Transvesical bladder diverticulectomy via bladder neck opening during robot-assisted radical prostatectomy.

INTRODUCTION: As bladder diverticula in older adults are often secondary to bladder outlet obstruction, bladder diverticulectomy is often performed with prostate treatment. Cases of sequentially performed robot-assisted bladder diverticulectomy and prostatectomy have been reported; however, performing cystotomy for each procedure may increase the risk of complications and prolong operative time. MATERIALS AND SURGICAL TECHNIQUE: We reported the cases of three patients who underwent diverticulectomy without additional cystotomy via the bladder opening during robot-assisted laparoscopic radical prostatectomy in our hospital. DISCUSSION: This technique corresponds to a transvesical approach through the bladder neck opening. Hence, it is especially useful for well-visualized diverticula close to the ureteral orifice or on the posterior wall. Although other approaches may be better depending on the location of the diverticulum, it is considered a reasonable approach that does not require an additional cystotomy.

Impact of the coronavirus disease pandemic on robot-assisted radical prostatectomy and urologists' treatment behaviors: A single tertiary center retrospective study.

OBJECTIVES: To assess whether the coronavirus disease (COVID-19) pandemic affected the outcomes of robot-assisted radical prostatectomy (RARP) and urologists' treatment behaviors. METHODS: We retrospectively examined the medical records of 208 patients who had undergone RARP between August 2017 and December 2022. We compared the rate of preoperative androgen deprivation therapy (ADT), waiting period for RARP, patients' baseline characteristics and quality of life (QOL), proportion of adverse pathology on the RARP specimen, rate of Gleason grade group upgrading from biopsy to the RARP specimen, and prostate-specific antigen (PSA) recurrence-free survival between the pre-pandemic and pandemic groups. RESULTS: The rate of preoperative ADT was significantly higher during than before the COVID-19 pandemic (13.7% vs. 1.9%; p = 0.002). The baseline physical and mental QOL scores did not differ significantly between the groups. The proportion of D'Amico low-risk patients was significantly lower (13.6% vs. 1.2%, p = 0.005) and waiting period for RARP was significantly shorter (median 3.5 months vs. 4.0 months, p = 0.016) in the pandemic group than in the pre-pandemic group. There was no significant difference in the proportion of adverse pathology between the groups (p = 0.104); however, the upgrading rate was significantly higher in the pre-pandemic group (p = 0.002). There was no significant difference in PSA recurrence-free survival between the groups (log-rank, p = 0.752). CONCLUSIONS: The COVID-19 pandemic did not adversely affect the oncologic outcomes of RARP and QOL before RARP. However, it caused urologists to increase the use of preoperative ADT and to reserve RARP for higher-risk cases.

Impact of frailty on cancer-related fatigue and quality of life in outpatients with prostate cancer: a cross-sectional study of patient-reported outcomes.

OBJECTIVE: To investigate the prevalence of frailty and its effects on cancer-related fatigue and quality of life among patients with prostate cancer. METHODS: In this cross-sectional study, questionnaires were administered to 254 outpatients who visited the Department of Urology at Kagawa University Hospital for prostate cancer; finally, 108 outpatients were analyzed. Frailty, cancer-related fatigue and quality of life were assessed using the G8 screening tool, Japanese version of the Brief Fatigue Inventory and Japanese version of the Short Form 8 Health Survey, respectively. We defined frailty based on a score ≤14 points and divided the patients into frailty and no-frailty groups. We also compared the severity of cancer-related fatigue and quality of life between groups. RESULTS: The prevalence of frailty among 108 outpatients was 63%. Older age correlated with frailty severity (P = 0.0007) but not cancer-related fatigue severity (P = 0.2391). The proportion of patients on treatment or with metastasis was not significantly different between groups. The frailty group had higher cancer-related fatigue severity (P = 0.004) and decreased levels of general activity, mood, walking ability, normal work and enjoyment of life, especially on the Brief Fatigue Inventory subscale. The frailty group had lower physical and mental quality of life than the no-frailty group or general population. CONCLUSIONS: The frailty rate for these patients increased with age, exceeding 60% regardless of the treatment status, and was associated with worsened cancer-related fatigue severity and reduced quality of life. Our study highlights the importance of assessing frailty when selecting treatment, especially in older patients.

Peripheral neuropathy and nerve electrophysiological changes with enfortumab vedotin in patients with advanced urothelial carcinoma: a prospective multicenter cohort study.

BACKGROUND: Enfortumab vedotin is a novel antibody-drug conjugate used as a third-line therapy for the treatment of urothelial cancer. We aimed to elucidate the effect of enfortumab vedotin-related peripheral neuropathy on its efficacy and whether enfortumab vedotin-induced early electrophysiological changes could be associated with peripheral neuropathy onset. METHODS: Our prospective multicenter cohort study enrolled 34 patients with prior platinum-containing chemotherapy and programmed cell death protein 1/ligand 1 inhibitor-resistant advanced urothelial carcinoma and received enfortumab vedotin. The best overall response, progression-free survival, overall survival, and safety were assessed. Nerve conduction studies were also performed in 11 patients. RESULTS: The confirmed overall response rate and disease control rate were 52.9% and 73.5%, respectively. The median overall progression-free survival and overall survival were 6.9 and 13.5 months, respectively, during a median follow-up of 8.6 months. The patients with disease control had significantly longer treatment continuation and overall survival than did those with uncontrolled disease. Peripheral neuropathy occurred in 12.5% of the patients. The overall response and disease control rates were 83.3% and 100%, respectively: higher than those in patients without peripheral neuropathy (p = 0.028 and p = 0.029, respectively). Nerve conduction studies indicated that enfortumab vedotin reduced nerve conduction velocity more markedly in sensory nerves than in motor nerves and the lower limbs than in the upper limbs, with the sural nerve being the most affected in the patients who developed peripheral neuropathy (p = 0.011). CONCLUSION: Our results indicated the importance of focusing on enfortumab vedotin-induced neuropathy of the sural nerve to maximize efficacy and improve safety.

A TLR4/TRAF6-dependent signaling pathway mediates NCoR coactivator complex formation for inflammatory gene activation.

The nuclear receptor corepressor (NCoR) forms a complex with histone deacetylase 3 (HDAC3) that mediates repressive functions of unliganded nuclear receptors and other transcriptional repressors by deacetylation of histone substrates. Recent studies provide evidence that NCoR/HDAC3 complexes can also exert coactivator functions in brown adipocytes by deacetylating and activating PPARγ coactivator 1α (PGC1α) and that signaling via receptor activator of nuclear factor kappa-B (RANK) promotes the formation of a stable NCoR/HDAC3/PGC1ß complex that coactivates nuclear factor kappa-B (NFκB)- and activator protein 1 (AP-1)-dependent genes required for osteoclast differentiation. Here, we demonstrate that activation of Toll-like receptor (TLR) 4, but not TLR3, the interleukin 4 (IL4) receptor nor the Type I interferon receptor, also promotes assembly of an NCoR/HDAC3/PGC1ß coactivator complex. Receptor-specific utilization of TNF receptor-associated factor 6 (TRAF6) and downstream activation of extracellular signal-regulated kinase 1 (ERK1) and TANK-binding kinase 1 (TBK1) accounts for the common ability of RANK and TLR4 to drive assembly of an NCoR/HDAC3/PGC1ß complex in macrophages. ERK1, the p65 component of NFκB, and the p300 histone acetyltransferase (HAT) are also components of the induced complex and are associated with local histone acetylation and transcriptional activation of TLR4-dependent enhancers and promoters. These observations identify a TLR4/TRAF6-dependent signaling pathway that converts NCoR from a corepressor of nuclear receptors to a coactivator of NFκB and AP-1 that may be relevant to functions of NCoR in other developmental and homeostatic processes.

RANK ligand converts the NCoR/HDAC3 co-repressor to a PGC1ß- and RNA-dependent co-activator of osteoclast gene expression.

The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression. Mechanistically, RANK signaling promotes RNA-dependent interaction of the transcriptional co-activator PGC1ß with the NCoR/HDAC3 complex, resulting in the activation of PGC1ß and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12, which are associated with altered human bone homeostasis, promote NCoR/HDAC3 complex assembly and are necessary for RANKL-induced osteoclast differentiation in vitro. These findings may be prototypic for signal-dependent functions of NCoR in other biological contexts.

Discrimination of cell-intrinsic and environment-dependent effects of natural genetic variation on Kupffer cell epigenomes and transcriptomes.

Noncoding genetic variation drives phenotypic diversity, but underlying mechanisms and affected cell types are incompletely understood. Here, investigation of effects of natural genetic variation on the epigenomes and transcriptomes of Kupffer cells derived from inbred mouse strains identified strain-specific environmental factors influencing Kupffer cell phenotypes, including leptin signaling in Kupffer cells from a steatohepatitis-resistant strain. Cell-autonomous and non-cell-autonomous effects of genetic variation were resolved by analysis of F1 hybrid mice and cells engrafted into an immunodeficient host. During homeostasis, non-cell-autonomous trans effects of genetic variation dominated control of Kupffer cells, while strain-specific responses to acute lipopolysaccharide injection were dominated by actions of cis-acting effects modifying response elements for lineage-determining and signal-dependent transcription factors. These findings demonstrate that epigenetic landscapes report on trans effects of genetic variation and serve as a resource for deeper analyses into genetic control of transcription in Kupffer cells and macrophages in vitro.

Impact of renal sinus protrusions on achieving trifecta in robot-assisted partial nephrectomy.

Objective: The objective of this work is to assess the relationship between the morphological characteristics of a central tumour and the perioperative outcomes of robot-assisted partial nephrectomy (RAPN). Subjects and Methods: We retrospectively analysed the data from 186 patients with central tumours involving the renal sinus, who underwent RAPN in a single-centre study between February 2015 and June 2022. All cases were assigned a RENAL nephrometry score based on preoperative images. The shape of the protruding portion of the tumour was classified into four types: 'flat', 'spherical', 'single-hump', and 'complex-hump', and was independently assessed by two readers. The trifecta is defined as the warm ischemia time within 25 min, negative surgical margins, and no major postoperative complications. Univariate and multivariate analyses were performed to identify the factors associated with the failing trifecta. Results: Trifecta was achieved in 113 cases (60.8%), and the achievement rate in flat, spherical, single-hump, and complex-hump types was 83.3%, 74.5%, 64.3%, and 21.3%, respectively. Prolonged warm ischemia time was the primary cause of the failure to achieve the trifecta. The rate of positive surgical margins and upstage to pathological T3a was greater for complex humps while the rate of major complications and postoperative GFR preservation did not differ between shapes. On multivariate analysis for failing trifecta achievement, the complex-hump protrusion was found to be an independent positive predictor (odds ratio: 15.8; p < 0.001), whereas the height and width of protrusion were not significantly related. Conclusions: The degree of difficulty varied among central tumours, and it was not possible to precisely measure it with existing scoring systems. Complex-hump protrusions strongly correlate with failure to achieve the trifecta. Preoperative assessment of the morphology of protrusion is useful for predicting outcomes.

Oral 5-aminolevulinic acid administration before transurethral resection of bladder tumor induces perioperative nausea and vomiting.

BACKGROUND: The efficacy of photodynamic diagnosis using 5-aminolevulinic acid during transurethral resection of bladder tumors has been demonstrated, albeit with limited information regarding its side effects. This study aimed to clarify the impact of oral 5-aminolevulinic acid on perioperative nausea and vomiting (NV) for the first time in a real-world clinical practice setting. METHODS: Patients who underwent transurethral surgery at Kagawa University between April 2017 and March 2020 were included. Perioperative NV and antiemetic use status were prospectively assessed and compared between the patients who received oral 5-aminolevulinic acid and those who did not. Additionally, univariate and multivariate analyses were performed for predicting postoperative nausea and vomiting. RESULTS: Of 214 patients, 74 (34.6%) received oral 5-aminolevulinic acid preoperatively. The proportions of preoperative NV and antiemetic use in the patients who received 5-aminolevulinic acid were 9.5% and 4.1%, respectively, and higher than in those who did not (0% and 0%; P < 0.01 and P = 0.04, respectively). Postoperative NV (25.7%) and antiemetics use (8.0%) ratios in the patients who received 5-aminolevulinic acid were significantly different from those in the non-users group (3.6% and 2.1%, P < 0.01 and P < 0.01, respectively). Although no differences in risk factors were found for postoperative NV between the two groups, multivariate analyses indicated 5-aminolevulinic acid use as an independent predictive factor for postoperative NV (odds ratio, 11.5; 95% confidence interval, 3.98-33.3; P < 0.01). CONCLUSIONS: Our study clearly showed that oral administration of 5-aminolevulinic acid was associated with perioperative NV even without risk factors, highlighting the need for addressing its application.

[A Case of Retroperitoneal Lymphangioleiomyomatosis].

Contrast-enhanced computed tomography (CT) revealed a multilocular cystic mass extending from the level of the renal artery origin to the internal and external iliac artery regions in a woman in her 40s who presented with vomiting and diarrhea. A percutaneous biopsy was performed, and histopathological examination revealed bundle-like proliferations of spindle-shaped cells with oval nuclei in acidophilic cytoplasm. Immunohistochemical staining was positive for HMB-45, alpha-smooth muscle actin, E-cadherin, and estrogen and progesterone receptors; the provisional diagnosis was perivascular epithelioid cell tumor. Considering the patient's age and sex, the final diagnosis was primary retroperitoneal lymphangioleiomyomatosis (LAM). She did not meet the diagnostic criteria for tuberous sclerosis complex and was considered to have sporadic LAM. As complete surgical resection was considered to be impossible and no lung lesions, which indicate poor prognosis, were observed, we decided to keep her under surveillance. The patient was asymptomatic, with no significant changes on imaging for 6 months.

[A Case of m0CRPC after Hormone Therapy for Pelvic Lymph Node Metastasis in which Salvage RARP was Effective].

The patient was a 63-year-old man with biopsy Gleason score of 4＋5 prostate cancer with an initial prostate specific antigen level of (PSA) 51.2ng/ml. On imaging examination, extracapsular invasion, rectal invasion, and pararectal lymph node metastasis were found (cT4N1M0). After 4 years of androgen deprivation therapy, PSA decreased to 0.631ng/ml, and then increased gradually to1.2ng/ml. Computed tomographic scan showed that the primary tumor had shrunk and lymph node metastasis had disappeared; so salvage robot-assisted resection of the prostate (RARP) was performed for non-metastatic castration-resistant prostate cancer (m0CRPC). Since PSA decreased to an undetactable level, hormone therapy was terminated at 1 year. The patient remained recurrence-free for 3 years after surgery. RARP may be effective for m0CRPC, enabling discontinuation of androgen deprivation therapy.

Necessity of prophylactic drainage tube in retroperitoneal laparoscopic nephroureterectomy with open distal ureterectomy: A matched-pair analysis.

OBJECTIVES: To assess the necessity of prophylactic drain placement in retroperitoneal laparoscopic nephroureterectomy with open distal ureterectomy for upper tract urothelial cancer. METHODS: Between July 2011 and March 2021, 200 patients with localized clinical Tis-T3 upper urinary tract urothelial carcinoma underwent laparoscopic nephroureterectomy with open distal ureterectomy. After removing the specimen, drainage tubes were placed on the renal beds and/or in the retrovesical spaces. Drain tubes were omitted for most patients after 2017. We compared the postoperative outcomes between the patients with drain placement (D+ group) and without drain placement (D- group) using propensity score matching. RESULTS: A total of 164 patients (90 in the D+ group and 74 in the D- group) were enrolled, and matched pairs of 108 patients were analyzed. There was no significant difference in the incidence of complications according to Clavien-Dindo grade in the two groups after the propensity score matching. There was no significant difference in the incidence of postoperative lymphocele (n = 5 vs. 9, p = 0.395) and symptomatic lymphocele (n = 1 vs. 1, p = 1) between the two groups. The length of hospital stay was significantly shorter in the D- group (11 vs. 8 days, p < 0.0001). CONCLUSIONS: We found that omitting the drainage tube after laparoscopic radical nephroureterectomy did not increase postoperative complications or lymphocele and shortened the post-hospital stay.

Robot-assisted transperitoneal reconstruction of a retrocaval ureter: A report of two cases.

A retrocaval ureter (RCU) is a rare cause of congenital ureteral obstruction that often requires surgical repair. We report two cases of RCU in adults treated with robot-assisted laparoscopic surgery. In both cases, we performed robotic ureteroureterostomy with dissection of the entire length of the retrocaval portion of the right ureter without complications. In the second case, renal stone removal was simultaneously performed. The robot-assisted procedure we performed could be considered safe and feasible for the surgical repair of an RCU.

Effect of continued perioperative antithrombotic therapy on bleeding outcomes following laparoscopic nephrectomy and nephroureterectomy.

INTRODUCTION: In this study, we aimed to assess the impact of perioperative continuation of antithrombotic therapy on bleeding and complications in patients undergoing laparoscopic radical nephrectomy (LRN) and nephroureterectomy (LNU). METHODS: This was a retrospective observational study. Patients who underwent LRN and LNU between January 2017 and July 2019 at our institution were recruited. All patients taking antithrombotic agents continued taking them during the perioperative phase (AA group). Surgical outcomes of patients in the AA group were compared with those of patients who were not taking antithrombotic agents (NA group). The primary outcome was the rate of bleeding complications. Secondary outcomes included intraoperative estimated blood loss, transfusion rate, and complications for up to 90 days. RESULTS: A total of 100 patients were included in the analysis, with 36 and 64 patients assigned to the AA and NA groups, respectively. Patients in the AA group were found to have more severe comorbidities than those in the NA group, with a Charlson Comorbidity Index ≥5, totaling 14 (39%) and 12 (19%), respectively (P = .03). According to surgical outcomes, none of the patients in the AA group required secondary procedures for bleeding complications. Moreover, there were no significant differences between the groups in intraoperative blood loss, hemoglobin deficit, rate of perioperative transfusion, readmission rate, or high-grade complications. DISCUSSION: These results indicate that perioperative use of antithrombotic agents does not increase the risk of bleeding and can be considered safe during LRN and LNU.

MYPT1-PP1ß phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige adipogenesis.

Protein kinase A promotes beige adipogenesis downstream from ß-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1ß (MYPT1-PP1ß) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1ß depletion results in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1ß also dephosphorylates myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ which directly stimulates Ucp1 gene expression. Pre-adipocyte specific Mypt1 deficiency increases cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice, confirming this regulatory mechanism in vivo. Thus, we have uncovered regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of the mechano-sensitive YAP/TAZ transcriptional co-activators.

Surgical and functional outcomes of robot-assisted versus laparoscopic partial nephrectomy with cortical renorrhaphy omission.

To evaluate the surgical and functional outcomes between robot-assisted (CRO-RAPN) vs. laparoscopic (CRO-LPN) methods of cortical-renorrhaphy-omitting partial nephrectomy. Between July 2012 and June 2020, patients with localized clinical T1-2 renal masses who underwent CRO-RAPN or CRO-LPN were reviewed. The outcomes of the two groups were compared using propensity-score matching. Trifecta was defined as negative surgical margin, warm ischemic time < 25 min, and absence of complications of Clavien-Dindo grade III or more until three months postoperatively. The preservation rate of the estimated glomerular filtration rate (eGFR) was evaluated at six months postoperatively. Among 291 patients (CRO-RAPN, n = 210; CRO-LPN, n = 81) included in the study, 150 matched pairs of patients were analyzed. Compared to the CRO-LPN group, the CRO-RAPN group was associated with shorter warm ischemic time (13 min vs. 20 min, P < 0.001), shorter total operation time (162 min vs. 212 min, P < 0.001), less estimated blood loss (40 mL vs. 119 mL, P = 0.002), lower incidence of overall complications (3% vs. 16%, P = 0.001), higher preservation rate of eGFR at six months postoperatively (93% vs. 89%, P = 0.003), and higher trifecta achievement rate (84% vs. 64%, P = 0.004). CRO-RAPN contributed to shorter warm ischemic time, less blood loss, fewer complications, and higher preservation of renal function, all of which allowed this technique to achieve a higher rate of trifecta compared to CRO-LPN.

RORγt phosphorylation protects against T cell-mediated inflammation.

RAR-related orphan receptor-γ (RORγt) is an essential transcription factor for thymic T cell development, secondary lymphoid tissue organogenesis, and peripheral immune cell differentiation. Serine 182 phosphorylation is a major post-translational modification (PTM) on RORγt. However, the in vivo contribution of this PTM in health and disease settings is unclear. We report that this PTM is not involved in thymic T cell development and effector T cell differentiation. Instead, it is a critical regulator of inflammation downstream of IL-1ß signaling and extracellular signal regulated kinases (ERKs) activation. ERKs phosphorylation of serine 182 on RORγt serves to simultaneously restrict Th17 hyperactivation and promote anti-inflammatory cytokine IL-10 production in RORγt+ Treg cells. Phospho-null RORγtS182A knockin mice experience exacerbated inflammation in models of colitis and experimental autoimmune encephalomyelitis (EAE). In summary, the IL-1ß-ERK-RORγtS182 circuit protects against T cell-mediated inflammation and provides potential therapeutic targets to combat autoimmune diseases.

Monosodium urate crystals regulate a unique JNK-dependent macrophage metabolic and inflammatory response.

Monosodium urate crystals (MSUc) induce inflammation in vivo without prior priming, raising the possibility of an initial cell-autonomous phase. Here, using genome-wide transcriptomic analysis and biochemical assays, we demonstrate that MSUc alone induce a metabolic-inflammatory transcriptional program in non-primed human and murine macrophages that is markedly distinct to that induced by LPS. Genes uniquely upregulated in response to MSUc belong to lipid and amino acid metabolism, glycolysis, and SLC transporters. This upregulation leads to a metabolic rewiring in sera from individuals and mice with acute gouty arthritis. Mechanistically, the initiating inflammatory-metabolic changes in acute gout flares are regulated through a persistent expression and increased binding of JUN to the promoter of target genes through JNK signaling-but not P38-in a process that is different than after LPS stimulation and independent of inflammasome activation. Finally, pharmacological JNK inhibition limits MSUc-induced inflammation in animal models of acute gouty inflammation.

Self-Pierce Riveting of Three Thin Sheets of Aluminum Alloy A5052 and 980 MPa Steel.

Self-pierce riveting of three thin sheets of 980 MPa steel and 5052 aluminum alloy was performed to investigate the effect of sheet configuration on the deforming behaviors of the sheets and the rivet and joint strength. When the lower sheet was aluminum alloy, the joining range was relatively wide, i.e., the interlock hooking the rivet leg tended to be large. In the sheet configuration in which the upper and lower sheets were A5052 and the middle sheet was 980 MPa steel, the rivet leg spread out moderately and the joint without defects was obtained. In the lower 980 MPa steel sheet, fracture tended to occur due to the low ductility of the lower sheet, and the joining range was narrow with the small interlock although the three sheets were joined by an appropriate die shape. In joint strength of joined three sheets, fracture occurred in the lower-strength aluminum alloy sheet if interlocks of about 300 µm and 150 µm could be formed in the lower aluminum alloy sheet and 980 MPa steel sheet, respectively.