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Objective: To investigate the optimal number of induction chemotherapy cycles needed to achieve a pathological response in patients with clinically lymph node‐positive (cN+) bladder cancer (BCa) who received three or four cycles of induction chemotherapy followed by consolidative radical cystectomy (RC) with pelvic lymph node dissection. Patients and Methods: We included 388 patients who received three or four cycles of cisplatin/gemcitabine or (dose‐dense) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), followed by consolidative RC for cTanyN1–3M0 BCa. We compared pathological complete (pCR = ypT0N0) and objective response (pOR = yp ≤T1N0) between treatment groups. Predictors of pCR and/or pOR were assessed using uni‐ and multivariable logistic regression analysis. The secondary endpoints were overall (OS) and cancer‐specific survival (CSS). We evaluated the association between the number of induction chemotherapy cycles administered and survival outcomes on multivariable Cox regression. Results: Overall, 101 and 287 patients received three or four cycles of induction chemotherapy, respectively. Of these, 72 (19%) and 128 (33%) achieved pCR and pOR response, respectively. The pCR (20%, 18%) and pOR (40%, 31%) rates did not differ significantly between patients receiving three or four cycles (P > 0.05). The number of cycles was not associated with pCR or pOR on multivariable logistic regression analyses. The 2‐year OS estimates were 63% (95% confidence interval [CI] 0.53–0.74) and 63% (95% CI 0.58–0.7) for patients receiving three or four cycles, respectively. Receiving three vs four cycles was not associated with OS and CSS on uni‐ or multivariable Cox regression analyses. Conclusion: Pathological response and survival outcomes did not differ between administering three or four induction chemotherapy cycles in patients with cN+ BCa. A fewer cycles (minimum three) may be oncologically sufficient in patients with cN+ BCa, while decreasing the wait for definitive local therapy in those patients who end up without a response to chemotherapy. This warrants further validation. [ABSTRACT FROM AUTHOR]

Objective: To determine the oncological impact of extended pelvic lymph node dissection (ePLND) vs standard PLND (sPLND) during radical cystectomy (RC) in clinically lymph node‐positive (cN+) bladder cancer (BCa). Patients and Methods: In this retrospective, multicentre study we included 969 patients who underwent RC with sPLND (internal/external iliac and obturator lymph nodes) or ePLND (sPLND plus common iliac and presacral nodes) with or without platin‐based peri‐operative chemotherapy for cTany N1‐3 M0 BCa between 1991 and 2022. We assessed the impact of ePLND on recurrence‐free survival (RFS) and the distribution of recurrences (locoregional and distant recurrences). The secondary endpoint was overall survival (OS). We performed propensity‐score matching using covariates associated with the extent of PLND in univariable logistic regression analysis. The association of the extent of PLND with RFS and OS was investigated using Cox regression models. Results: Of 969 cN+ patients, 510 were 1:1 matched on propensity scores. The median (interquartile range [IQR]) time to recurrence was 8 (4–16) months, and median (IQR) follow‐up of alive patients was 30 (13–51) months. Disease recurrence was observed in 104 patients in the ePLND and 107 in the sPLND group. Of these, 136 (27%), 47 (9.2%) and 19 patients (3.7%) experienced distant, locoregional, or both distant and locoregional disease recurrence, respectively. When stratified by the extent of PLND, we did not find a difference in recurrence patterns (P > 0.05). ePLND improved neither RFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.70–1.19; P = 0.5) nor OS (HR 0.78, 95% CI 0.60–1.01; P = 0.06) compared to sPLND. Stratification by induction chemotherapy did not change outcomes. Conclusion: Performing an ePLND at the time of RC in cN+ patients improved neither RFS nor OS compared to sPLND, regardless of induction chemotherapy status. Pretreatment risk stratification is paramount to identify ideal candidates for RC with ePLND as part of a multimodal treatment approach. [ABSTRACT FROM AUTHOR]

Objectives To address the association of perioperative surgical checklist across variable surgical expertise with transurethral resection of bladder tumour (TURBT) accuracy and oncological outcomes in non-muscle-invasive bladder cancer. Patients and Methods We relied on our prospective collaborative database of patients treated with TURBT between 2012 and 2017. Surgical experience was stratified into three groups: resident vs young vs expert consultants. The association of surgical experience with detrusor muscle (DM) presence and adherence to the standardised peri-procedural nine-items TURBT checklist was evaluated with logistic regression models. A Cox regression model was used to investigate the association of surgical experience with recurrence-free survival (RFS). Results A total of 503 patients were available for analysis. TURBT was performed by expert consultants in 265 (52.7%) patients, by young consultants in 149 (29.6%) and by residents in 89 (17.7%). Residents were more likely to have DM in the TURBT specimen than expert consultants (odds ratio [OR] 1.75, 95% confidence interval [CI] 1.03-2.99, P = 0.04). Conversely, no differences in DM presence were seen between young vs expert consultants (OR 1.09, 95% CI 0.71-1.70, P = 0.69). The median checklist completion rate was higher for both residents and young consultants when compared to experts' counterparts (56% and 56% vs 44%, P = 0.009). When focusing on patients receiving a second-look TURBT, the persistent disease was associated with resident status (OR 4.24, 95% CI 1.14-17.70, P = 0.037) at initial TURBT. Surgical experience was not associated with 5-years RFS. Conclusion Surgeon's experience in the case of adequate perioperative surgical checklist implementation was inversely associated with the presence of DM in the specimen but directly linked to higher probability of persistent disease at re-TURBT, although no 5-year RFS differences were noted. [ABSTRACT FROM AUTHOR]

Objectives: Technical limitations of ureteroscopic (URS) biopsy has been considered responsible for substantial upgrading rate in upper tract urothelial carcinoma (UTUC). However, the impact of tumor specific factors for upgrading remain uninvestigated. Methods: Patients who underwent URS biopsy were included between 2005 and 2020 at 13 institutions. We assessed the prognostic impact of upgrading (low‐grade on URS biopsy) versus same grade (high‐grade on URS biopsy) for high‐grade UTUC tumors on radical nephroureterectomy (RNU) specimens. Results: This study included 371 patients, of whom 112 (30%) and 259 (70%) were biopsy‐based low‐ and high‐grade tumors, respectively. Median follow‐up was 27.3 months. Patients with high‐grade biopsy were more likely to harbor unfavorable pathologic features, such as lymphovascular invasion (p < 0.001) and positive lymph nodes (LNs; p < 0.001). On multivariable analyses adjusting for the established risk factors, high‐grade biopsy was significantly associated with worse overall (hazard ratio [HR] 1.74; 95% confidence interval [CI], 1.10–2.75; p = 0.018), cancer‐specific (HR 1.94; 95% CI, 1.07–3.52; p = 0.03), and recurrence‐free survival (HR 1.80; 95% CI, 1.13–2.87; p = 0.013). In subgroup analyses of patients with pT2‐T4 and/or positive LN, its significant association retained. Furthermore, high‐grade biopsy in clinically non‐muscle invasive disease significantly predicted upstaging to final pathologically advanced disease (≥pT2) compared to low‐grade biopsy. Conclusions: High tumor grade on URS biopsy is associated with features of biologically and clinically aggressive UTUC tumors. URS low‐grade UTUC that becomes upgraded to high‐grade might carry a better prognosis than high‐grade UTUC on URS. Tumor specific factors are likely to be responsible for upgrading to high‐grade on RNU. [ABSTRACT FROM AUTHOR]

Introduction: The aim of the present study was to evaluate the effect of 18‐week monotherapy with imeglimin on glucose tolerance and on insulin secretion/sensitivity in type 2 diabetic (T2D) patients. Methods: The study was an 18‐week, double‐blind clinical trial in T2D subjects previously treated with stable metformin therapy and washed out for 4 weeks. Subjects were randomized 1:1 to receive a 1500 mg bid of imeglimin or placebo. The primary endpoint was the effect of imeglimin vs placebo on changes from baseline to week 18 in glucose tolerance (glucose area under the curve [AUC]) during a 3 h‐glucose tolerance test [OGTT]). Secondary endpoints included glycaemic control and calculated indices of insulin secretion and sensitivity. Results: A total of 59 subjects were randomized, 30 receiving imeglimin and 29 receiving placebo. The study met its primary endpoint. Least squares (LS) mean difference between treatment groups (imeglimin ‐ placebo) for AUC glucose from baseline to week 18 was −429.6 mmol/L·min (p =.001). Two‐hour post‐dose fasting plasma glucose was significantly decreased with LS mean differences of −1.22 mmol/L (p =.022) and HbA1c was improved with LS mean differences of −0.62% (p =.013). The AUC0‐180min ratio C‐peptide/glucose [LS mean differences of 0.041 nmol/mmol (p <.001)] and insulinogenic index were significantly increased by imeglimin treatment. The increase in insulin secretion was associated with an increase in beta‐cell glucose sensitivity. Additionally, the insulin sensitivity indices derived from the OGTT Stumvoll (p =.001) and Matsuda (not significant) were improved in the imeglimin group vs placebo. Imeglimin was well tolerated with 26.7% of subjects presenting at least one treatment‐emergent adverse event versus 58.6% of subjects in the placebo group. Conclusions: Results are consistent with a mode of action involving insulin secretion as well as improved insulin sensitivity and further support the potential for imeglimin to improve healthcare in T2D patients. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) risk is lower in females than males. It has been reported that females have greater pancreatic 훽‐cell function than males, which may at least in part contribute to the T2D risk in females. 훽‐cell function is influenced by exercise training; however, previous trials comparing 훽‐cell function between the sexes have not included participants matched for training status. Furthermore, the acute effects of different modes of exercise on 훽‐cell function, and whether sex inherently influences these effects, are largely unexamined. Males and females (12/sex) completed a 120‐min oral glucose tolerance test (OGTT) at rest (CON) and following acute bouts of high‐intensity interval exercise (HIIE), moderate intensity continuous (MIC) exercise, and low‐load high‐repetition (LLHR) resistance exercise to assess whether sex inherently influences baseline and/or post‐exercise pancreatic function in the absence of pathology. We found no sex differences in basal pancreatic 훽‐cell function. Females had greater basal insulin clearance following MIC exercise compared to males (p = 0.01) and males tended to have a higher potentiation ratio following HIIE (p = 0.07). Females also had lower glucose sensitivity following MIC exercise compared to HIIE (p = 0.007) and LLHR (p = 0.003). Insulin clearance during the OGTT was greater following HIIE as compared with CON and MIC exercise (p = 0.02). 2‐H oral glucose insulin sensitivity was greater following LLHR compared to CON (p = 0.01). Acute bouts of different modes of exercise do not differentially influence 훽‐cell function but do influence insulin clearance and insulin sensitivity. Therefore, sex and exercise mode interact to differentially influence insulin clearance and glucose sensitivity. [ABSTRACT FROM AUTHOR]

Aim: To examine the determinants and metabolic impact of the reduction in fasting and postload insulin levels after a low n‐6 to n‐3 polyunsaturated fatty acid (PUFA) ratio diet in obese youth. Materials and Methods: Insulin secretion and clearance were assessed by measuring and modelling plasma insulin and C‐peptide in 17 obese youth who underwent a nine‐point, 180‐minute oral glucose tolerance test (OGTT) before and after a 12‐week, eucaloric low n‐6:n‐3 polyunsaturated fatty acid (PUFA) ratio diet. Hepatic fat content was assessed by repeated abdominal magnetic resonance imaging. Results: Insulin clearance at fasting and during the OGTT was significantly increased after the diet, while body weight, glucose levels, absolute and glucose‐dependent insulin secretion, and model‐derived variables of β‐cell function were not affected. Dietary‐induced changes in insulin clearance positively correlated with changes in whole‐body insulin sensitivity and β‐cell glucose sensitivity, but not with changes in hepatic fat. Subjects with greater increases in insulin clearance showed a worse metabolic profile at enrolment, characterized by impaired insulin clearance, β‐cell glucose sensitivity, and glucose tolerance, and benefitted the most from the diet, achieving greater improvements in glucose‐stimulated hyperinsulinaemia, insulin resistance, and β‐cell function. Conclusions: We showed that a 12‐week low n‐6:n‐3 PUFA ratio diet improves hyperinsulinaemia by increasing fasting and postload insulin clearance in obese youth, independently of weight loss, glucose concentrations, and insulin secretion. [ABSTRACT FROM AUTHOR]

Objectives: Martini et al. developed a nomogram to predict significant (>25%) renal function loss after robot‐assisted partial nephrectomy and identified four risk categories. We aimed to externally validate Martini's nomogram on a large, national, multi‐institutional data set including open, laparoscopic, and robot‐assisted partial nephrectomy. Methods: Data of 2584 patients treated with partial nephrectomy for renal masses at 26 urological Italian centers (RECORD2 project) were collected. Renal function was assessed at baseline, on third postoperative day, and then at 6, 12, 24, and 48 months postoperatively. Multivariable models accounting for variables included in the Martini's nomogram were applied to each approach predicting renal function loss at all the specific timeframes. Results: Multivariable models showed high area under the curve for robot‐assisted partial nephrectomy at 6‐ and 12‐month (87.3% and 83.6%) and for laparoscopic partial nephrectomy (83.2% and 75.4%), whereas area under the curves were lower in open partial nephrectomy (78.4% and 75.2%). The predictive ability of the model decreased in all the surgical approaches at 48 months from surgery. Each Martini risk group showed an increasing percentage of patients developing a significant renal function reduction in the open, laparoscopic and robot‐assisted partial nephrectomy group, as well as an increased probability to develop a significant estimated glomerular filtration rate reduction in the considered time cutoffs, although the predictive ability of the classes was <70% at 48 months of follow‐up. Conclusions: Martini's nomogram is a valid tool for predicting the decline in renal function at 6 and 12 months after robot‐assisted partial nephrectomy and laparoscopic partial nephrectomy, whereas it showed a lower performance at longer follow‐up and in patients treated with open approach at all these time cutoffs. [ABSTRACT FROM AUTHOR]

Aim: Multiple studies support the efficacy of combining a glucagon‐like peptide 1 receptor agonist (GLP‐1RA) with basal insulin in people with type 2 diabetes inadequately controlled on dual/triple oral therapy. Fixed‐ratio combinations of basal insulin + GLP‐1RA represent a further advance to facilitate management. We assessed the impact of fixed‐ratio combination basal insulin + GLP‐1RA treatment on β‐cell function. Materials and Methods: We analysed data from 351 participants in the LixiLan‐G trial (NCT02787551) randomized to receive iGlarLixi (insulin glargine 100 U/ml + lixisenatide) or to continue daily/weekly GLP‐1RA, both on top of metformin. Participants received a 2‐h meal tolerance test before randomization and at study end (26 weeks), with timed plasma glucose and C‐peptide determinations. β‐cell function parameters were resolved using mathematical modelling. Results: In the GLP‐1RA group (n = 162), both body weight and glycated haemoglobin decreased at week 26, yet none of the insulin secretion/β‐cell function parameters changed significantly. In contrast, in the iGlarLixi group (n = 189), glycated haemoglobin decreased significantly more than in the GLP‐1RA group (p <.0001) despite an increase in body weight (+1.7 ± 3.9 kg, p <.0001). Fasting and stimulated insulin secretion decreased at Week 26 (both p <.0001 vs. GLP‐1RA), while β‐cell glucose sensitivity increased by a median 35% (p =.0032 vs. GLP‐1RA). The incremental meal tolerance test glucose area showed a larger reduction with iGlarLixi versus GLP‐1RA (p <.0001). Conclusions: In people with type 2 diabetes on metformin, 26‐week treatment with iGlarLixi resulted in a marked improvement in β‐cell function concomitant with sparing of endogenous insulin release and a reduction in meal absorption. [ABSTRACT FROM AUTHOR]

Objectives: To compare the functional outcomes of on‐ vs off‐clamp robot‐assisted partial nephrectomy (RAPN) within a randomized controlled trial (RCT). Materials and Methods: The CLOCK study (CLamp vs Off Clamp the Kidney during robotic partial nephrectomy; NCT 02287987) is a multicentre RCT including patients with normal baseline function, two kidneys and masses with RENAL scores ≤ 10. Pre‐ and postoperative renal scintigraphy was prescribed. Renal defatting and hilum isolation were required in both study arms; in the on‐clamp arm, ischaemia was imposed until the completion of medullary renorraphy, while in the off‐clamp condition it was not allowed throughout the procedure. The primary endpoint was 6‐month absolute variation in estimated glomerular filtration rate (AV‐GFR); secondary endpoints were: 12, 18 and 24‐month AV‐GFR; 6‐month estimated glomerular filtration rate variation >25% rate (RV‐GFR >25); and absolute variation in ipsilateral split renal function (AV‐SRF). The planned sample size was 102 + 102 cases, after taking account crossover of cases to the alternate study arm; a 1:1 randomization was performed. AV‐GFR and AV‐SRF were compared using analysis of covariation, and RV‐GFR >25 was assessed using multivariable logistic regression. Intention‐to‐treat (ITT) and per‐protocol analyses (PP) were performed. Results: A total of 160 and 164 patients were randomly assigned to on‐ and off‐clamp RAPN, respectively; crossover was observed in 14% and 43% of the on‐ and off‐clamp arms, respectively. We were unable to find any statistically significant difference between on‐ vs off‐clamp with regard to the primary endpoint (ITT: 6‐month AV‐GFR −6.2 vs −5.1 mL/min, mean difference 0.2 mL/min, 95% confidence interval [CI] −3.1 to 3.4 [P = 0.8]; PP: 6‐month AV‐GFR −6.8 vs −4.2 mL/min, mean difference 1.6 mL/min, 95% CI −2.3 to 5.5 [P = 0.7]) or with regard to the secondary endpoints. The median warm ischaemia time was 14 vs 15 min in the ITT analysis and 14 vs 0 min in the PP analysis. Conclusion: In patients with regular baseline function and two kidneys, we found no evidence of differences in functional outcomes for on‐ vs off‐clamp RAPN. [ABSTRACT FROM AUTHOR]

High-risk non-muscle-invasive bladder cancer (NMIBC) is a common and heterogeneous entity and it often represents a clinical dilemma for urologists due to need to balance the risk of recurrence and progression with the risk of overtreatment (i.e., early radical cystectomy).1 Transurethral resection of bladder tumor (TURBT) is the standard diagnostic and therapeutic approach to NMIBC. Bladder cancer prospective cohort study on high-risk non-muscle invasive bladder cancer after photodynamic diagnosis-assisted transurethral resection of the bladder tumor (BRIGHT study). Editorial Comment from Dr Tellini et al. to Bladder cancer prospective cohort study on high-risk non-muscle invasive bladder cancer after photodynamic diagnosis-assisted transurethral resection of the bladder tumor (BRIGHT study). [Extracted from the article]

Objectives Materials and Methods Results Conclusions To assess the risk of venous thromboembolic events (VTEs) and bleeding with or without thromboprophylaxis during neoadjuvant chemotherapy in bladder cancer patients scheduled for radical cystectomy.We conducted a retrospective cohort study in 4886 patients with non‐metastatic bladder cancer undergoing cystectomy across 28 centres in 13 countries between 1990 and 2021. Inverse probability weighting analyses were performed to estimate the effect of thromboprophylaxis on VTE and bleeding.In 147 patients (3%) VTEs were recorded within the first year. These occurred a median (interquartile range [IQR]) of 127 (82–198) days after bladder cancer diagnosis. Bleeding events occurred in 131 patients (3%) within the first year. These occurred a median (IQR) of 101 (83–171) days after cancer diagnosis. In inverse probability weighting analyses, compared to patients without thromboprophylaxis during chemotherapy, patients with thromboprophylaxis had not only a lower risk of VTE (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.12–0.81; P = 0.016) but also a lower bleeding risk (HR 0.03, 95% CI 0.09–0.12; P <0.0001). The retrospective nature of the study was its main limitation.In this retrospective analysis, the benefit of thromboprophylaxis during neoadjuvant chemotherapy before cystectomy is in line with data from randomised trials in other malignancies. Our data suggest thromboprophylaxis is protective against VTEs and should be the standard of care during neoadjuvant chemotherapy. [ABSTRACT FROM AUTHOR]