderate. These results support the conditional recommendation to initiate pharmacotherapies for patients with calcium oxalate stones and abnormal urine chemistry.

Japanese clinical practice guidelines for prostate cancer 2023.

This fourth edition of the Japanese Clinical Practice Guidelines for Prostate Cancer 2023 is compiled. It was revised under the leadership of the Japanese Urological Association, with members selected from multiple academic societies and related organizations (Japan Radiological Society, Japanese Society for Radiation Oncology, the Department of EBM and guidelines, Japan Council for Quality Health Care (Minds), Japanese Society of Pathology, and the patient group (NPO Prostate Cancer Patients Association)), in accordance with the Minds Manual for Guideline Development (2020 ver. 3.0). The most important feature of this revision is the adoption of systematic reviews (SRs) in determining recommendations for 14 clinical questions (CQs). Qualitative SRs for these questions were conducted, and the final recommendations were made based on the results through the votes of 24 members of the guideline development group. Five algorithms based on these results were also created. Contents not covered by the SRs, which are considered textbook material, have been described in the general statement. In the general statement, a literature search for 14 areas was conducted; then, based on the general statement and CQs of the Japanese Clinical Practice Guidelines for Prostate Cancer 2016, the findings revealed after the 2016 guidelines were mainly described. This article provides an overview of these guidelines.

Implication of KMT2C and TSC2 variants in the tumorigenesis of acquired cystic disease-associated renal cell carcinomas.

In 2020, acquired cystic disease-associated renal cell carcinomas (ACD-RCCs) were reported to harbor KMT2C and TSC2 variants: however, their carcinogenic implication has not yet been reported. This study aimed to explore the variant features of KMT2C and TSC2 in ACD-RCC and their implication in ACD-RCC tumorigenesis. Eleven ACD-RCCs, 10 ACD-RCC-like cysts, and 18 background kidneys were retrieved. The background kidneys consisted of atrophic thyroid follicle-like tubules. They included four with clustered cysts, two with eosinophilic changes, and one each with clear cell changes and sieve-like changes in the renal tubules. First, DNA-targeted sequencing of KMT2C and TSC2 whole exons was performed on eight ACD-RCC samples. Subsequently, a custom DNA panel was designed to include the recurrent KMT2C and TSC2 variants based on the sequencing results. Second, DNA-targeted sequencing was performed on the remaining samples using a custom panel targeting the recurrent variants. Additionally, immunohistochemistry was performed for KMTC, H3K4me1, H3K4me3, TSC2, and GPNMB on the ACD-RCCs. Six of the 11 ACD-RCC cases harbored KMT2C and TSC2 variants, including nine likely pathogenic variants. In contrast to ACD-RCC, 1 of the 9 ACD-RCC-like cysts harbored both variants. Immunohistochemical analysis did not support the loss of function in ACD-RCCs harboring KMT2C and TSC2 variants. KMT2C and TSC2 variant frequencies were higher in ACD-RCC than in other renal cell carcinomas. However, KMT2C and TSC2 are unlikely to be the primary drivers of ACD-RCC development.

Lower extremity pain and/or numbness after laparoscopic surgery and robot-assisted surgery in the lithotomy position combined with the Trendelenburg position.

PURPOSE: The purpose of this study was to investigate the incidence and risk factors of lower extremity pain and/or numbness after laparoscopic colorectal surgery and robot-assisted laparoscopic radical prostatectomy in the lithotomy position combined with the Trendelenburg position. The relationship between creatine kinase (CK) levels and lower extremity pain and/or numbness was also investigated. METHODS: We retrospectively reviewed adult patients who underwent laparoscopic colorectal surgery and robot-assisted laparoscopic radical prostatectomy in the lithotomy position combined with the Trendelenburg position between May 2015 and April 2020. Logistic regression analysis was used to identify risk factors of lower extremity pain and/or numbness. Preoperative and postoperative CK levels were compared in patients with and those without lower extremity pain and/or numbness. RESULTS: Among 940 patients, 1.9% experienced lower extremity pain and/or numbness postoperatively. The incidences of lower extremity pain and/or numbness after laparoscopic colorectal surgery and after robot-assisted laparoscopic radical prostatectomy were 1.7% and 2.1%, respectively. Multivariate logistic regression analysis revealed that only duration of surgery > 4 h (odds ratio = 3.144, 95% CI: 1.102-8.969, p = 0.032) was a significant predictor of lower extremity pain and/or numbness. Postoperative median CK level in patients with lower extremity pain and/or numbness was significantly higher than that in patients without lower extremity pain and/or numbness. CONCLUSION: The incidence of lower extremity pain and/or numbness after laparoscopic colorectal surgery was comparable to that after robot-assisted laparoscopic radical prostatectomy. Prolonged duration of surgery contributed to lower extremity pain and/or numbness. Significantly elevated CK levels in patients with lower extremity pain and/or numbness suggest the involvement of muscle injury in these symptoms.

Prognostic significance of pre-treatment albumin-bilirubin grade in metastatic urothelial carcinoma receiving pembrolizumab.

BACKGROUND: Pre-treatment albumin-bilirubin grade is a useful biomarker for predicting prognosis in patients receiving immune checkpoint inhibitors for advanced malignancies. We evaluated the prognostic impact of pre-treatment albumin-bilirubin grade in patients receiving pembrolizumab for metastatic urothelial carcinoma. METHODS: In this multicenter retrospective study, we calculated pre-treatment albumin-bilirubin scores of 96 patients who received pembrolizumab for metastatic urothelial carcinoma between January 2018 and March 2022. Patients were classified according to albumin-bilirubin grade. Progression-free survival and cancer-specific survival were compared between the groups. To evaluate the prognostic impact of pre-treatment albumin-bilirubin grade, we also performed Cox proportional regression analyses for progression-free survival and cancer-specific survival. RESULTS: The median pre-treatment albumin bilirubin score was -2.52 (quartile: -2.76 to -2.10), and albumin-bilirubin grade was grade 1 in 37 patients (39%), grade 2a in 30 patients (31%), 2b in 22 patients (23%) and grade 3 in 7 patients (7%). The median progression-free survival and cancer-specific survival were 2 and 7 months, respectively. Progression-free survival and cancer-specific survival were significantly different between the albumin-bilirubin grade groups (P < 0.01 and P < 0.01, respectively) and prognosis became poorer as albumin-bilirubin grade increased. High albumin-bilirubin grade was shown in multivariable Cox proportional analyses to be independently associated with both poor progression-free survival and poor cancer-specific survival. CONCLUSIONS: High pre-treatment albumin-bilirubin grade could be a significant independent predictor of poor prognosis in patients receiving pembrolizumab for advanced urothelial carcinoma.

Increasing age predicts adverse pathology including intraductal carcinoma of the prostate and cribriform patterns in deferred radical prostatectomy after upfront active surveillance for Gleason grade group 1 prostate cancer: analysis of prospective observational study cohort.

BACKGROUND: In men undergoing upfront active surveillance, predictors of adverse pathology in radical prostatectomy specimens, including intraductal carcinoma of the prostate and cribriform patterns, remain unknown. Therefore, we aimed to examine whether adverse pathology in radical prostatectomy specimens could be predicted using preoperative patient characteristics. METHODS: We re-reviewed available radical prostatectomy specimens from 1035 men prospectively enrolled in the PRIAS-JAPAN cohort between January 2010 and September 2020. We defined adverse pathology on radical prostatectomy specimens as Gleason grade group ≥3, pT stage ≥3, pN positivity or the presence of intraductal carcinoma of the prostate or cribriform patterns. We also examined the predictive factors associated with adverse pathology. RESULTS: All men analyzed had Gleason grade group 1 specimens at active surveillance enrolment. The incidence of adverse pathologies was 48.9% (with intraductal carcinoma of the prostate or cribriform patterns, 33.6%; without them, 15.3%). The addition of intraductal carcinoma of the prostate or cribriform patterns to the definition of adverse pathology increased the incidence by 10.9%. Patients showing adverse pathology with intraductal carcinoma of the prostate or cribriform patterns had lower biochemical recurrence-free survival (log-rank P = 0.0166). Increasing age at active surveillance enrolment and before radical prostatectomy was the only predictive factor for adverse pathology (odds ratio: 1.1, 95% confidence interval: 1.02-1.19, P = 0.0178; odds ratio: 1.12, 95% confidence interval: 1.02-1.22, P = 0.0126). CONCLUSIONS: Increasing age could be a predictive factor for adverse pathology. Our findings suggest that older men could potentially derive advantages from adhering to the examination schedule in active surveillance.

Clinical outcomes of intraductal carcinoma or cribriform in radical prostatectomy specimens of men opting for active surveillance: data from the PRIAS-JAPAN study.

BACKGROUND: Among early stage prostate cancer patients, intraductal carcinoma of the prostate (IDC-P) and invasive cribriform are key prognostic factors; however, their presence and clinical significance following active surveillance (AS) are unknown. In men who opted for AS, we aimed to examine the presence and impact of IDC-P or cribriform, utilizing radical prostatectomy (RP) specimens. METHODS: We re-reviewed 137 RP specimens available in the PRIAS-JAPAN prospective cohort between January 2010 and September 2020. We assessed the presence of IDC-P or cribriform, and compared the patients' characteristics and prostate-specific antigen (PSA) recurrence-free survival after RP between groups with and without IDC-P or cribriform. In addition, we examined the predictive factors associated with IDC-P or cribriform. RESULTS: The percentage of patients with IDC-P or cribriform presence was 34.3% (47 patients). IDC-P or cribriform pattern was more abundant in the higher Gleason grade group in RP specimens (P < 0.001). The rates of PSA recurrence-free survival were significantly lower in the IDC-P or cribriform groups than in those without them (log rank P = 0.0211). There was no association between IDC-P or cribriform on RP with the Prostate Imaging-Reporting and Data System (PI-RADS) 4,5 score on magnetic resonance imaging (MRI) before RP even with adjustments for other covariates (OR, 1.43; 95% confidence interval [CI] 0.511-3.980, P = 0.497). CONCLUSIONS: IDC-P or cribriform comprised approximately one-third of all RP specimens in men who underwent RP following AS, confirming their prognostic significance.

High aldehyde dehydrogenase 1 activity is related to radiation resistance due to activation of AKT signaling after insulin stimulation in prostate cancer.

The association between type 2 diabetes mellitus and prostate cancer is still under investigation, and the relationship between hyperinsulinemia and prostate cancer stem-like cells (CSCs) is elusive. Here, we investigated the function of insulin/AKT signaling in prostate CSCs. We isolated prostate CSCs as aldehyde dehydrogenase 1-high (ALDH1high) cells from the human prostate cancer 22Rv1 cell line using an ALDEFLUOR assay and established several ALDH1high and ALDH1low clones. ALDH1high clones showed high ALDH1 expression which is a putative CSC marker; however, they showed heterogeneity regarding tumorigenicity and resistance to radiation and chemotherapy. Interestingly, all ALDH1high clones showed lower phosphorylated AKT (Ser473) (pAKT) levels than the ALDH1low clones. PI3K/AKT signaling is a key cell survival pathway and we analyzed radiation resistance under AKT signaling activation by insulin. Insulin increased pAKT levels in ALDH1high and ALDH1low cells; the fold increase rate of pAKT was higher in ALDH1high cells than in ALDH1low cells. Insulin induced resistance to radiation and chemotherapy in ALDH1high cells, and the increased levels of pAKT induced by insulin were significantly related to radiation resistance. These results suggest that ALDH1 suppresses baseline pAKT levels, but AKT can be activated by insulin, leading to treatment resistance.

Comprehensive endoscopic management of impacted ureteral stones: Literature review and expert opinions.

Treatment of urolithiasis, a benign disease, requires high efficacy and safety. Endoscopic treatment of impacted ureteral stones remains a challenging procedure for urologists, despite recent remarkable advances in surgical technology in treatment of urolithiasis. The success rate of endoscopic treatment in patients with impacted stones is reported to be lower than that in patients with nonimpacted stones. Moreover, the presence of stone impaction is associated with high rates of intraoperative and postoperative complications. The best management for patients with impacted ureteral stones should therefore be devised based on the latest knowledge and techniques. The present review focuses on the preoperative prediction of stone impaction, the safest and most effective endoscopic surgical procedures, and the most appropriate management for postoperative ureteral strictures. We overview comprehensive endoscopic management for impacted ureteral stones based on literature review and expert opinions.

Hinotori Surgical Robot System, a novel robot-assisted surgical platform: Preclinical and clinical evaluation.

OBJECTIVES: To evaluate the safety and efficacy of the hinotori™ Surgical Robot System in preclinical and clinical studies. METHODS: Preclinical studies on 10 living female porcine and four fresh male cadavers were conducted. Different types of urologic surgical procedures were performed by experienced urological surgeons using the hinotori system: partial nephrectomy, vesicourethral anastomosis, and pelvic lymph node dissection in porcine, and partial nephrectomy, radical prostatectomy, and pelvic lymph node dissection in cadavers. In a multi-institutional single-arm clinical study, radical prostatectomy was performed in 30 patients with localized prostate cancer to evaluate safety outcomes. The primary endpoint was safety profiles, including device errors and perioperative complications, and the secondary endpoints were console time, blood loss, and positive surgical margin rate. RESULTS: The preclinical results were similar to those reported for the daVinci surgical system. The performance of the hinotori was equivalent to that of the daVinci surgical system, based on a global assessment by the surgeons. Safety was confirmed in a first-in-human clinical study of robot-assisted radical prostatectomy using hinotori in 30 patients. The procedures were completed as planned in all cases, and three (10%) perioperative adverse events were observed. CONCLUSIONS: The safety of the newly developed hinotori surgical system was shown in the present preclinical and clinical studies. Further studies are required to confirm its clinical efficacy.

Myosteatosis as a novel predictor of urinary incontinence after robot-assisted radical prostatectomy.

OBJECTIVES: To evaluate the impact of sarcopenia and myosteatosis on urinary incontinence after prostatectomy. METHODS: We retrospectively reviewed consecutive patients who underwent robot-assisted radical prostatectomy without nerve sparing between December 2012 and March 2019. Psoas muscle index and average total psoas density, which were measured on preoperative computed tomography images at level L3, were used to evaluate sarcopenia and myosteatosis, respectively. In addition, several magnetic resonance imaging variables associated with pelvic muscles, the urethra and the prostate were measured. Urinary continence was defined as non-use or use of just one incontinence pad per day. Logistic regression analyses aimed to identify the predictors of urinary incontinence 3 and 12 months after surgery. RESULTS: Overall, 121 patients were included in the analysis. The incidence rates of urinary incontinence 3 and 12 months after surgery were 42% (51/121 cases) and 16% (19/121 cases), respectively. Logistic multivariable analysis showed that low average total psoas density was the only significant independent predictor of urinary incontinence 3 months after surgery (P < 0.01), and low obturator internus muscle thickness (P = 0.01), short membranous urethral length (P = 0.01) and low average total psoas density (P < 0.01) were significant independent predictors of urinary incontinence 12 months after surgery. By contrast, psoas muscle index was not statistically associated with urinary incontinence after surgery. CONCLUSIONS: Myosteatosis (low average total psoas density) could be a novel predictor of urinary incontinence after robot-assisted radical prostatectomy.