The Urothelium: Life in a Liquid Environment.

The urothelium, which lines the renal pelvis, ureters, urinary bladder, and proximal urethra, forms a high-resistance but adaptable barrier that surveils its mechanochemical environment and communicates changes to underlying tissues including afferent nerve fibers and the smooth muscle. The goal of this review is to summarize new insights into urothelial biology and function that have occurred in the past decade. After familiarizing the reader with key aspects of urothelial histology, we describe new insights into urothelial development and regeneration. This is followed by an extended discussion of urothelial barrier function, including information about the roles of the glycocalyx, ion and water transport, tight junctions, and the cellular and tissue shape changes and other adaptations that accompany expansion and contraction of the lower urinary tract. We also explore evidence that the urothelium can alter the water and solute composition of urine during normal physiology and in response to overdistension. We complete the review by providing an overview of our current knowledge about the urothelial environment, discussing the sensor and transducer functions of the urothelium, exploring the role of circadian rhythms in urothelial gene expression, and describing novel research tools that are likely to further advance our understanding of urothelial biology.

Permissive ureter specification by TBX18-mediated repression of metanephric gene expression.

The murine kidney and ureter develop in a regionalized fashion from the ureteric bud and its surrounding mesenchyme. Whereas the factors that establish the metanephric cell lineages have been well characterized, much less is known about the molecular cues that specify the ureter. Here, we have identified a crucial patterning function in this process for Tbx18, a T-box transcription factor gene specifically expressed in the mesenchymal primordium of the ureter. Using misexpression and loss-of-function mice combined with molecular profiling approaches, we show that Tbx18 is required and sufficient to repress metanephric mesenchymal gene programs. We identify Wt1 as a functional target of TBX18. Our work suggests that TBX18 acts as a permissive factor in ureter specification by generating a mesenchymal domain around the distal ureteric bud where SHH and BMP4 signaling can occur.

Notch signaling is a novel regulator of visceral smooth muscle cell differentiation in the murine ureter.

The contractile phenotype of smooth muscle cells (SMCs) is transcriptionally controlled by a complex of the DNA-binding protein SRF and the transcriptional co-activator MYOCD. The pathways that activate expression of Myocd and of SMC structural genes in mesenchymal progenitors are diverse, reflecting different intrinsic and extrinsic signaling inputs. Taking the ureter as a model, we analyzed whether Notch signaling, a pathway previously implicated in vascular SMC development, also affects visceral SMC differentiation. We show that mice with a conditional deletion of the unique Notch mediator RBPJ in the undifferentiated ureteric mesenchyme exhibit altered ureter peristalsis with a delayed onset, and decreased contraction frequency and intensity at fetal stages. They also develop hydroureter 2 weeks after birth. Notch signaling is required for precise temporal activation of Myocd expression and, independently, for expression of a group of late SMC structural genes. Based on additional expression analyses, we suggest that a mesenchymal JAG1-NOTCH2/NOTCH3 module regulates visceral SMC differentiation in the ureter in a biphasic and bimodal manner, and that its molecular function differs from that in the vascular system.

GATA6 is a crucial factor for Myocd expression in the visceral smooth muscle cell differentiation program of the murine ureter.

Smooth muscle cells (SMCs) are a crucial component of the mesenchymal wall of the ureter, as they account for the efficient removal of the urine from the renal pelvis to the bladder by means of their contractile activity. Here, we show that the zinc-finger transcription factor gene Gata6 is expressed in mesenchymal precursors of ureteric SMCs under the control of BMP4 signaling. Mice with a conditional loss of Gata6 in these precursors exhibit a delayed onset and reduced level of SMC differentiation and peristaltic activity, as well as dilatation of the ureter and renal pelvis (hydroureternephrosis) at birth and at postnatal stages. Molecular profiling revealed a delayed and reduced expression of the myogenic driver gene Myocd, but the activation of signaling pathways and transcription factors previously implicated in activation of the visceral SMC program in the ureter was unchanged. Additional gain-of-function experiments suggest that GATA6 cooperates with FOXF1 in Myocd activation and SMC differentiation, possibly as pioneer and lineage-determining factors, respectively.

FGFR2 signaling enhances the SHH-BMP4 signaling axis in early ureter development.

The patterned array of basal, intermediate and superficial cells in the urothelium of the mature ureter arises from uncommitted epithelial progenitors of the distal ureteric bud. Urothelial development requires signaling input from surrounding mesenchymal cells, which, in turn, depend on cues from the epithelial primordium to form a layered fibro-muscular wall. Here, we have identified FGFR2 as a crucial component in this reciprocal signaling crosstalk in the murine ureter. Loss of Fgfr2 in the ureteric epithelium led to reduced proliferation, stratification, intermediate and basal cell differentiation in this tissue, and affected cell survival and smooth muscle cell differentiation in the surrounding mesenchyme. Loss of Fgfr2 impacted negatively on epithelial expression of Shh and its mesenchymal effector gene Bmp4. Activation of SHH or BMP4 signaling largely rescued the cellular defects of mutant ureters in explant cultures. Conversely, inhibition of SHH or BMP signaling in wild-type ureters recapitulated the mutant phenotype in a dose-dependent manner. Our study suggests that FGF signals from the mesenchyme enhance, via epithelial FGFR2, the SHH-BMP4 signaling axis to drive urothelial and mesenchymal development in the early ureter.

Mesenchymal FGFR1 and FGFR2 control patterning of the ureteric mesenchyme by balancing SHH and BMP4 signaling.

The coordinated development of the mesenchymal and epithelial progenitors of the murine ureter depends on a complex interplay of diverse signaling activities. We have recently shown that epithelial FGFR2 signaling regulates stratification and differentiation of the epithelial compartment by enhancing epithelial Shh expression, and mesenchymal SHH and BMP4 activity. Here, we show that FGFR1 and FGFR2 expression in the mesenchymal primordium impinges on the SHH/BMP4 signaling axis to regulate mesenchymal patterning and differentiation. Mouse embryos with conditional loss of Fgfr1 and Fgfr2 in the ureteric mesenchyme exhibited reduced mesenchymal proliferation and prematurely activated lamina propria formation at the expense of the smooth muscle cell program. They also manifested hydroureter at birth. Molecular profiling detected increased SHH, WNT and retinoic acid signaling, whereas BMP4 signaling in the mesenchyme was reduced. Pharmacological activation of SHH signaling in combination with inhibition of BMP4 signaling recapitulated the cellular changes in explant cultures of wild-type ureters. Additional experiments suggest that mesenchymal FGFR1 and FGFR2 act as a sink for FGF ligands to dampen activation of Shh and BMP receptor gene expression by epithelial FGFR2 signaling.

Expression and localization of HSD17B13 along mouse urinary tract.

17ß-Hydroxysteroid dehydrogenase-13 (HSD17B13), a newly identified lipid droplet-associated protein, plays an important role in the development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Emerging evidence demonstrates that NASH is an independent risk factor for chronic kidney disease, which is frequently accompanied by renal lipid accumulation. In addition, the HSD17B13 rs72613567 variant is associated with lower levels of albuminuria in patients with biopsy-proven NAFLD. At present, the role of HSD17B13 in lipid accumulation in the kidney is unclear. This study utilized bioinformatic and immunostaining approaches to examine the expression and localization of HSD17B13 along the mouse urinary tract. We found that HSD17B13 is constitutively expressed in the kidney, ureter, and urinary bladder. Our findings reveal for the first time, to our knowledge, the precise localization of HSD17B13 in the mouse urinary system, providing a basis for further studying the pathogenesis of HSD17B13 in various renal and urological diseases.NEW & NOTEWORTHY HSD17B13, a lipid droplet-associated protein, is crucial in nonalcoholic fatty liver disease (NAFLD) development. NAFLD also independently raises chronic kidney disease (CKD) risk, often with renal lipid buildup. However, HSD17B13's role in CKD-related lipid accumulation is unclear. This study makes the first effort to examine HSD17B13 expression and localization along the urinary system, providing a basis for exploring its physiological and pathophysiological roles in the kidney and urinary tract.

Phase 1b Trial Evaluating Tolerability and Activity of Targeted Fibroblast Growth Factor Receptor Inhibition in Localized Upper Tract Urothelial Carcinoma.

PURPOSE: We initiated a biomarker-informed preoperative study of infigratinib, a fibroblast growth factor receptor (FGFR) inhibitor, in patients with localized upper tract urothelial carcinoma (UTUC), a population with high unmet needs and tumor with a high frequency of FGFR3 alterations. MATERIALS AND METHODS: Patients with localized UTUC undergoing ureteroscopy or nephroureterectomy/ureterectomy were enrolled on a phase 1b trial (NCT04228042). Once-daily infigratinib 125 mg by mouth × 21 days (28-day cycle) was given for 2 cycles. Tolerability was monitored by Bayesian design and predefined stopping boundaries. The primary endpoint was tolerability, and the secondary endpoint was objective response based on tumor mapping, done after endoscopic biopsy and post-trial surgery. Total planned enrollment: 20 patients. Targeted sequencing performed using a NovaSeq 6000 solid tumor panel. RESULTS: From May 2021 to November 2022, 14 patients were enrolled, at which point the trial was closed due to termination of all infigratinib oncology trials. Two patients (14.3%) had treatment-terminating toxicities, well below the stopping threshold. Responses occurred in 6 (66.7%) of 9 patients with FGFR3 alterations. Responders had median tumor size reduction of 67%, with 3 of 5 patients initially planned for nephroureterectomy/ureterectomy converted to ureteroscopy. Median follow-up in responders was 24.7 months (14.9-28.9). CONCLUSIONS: In this first trial of targeted therapy for localized UTUC, FGFR inhibition was well tolerated and had significant activity in FGFR3 altered tumors. Renal preservation was enabled in a substantial proportion of participants. These data support the design of a biomarker-driven phase 2 trial of FGFR3 inhibition in this population with significant unmet clinical needs.

Ureteroscopy vs laparoscopic ureterolithotomy for large proximal ureteric stone: a randomised trial.

OBJECTIVE: To compare the outcomes of retrograde flexible ureteroscopy (fURS) with retroperitoneal laparoscopic ureterolithotomy (RLU) for large proximal ureteric stones. PATIENTS AND METHODS: A prospective randomised trial was conducted from January 2018 through December 2022 including patients with impacted proximal ureteric stones of 15-25 mm. Patients underwent fURS or RLU. Primary outcome was the stone-free rate. Demographic data, stone features, and complications rates were also compared between groups. RESULTS: A total of 64 patients were enrolled, 32 in each group. The mean impacted stone time was similar between groups, as well as stone size (17 mm) and stone density (>1000 Hounsfield Units). The ureteric stone-free rates between the two groups (93.7% in fURS vs 96.8% in RLU; odds ratio [OR] 0.72, 95% confidence interval [CI] -1.72 to 3.17; P = 0.554), and overall success rates, which take into account residual fragments in the kidney (84.3% in fURS vs 93.7% in RLU; OR 1.02, 95% CI -0.69 to 2.74; P = 0.23), were similar. Operative time was also not statistically significantly different between groups (median 80 vs 82 min; P = 0.101). There was no difference in hospital length of stay. Retropulsion rate was higher with fURS (65.6% vs 3.1%; p < 0.001). Residual hydronephrosis (34.3% each group) and complication rates did no differ according to treatment. CONCLUSION: Flexible URS and RLU are both highly efficient and present low morbidity for large impacted proximal ureteric stone treatment. RLU is not superior to fURS.

Risk factors for migration of retrievable covered expandable metallic stent in patients with persistent benign ureter strictures.

PURPOSE: The purpose of this study is to evaluate the incidence, risk factors, and salvage management of retrievable covered expandable metallic stent (RCEMS) migration in patients with persistent benign ureter strictures. MATERIALS AND METHODS: A retrospective study was performed on 117 consecutive patients who underwent implantation of RCEMS. Univariate and multivariate analyses were used to identify prognostic factors for stent migration, including stricture location and length, hydronephrosis-cortex ratio, ureteral dilation, and the diameter of the narrowest portion of the stricture. RESULTS: Stent migration occurred in 22 (19.5%) of 113 patients who met inclusion criteria. Of the 22 patients, 16 (72.7%) had ordinary ureteral stricture, 3 (13.6%) had stricture in transplanted kidneys, and 3 patients (13.6%) had ureter stricture in orthotopic neobladders. The mean creatinine for the entire cohorts showed significant improvement (p = 0.038). Multivariate analysis identified the following prognostic factors for migration: distal ureteral stricture (p = 0.006), patients who underwent balloon dilation (p = 0.003), hydronephrosis-cortex ratio ≧10 (p = 0.017), larger diameter of wasting of RCEMS (p < 0.001), and patients with a shorter stricture length (p = 0.006). Salvage management was required in 4 of the 22 patients. The strictures in the remaining 18 patients improved with observation. CONCLUSIONS: Stent migration is more likely to occur in patients with the five prognostic factors mentioned above. Our study developed a nomogram to predict stent migration in patients with ureteral strictures treated using RCEMS.

Bacteriuria in patients with stented ureters: predictors of infection in patients presenting to the hospital and when not to treat.

PURPOSE: Patients with ureteric stents have symptoms that overlap with infection symptoms. Thus, clinicians unnecessarily give antibiotics to stented patients with bacteriuria despite guidelines. In stented patients, little is known about risk factors for developing bacteriuria or urosepsis. The objectives were to identify the frequency and risk factors for developing bacteriuria and urosepsis in patients with stents. METHODS: In this retrospective cohort study, we reviewed patients with ureteric stents placed or exchanged over 1 year. We examined associations between bacteriuria or urosepsis and host risk factors. Univariable and multivariable logistic analyses were performed. RESULTS: Of 286 patients (mean age: 57.2 years), 167 (58.4%) were male. The main stent indications were stone, stricture, cancer and extrinsic compression. The median stented period was 61 days. The frequency of bacteriuria was 59/286 (21%). ASA status 3 and 4 had 5 times the odds of having bacteriuria relative to ASA status 1. Stent duration > 2 months had 5.5 times the odds relative to ≤ 2 months. Urosepsis was infrequent, 13/286 (4.5%). Five patients had bacteraemia. A stent duration over 2 months had nearly 6 times the odds of urosepsis. CONCLUSION: ASA status higher than 2 and stent time greater than 2 months raise the odds of developing bacteriuria. A stent duration longer than 2 months was the only predictor of urosepsis. Though 21% of patients had bacteriuria, 4.5% had urosepsis. Hence, bacteriuria without sepsis should not be treated with antibiotics, thus aiding antimicrobial stewardship.

Ureteroplasty with buccal mucosa graft without omental wrap: an effective method to treat ureteral strictures.

PURPOSE: Successful treatment options for ureteral strictures are limited. Surgical options such as ileal interposition and kidney autotransplantation are difficult and associated with morbidity and complications. Techniques such as Boari flap and psoas hitch are limited to distal strictures. Only limited case studies on the success of open buccal mucosa graft (BMG) ureteroplasty exist to this date. The purpose of this study was to evaluate the success of open BMG ureteroplasty without omental wrap. METHODS: In this single-center retrospective study between July 2020 and January 2023, we included 14 consecutive patients with ureteric strictures who were treated with open BMG ureteroplasty without omental wrap. The primary outcome was the success of open BMG ureteroplasty. Further endpoints were complications and hospital readmission. Outcome variables were assessed by clinical examination, kidney sonography, and patient anamnesis. RESULTS: Out of 14 patients, 13 were stricture and ectasia-free without a double-J stent at a median follow-up of 15 months (success rate 93%). No complications were observed at the donor site, and the complication rate overall was low with 3 out of 14 patients (21%) having mild-to-medium complications. CONCLUSIONS: Open BMG ureteroplasty without omental wrap is a successful and feasible technique for ureteric stricture repair.

Peristalsis prevents ureteral dilation.

PURPOSE: The etiology of ureteral dilation in primary nonrefluxing, nonobstructing megaureters is still not well understood. Impaired ureteral peristalsis has been theorized as one of the contributing factors. However, ureteral peristalsis and its "normal" function is not well defined. In this study, using mathematical modeling techniques, we aim to better understand how ureteral peristalsis works. This is the first model to consider clinically observed, back-and-forth, cyclic wall longitudinal motion during peristalsis. We hypothesize that dysfunctional ureteral peristalsis, caused by insufficient peristaltic amplitudes (e.g., circular muscle dysfunction) and/or lack of ureteral wall longitudinal motion (e.g., longitudinal muscle dysfunction), promotes peristaltic reflux (i.e., retrograde flow of urine during an episode of peristalsis) and may result in urinary stasis, urine accumulation, and consequent dilation. METHODS: Based on lubrication theory in fluid mechanics, we developed a two-dimensional (planar) model of ureteral peristalsis. In doing so, we treated ureteral peristalsis as an infinite train of sinusoidal waves. We then analyzed antegrade and retrograde flows in the ureter under different bladder-kidney differential pressure and peristalsis conditions. RESULTS: There is a minimum peristaltic amplitude required to prevent peristaltic reflux. Ureteral wall longitudinal motion decreases this minimum required amplitude, increasing the nonrefluxing range of peristaltic amplitudes. As an example, for a normal bladder-kidney differential pressure of 5 cmH2 O, ureteral wall longitudinal motion increases nonrefluxing range of peristaltic amplitude by 65%. Additionally, ureteral wall longitudinal motion decreases refluxing volumetric flow rates. For a similar normal bladder pressure example of 5 cmH2 O, refluxing volumetric flow rate decreases by a factor of 18. Finally, elevated bladder pressure, not only increases the required peristaltic amplitude for reflux prevention but it increases maximum refluxing volumetric flow rates. For the case without wall longitudinal motion, as bladder-kidney differential pressure increases from 5 to 40 cmH2 O, minimum required peristaltic amplitude to prevent reflux increases by 40% while the maximum refluxing volumetric flow rate increases by approximately 100%. CONCLUSION: The results presented in this study show how abnormal ureteral peristalsis, caused by the absence of wall longitudinal motion and/or lack of sufficient peristaltic amplitudes, facilitates peristaltic reflux and retrograde flow. We theorize that this retrograde flow can lead to urinary stasis and urine accumulation in the ureters, resulting in ureteral dilation seen on imaging studies and elevated infection risk. Our results also show how chronically elevated bladder pressures are more susceptible to such refluxing conditions that could lead to ureteral dilation.

In vitro effects of ß3-adrenoceptor agonist mirabegron on the human ureter.

INTRODUCTION: This study aimed to investigate the effect of mirabegron, a ß3-adrenoceptor agonist with widespread clinical use for treating overactive bladder disease, on isolated healthy human ureter strips. MATERIALS AND METHODS: This was a prospective study employing a series of in vitro organ bath experiments using ureteral tissues of kidney grafts from 10 healthy donors. The ureteral strips were subjected to cumulative mirabegron concentrations (10-9-10-4.5 M). Effects on frequency or amplitude of spontaneous, 10 mM KCl- or EFS-induced contractions were evaluated. RESULTS: Mirabegron decreased the frequency of spontaneous ureteric contraction in a concentration-dependent manner. Statistically significant decrease in the frequency of spontaneous contraction was observed at 10-8-10-4.5 M. In 10 mM KCl medium, statistically significant change in frequency was observed at 10-9-10-4.5 M. Statistically significant decrease in the amplitudes of spontaneous contraction was observed at 10-7-10-4.5 M. In a 10 mM KCl medium, statistically significant change in amplitudes was observed at 10-8-10-4.5 M. CONCLUSIONS: Mirabegron reduced the amplitude and frequency of human ureter activity in in vitro organ bath studies. This effect was achieved in a dose-dependent manner on isolated tissue strips. Although monotherapy with mirabegron remains uncertain, this study has the potential to elucidate the mechanism underlying the effectiveness of mirabegron, particularly in combination therapy for ureteral stones.

Enfortumab vedotin following platinum-based chemotherapy and immune checkpoint inhibitors for advanced urothelial carcinoma: response, survival and safety analysis from a multicentre real-world Japanese cohort.

OBJECTIVE: Real-world evidence regarding enfortumab vedotin for unresectable or metastatic urothelial carcinoma is scarce, particularly in Japan. We investigated real-world data focusing on patient background, previous treatments, response, survival and adverse events in patients receiving enfortumab vedotin. METHODS: A multicentre database was used to register 556 patients diagnosed with metastatic urothelial carcinoma from 2008 to 2023; 34 patients (6.1%) treated with enfortumab vedotin were included. Best radiographic objective responses were evaluated using the Response Evaluation Criteria in Solid Tumors (v1.1) during treatments. Overall survival and progression-free survival were estimated (Kaplan-Meier method). Toxicities were reported according to the Common Terminology Criteria for Adverse Events, version 5.0. The relative dose intensity, which could impact oncological outcomes, was calculated. RESULTS: The median number of enfortumab vedotin therapy cycles was 5. The best objective response to enfortumab vedotin was partial response, stable disease and progressive disease in 19 (56%), 5 (15%) and 10 (29%) patients, respectively. The median overall survival and progression-free survival after the first enfortumab vedotin dose were 16 and 9 months, respectively. No significant relationship was observed between survival outcomes after enfortumab vedotin initiation and the enfortumab vedotin relative dose intensity. The median overall survival from first-line platinum-based chemotherapy initiation was 42 months. Twenty-six (76%) patients experienced any grade of enfortumab vedotin-related toxicities; eight (24%) experienced Grades 3-4 toxicities, the most common being skin toxicity (any grade, 47%; Grades 3-4, 12%). CONCLUSIONS: Here, we report real-world evidence for enfortumab vedotin therapy in Japan. Tumour responses and safety profiles were comparable with those of clinical trials on this novel treatment.

Spasmolytic Effect of Flopropione Does Not Involve Catechol-O- methyltransferase (COMT) Inhibition.

Flopropione (Flo) has been used for gallstone and urolithiasis as a spasmolytic agent almost exclusively in Japan. According to the package insert, its main mechanism is catechol-O-methyltransferase (COMT) inhibition and anti-serotonergic effect. This is obviously contrary to pharmacological common sense, but it is described that way in pharmacology textbooks and occurs in questions in the National Examination for Pharmacists in Japan. As this is a serious problem in education, we re-examined the action of Flo. The guinea pig ureter was hardly contracted by serotonin, but noradrenaline (NA) elicited repetitive twitch contraction, which was inhibited by Flo. The sphincter of Oddi (SO) exhibited a spontaneous repetitive twitch contraction, which was inhibited by NA and Flo. The inhibitory effect of NA was reversed by α- and ß-blockers, whereas that of Flo was not. Entacapone, a representative COMT inhibitor, did not affect the movement of the ureter and the SO. Nifedipine suppressed carbachol-induced contraction of the taenia coli, spontaneous movement of the SO, and NA-induced contraction of the ureter to almost the same extent, whereas Flo did not inhibit the taenia coli, but inhibited the contraction of the SO and the ureter. The inhibitory pattern of Flo resembled that of the ryanodine receptor agonist 4-chloro-m-cresol and the inositol 1,4,5-trisphosphate (IP3) receptor antagonist 2-aminoethoxydiphenyl borate. It is concluded that COMT inhibition or serotonin inhibition is not involved in the spasmolytic action of Flo. Flo might act on ryanodine receptors and/or IP3 receptors, which are responsible for periodic Ca release from Ca stores, to disrupt coordinated Ca dynamics.

Minimally invasive versus open ileal ureter with ileocystoplasty: comparative outcomes and 5-year experience.

PURPOSE: To present the experience of ileal ureter with ileocystoplasty (IUC), and compare the outcomes of IUC in minimally invasive procedures to open procedures. PATIENTS AND METHODS: From December 2017 to April 2023, twenty patients underwent IUC in open or minimally invasive (including laparoscopic and robotic) procedures. The baseline characteristics, perioperative data and follow-up outcomes were collected. Success was defined as relief of clinical symptoms, stable postoperative serum creatine and absence of radiographic obstruction. The perioperative and follow-up outcomes of open procedures and minimally invasive procedures were compared. RESULTS: The etiology included pelvic irradiation (14/20), urinary tuberculosis (3/20) and surgical injury (3/20). Bilateral ureter strictures were repaired in 15 cases. The surgeries conducted consisted of open procedures in 9 patients and minimally invasive procedures in 11 patients. Compared to open procedures, minimally invasive surgeries had less median estimated blood loss (EBL) (100 ml vs. 300 min, p = 0.010) and shorter postoperative hospitalization (27 d vs. 13 d, p = 0.004). Two patients in the open group experienced grade 3 complications (sigmoid fistula and acute cholecystitis in one patient, and pulmonary embolism in another patient). Over a median follow-up period of 20.1 months, the median bladder functional capacity was 300 ml, with a 100% success rate of IUC. CONCLUSION: IUC is feasible in both open and minimally invasive procedures, with acceptable complications and a high success rate. Minimally invasive procedures can have less EBL and shorter postoperative hospitalization than open procedure. However, prospective studies with larger groups and longer follow-up are needed.

Difference of oncological efficacy between two immune checkpoint inhibitors following first-line platinum-based chemotherapy in patients with unresectable, metastatic, advanced urothelial carcinoma: a multicenter real-world Japanese cohort.

BACKGROUND: Maintenance avelumab is currently recommended for patients with unresectable and/or metastatic (mUC) achieving at least stable disease (SD) on first-line platinum-based chemotherapy (1L-CT). Pembrolizumab is an alternative therapeutic avenue for this patient cohort in clinical practice. We investigated real-world data, focusing on the correlation between response to 1L-CT and oncological efficacy of subsequent immune checkpoint inhibitor (ICI) therapy with avelumab or pembrolizumab. METHODS: A multicenter database registered 626 patients with mUC diagnosed from 2008-2023; among these, 175 receiving 2-6 cycles of 1L-CT followed by ICI therapy. Patients were categorized based on response to 1L-CT using the Response Evaluation Criteria in Solid Tumors (v1.1). Objective response rate on ICI, progression to ICI-free survival (ICI-PFS), and overall survival from start of 1L-CT were compared between avelumab-treated and pembrolizumab-treated patients in each response subgroup. RESULTS: ICI-PFS was significantly longer in patients achieving partial response on 1L-CT and subsequently receiving pembrolizumab compared to those receiving avelumab. Notably, patients achieving SD on 1L-CT and subsequently receiving pembrolizumab manifested significantly higher objective response rate (14% and 41%, respectively) and prolonged ICI-PFS relative to those receiving avelumab. In contrast, overall survival did not delineate difference between patients treated with avelumab versus pembrolizumab. Similar findings were discerned in the subanalysis of patients having favorable SD (tumor shrinkage, from - 29 to 0%) and unfavorable SD (tumor enlargement, from + 1 to + 19%) on 1L-CT. CONCLUSIONS: Our study provides real-world evidence regarding difference of oncological efficacy between maintenance avelumab and subsequent pembrolizumab in patients with mUC who achieved partial response or SD on 1L-CT.

Combined Cystoscopic-Abdominal Versus Abdominal-Only Route for Complete Excision of Large Deep Endometriosis Nodules Infiltrating the Supratrigonal Area of the Bladder: A Comparative Study.

STUDY OBJECTIVE: Surgical excision of large deep endometriosis nodules infiltrating the bladder may be challenging, particularly when the nodule limits are close to the trigone and ureteral orifice. Bladder nodules have classically been approached abdominally. However, combining a cystoscopic with an abdominal approach may help to better identify the mucosal borders of the lesion to ensure complete excision without unnecessary resection of healthy bladder. This study aimed to compare classical excision of large bladder nodules by abdominal route with a combined cystoscopic-abdominal approach. DESIGN: Retrospective comparative study on data prospectively recorded in a database. Patients were managed from September 2009 to June 2022. SETTING: Two tertiary referral endometriosis centers. PATIENTS: A total of 175 patients with deep endometriosis infiltrating the bladder more than 2 cm undergoing surgical excision of bladder nodules. INTERVENTIONS: Excision of bladder nodules by either abdominal or combined cystoscopic-abdominal approaches. MEASUREMENTS AND MAIN RESULTS: A total of 141 women (80.6%) were managed by abdominal route and 34 women (19.4%) underwent a combined cystoscopic-abdominal approach. In 99.4% of patients, the approach was minimally invasive. Patients with nodules requiring the combined approach had a lower American Fertility Society revised score and endometriosis stage and less associated digestive tract nodules, but larger bladder nodules. They were less frequently associated with colorectal resection and preventive stoma. Operative time was comparable. The rate of early postoperative complications was comparable (8.8% vs 22%), as were the rates of ureteral fistula (2.2% vs 2.9%), bladder fistula (2.2% vs 0), and vesicovaginal fistula (0.7% vs 2.9%). CONCLUSION: In our opinion, the combined cystoscopic-abdominal approach is useful in patients with large bladder nodules with limits close to the trigone and ureteral orifice. These large deep bladder nodules seemed paradoxically associated to less nodules on the digestive tract, resulting in an overall comparable total operative time and complication rate.

The Diagnostic Accuracy of Transvaginal Ultrasound for Detection of Ureteral Involvement in Deep Infiltrating Endometriosis: A Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this study is to determine the accuracy of transvaginal ultrasound (TVU) for the diagnosis of ureteral involvement in women with deep infiltrating endometriosis (DIE). METHODS: The meta-analysis included primary studies comparing the use of TVU for diagnosing endometriotic involvement of the ureter, using laparoscopic surgery and histological diagnosis as the reference standard. Search was performed in several databases (Scopus, Web of Science, and PubMed/MEDLINE). The studies' quality and bias risk were assessed using the Quality Assessment of Diagnostic Accuracy Study-2 (QUADAS-2). Diagnostic performance was estimated by assessing pooled sensitivity and specificity. RESULTS: A total of 496 citations were found. Six articles were ultimately selected for this systematic review and meta-analysis after the inclusion and exclusion criteria were applied. Pooled sensitivity and specificity were 0.81 (95% CI: 0.42-0.96), 1.00 (95% CI: 0.93-1.00). The heterogeneity observed was high for both sensitivity and specificity. Overall risk of bias was low. CONCLUSION: TVU is a valuable tool for the pre-operative identification of ureteral involvement by DIE.