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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]

Aim: To evaluate whether intrahepatic fat accumulation contributes to impaired insulin clearance and hepatic insulin resistance across different ethnic groups. Methods: The intrahepatic fat content (HFF%) was quantified by magnetic resonance imaging in a multi‐ethnic cohort of 632 obese youths aged 7‐18 years at baseline and after a 2‐year follow‐up. Insulin secretion rate (ISR), endogenous insulin clearance (EIC) and hepatic insulin resistance index (HIRI) were estimated by modelling glucose, insulin and C‐peptide data during 3‐hour, 9‐point oral glucose tolerance tests. Results: African American youths exhibited the lowest HFF% and a prevalence of non‐alcoholic fatty liver disease (NAFLD) less than half of that shown by Caucasians and Hispanics. Furthermore, African Americans had lower EIC and glucose‐stimulated ISR, despite similar HIRI and plasma insulin levels, compared with Caucasians and Hispanics. EIC and HIRI were markedly reduced in individuals with NAFLD and declined across group‐specific HFF% tertiles in all ethnic groups. Consistently, the HFF% correlated with EIC and HIRI, irrespective of the ethnic background, after adjustment for age, sex, ethnicity, adiposity, waist‐hip ratio, pubertal status and plasma glucose levels. An increased HFF% at follow‐up was associated with decreased EIC and increased HIRI across all groups. Conclusions: Intrahepatic lipid accumulation is associated with reduced insulin clearance and hepatic insulin sensitivity in obese youths, irrespective of their ethnic background. [ABSTRACT FROM AUTHOR]

Aims: Recent clinical studies have shown enhanced brain glucose uptake during clamp and brain fatty acid uptake in insulin‐resistant individuals. Preclinical studies suggest that the brain may be involved in the control of insulin secretion. The aim of this study was to investigate whether brain metabolism assessed as brain glucose and fatty acid uptake is associated with the parameters of β‐cell function in humans. Materials and methods: We analysed cross‐sectional data of 120 subjects across a wide range of BMI and insulin sensitivity. Brain glucose uptake (BGU) was measured during euglycaemic‐hyperinsulinaemic clamp (n = 67) and/or during fasting (n = 45) using [18F]‐fluorodeoxyglucose (FDG) positron emission tomography (PET). In another group of subjects (n = 34), brain fatty acid uptake was measured using [18F]‐fluoro‐6‐thia‐heptadecanoic acid (FTHA) PET during fasting. The parameters of β‐cell function were derived from OGTT modelling. Statistical analysis was performed with whole‐brain voxel‐based statistical parametric mapping. Results: In non‐diabetics, BGU during euglycaemic hyperinsulinaemic clamp correlated positively with basal insulin secretion rate (r = 0.51, P =.0008) and total insulin output (r = 0.51, P =.0008), whereas no correlation was found in type 2 diabetics. BGU during clamp correlated positively with potentiation in non‐diabetics (r = 0.33, P =.02) and negatively in type 2 diabetics (r = −0.61, P =.02). The associations in non‐diabetics were not explained with whole‐body insulin sensitivity or BMI. No correlations were found between baseline (fasting) BGU and basal insulin secretion rate, whereas baseline brain fatty acid uptake correlated directly with basal insulin secretion rate (r = 0.39, P =.02) and inversely with potentiation (r = −0.36, P =.04). Conclusions: Our study provides coherent, though correlative, evidence that, in humans, the brain may be involved in the control of insulin secretion independently of insulin sensitivity. [ABSTRACT FROM AUTHOR]

Aim: Dipeptidyl peptidase‐4 (DPP‐4) inhibition has effects on both fasting and postprandial glucose. However, the extent of this effect over the whole day and whether different DPP‐4 inhibitors have the same effects have not been established. We therefore explored the whole day effects of three different DPP‐4 inhibitors versus placebo on glucose, islet and incretin hormones after ingestion of breakfast, lunch and dinner in subjects with metformin‐treated and well‐controlled type 2 diabetes. Methods: The study was single‐centre and crossover designed, involving 24 subjects [12 men, 12 women, mean age 63 years, body mass index 31.0 kg/m2, glycated haemoglobin 44.7 mmol/mol (6.2%)], who underwent four test days in random order. Each whole day test included ingestion of standardized breakfast (525 kcal), lunch (780 kcal) and dinner (560 kcal) after intake of sitagliptin (100 mg) or vildagliptin (50 mg twice), or saxagliptin (5 mg) or placebo. Results: Compared with placebo, DPP‐4 inhibition reduced glucose levels, increased beta‐cell function (insulin secretory rate in relation to glucose), suppressed glucagon, increased intact glucagon‐like‐peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) but suppressed total GLP‐1 and GIP after all three meals. The effects were sustained throughout the daytime period with similar changes after each meal and did not differ between the DPP‐4 inhibitors. Conclusions: DPP‐4 inhibition has persistent daytime effects on glucose, islet and incretin hormones with no difference between three different DPP‐4 inhibitors. [ABSTRACT FROM AUTHOR]

Objective: To identify meaningful predictors and to develop a nomogram of postoperative surgical complications in patients treated with partial nephrectomy (PN). Patients and Methods: We prospectively evaluated 4308 consecutive patients who had surgical treatment for renal tumours, between 2013 and 2016, at 26 Italian urological centres (RECORd 2 project). A multivariable logistic regression for surgical complications was performed. A nomogram was created from the multivariable model. Internal validation processes were performed using bootstrapping with 1000 repetitions. Results: Overall, 2584 patients who underwent PN were evaluated for the final analyses. The median (interquartile [IQR]) American Society of Anesthesiologists (ASA) score was 2 (2–3). In all, 72.4% of patients had clinical T1a (cT1a) stage tumours. The median (IQR) Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) score was 7 (6–8). Overall, 34.3%, 27.7%, 38% of patients underwent open PN (OPN), laparoscopic PN (LPN), and robot‐assisted PN (RAPN). Overall and major postoperative surgical complications were recorded in 10.2% and 2.5% of patients, respectively. At multivariable analysis, age, ASA score, cT2 vs cT1a stage, PADUA score, preoperative anaemia, OPN and LPN vs RAPN, were significant predictive factors of postoperative surgical complications. We used these variables to construct a nomogram for predicting the risk of postoperative surgical complications. At decision curve analysis, the nomogram led to superior outcomes for any decision associated with a threshold probability of >5%. Conclusion: Several clinical predictors have been associated with postoperative surgical complications after PN. We used this information to develop and internally validate a nomogram to predict such risk. [ABSTRACT FROM AUTHOR]

AIMS: One‐hour post‐load hyperglycaemia has been proposed as an independent predictor of type 2 diabetes in adults. We examined whether 1‐hour plasma glucose (1hPG) during an oral glucose tolerance test (OGTT) can predict changes in the glucose tolerance status of a multi‐ethnic cohort of youths with normal glucose tolerance (NGT). Materials and methods: A total of 202 obese youths with NGT (33.7% Caucasian, 31.1% Hispanic, 32.2% African American) underwent a 3‐hour OGTT at baseline and after a 2‐year follow‐up period. Whole‐body insulin sensitivity, insulin secretion, β‐cell function and insulin clearance were estimated by modeling plasma glucose, insulin and C‐peptide levels. Results: Obese youths with 1hPG ≥7.4 mmol/L (or 133 mg/dL; n = 83) exhibited higher body mass index (BMI), plasma triglycerides and fasting and post‐load glucose concentrations than individuals with 1hPG <7.4 mmol/L. Also, 1hPG ≥7.4 mmol/L was associated with a lower disposition index (DI) (P < 0.0001) and with alterations in whole‐body insulin sensitivity, β‐cell function and insulin clearance. Adolescents with 1hPG ≥7.4 mmol/L were approximately three times more likely to develop prediabetes (ie, impaired glucose tolerance and/or impaired fasting glucose) over time (OR, 2.92 [1.22‐6.98]; P = 0.02), independent of age, sex, race/ethnicity, BMI, insulin sensitivity, DI and plasma glucose concentrations. No differences emerged in the risk of prediabetes related to 1‐hour hyperglycaemia among different ethnic groups. Conclusions: A plasma glucose concentration ≥ 7.4 mmol/L at 1 hour during an OGTT is associated with a worse clinical and metabolic phenotype and may be an independent predictor of progression to prediabetes in obese youths with NGT. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the ability of original tumour contact surface area (CSA) to predict postoperative complications and renal function impairment in a series of patients who underwent elective partial nephrectomy (PN) for renal masses. Materials and Methods: We analysed the clinical records of 531 consecutive patients who underwent elective PN because of a suspicion of kidney cancer at five academic, high‐volume centres between January 2014 and December 2016. Each participating centre evaluated prospectively the radiological images to evaluate the CSA and to assign a PADUA score. Several expert surgeons performed the surgical procedures in each participating centre. Binary logistic regression was used to perform both univariable and multivariable analyses to identify predictors of postoperative complications. Linear regression analysis was used to identify independent predictors of absolute change in estimated glomerular filtration rate (eGFR; ACE). Results: The median (interquartile range) CSA value was 14.2 (7.4–25.1) cm2. A total of 349 tumours (65.7%) had a CSA ≤ 20 cm2 and the remaining 182 (34.3%) had a CSA > 20 cm2. PNs were performed using an open approach in 237 (44.6%) cases, a pure laparoscopic approach in 152 cases (28.6%), and a robot‐assisted approach in the remaining 142 cases (26.7%). Multivariable analyses found that only age (odds ratio [OR] 1.037, 95% confidence interval [CI] 1.018–1.057) and PADUA score (OR 1.289, 95%CI 1.132–1.469) were independent predictors of postoperative complications. Tumour CSA (OR 1.020, 95%CI 1.010–1.030) was found to be an independent predictor of postoperative complications only when PADUA score was removed from the model. Age (from −0.639 to −0.306; P < 0.001); body mass index (from 0.267 to 1.076; P = 0.001), age‐adjusted Charlson score (from −3.193 to −0.259; P = 0.02), preoperative eGFR value (from −0.939 to −0.862; P < 0.001) and tumour CSA (from −0.260 to −0.048; P = 0.005) were found to be independent predictors of ACE. Conclusions: Tumour CSA is an independent predictor of postoperative renal function. Conversely, at multivariable analysis, PADUA score outperformed tumour CSA to predict postoperative complications after PN. The complexity of The Leslie et al. formula for calculating tumour CSA is a potential limitation with regard to its diffusion and application in clinical practice. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the ability of original tumour contact surface area (CSA) to predict postoperative complications and renal function impairment in a series of patients who underwent elective partial nephrectomy (PN) for renal masses. Materials and Methods: We analysed the clinical records of 531 consecutive patients who underwent elective PN because of a suspicion of kidney cancer at five academic, high‐volume centres between January 2014 and December 2016. Each participating centre evaluated prospectively the radiological images to evaluate the CSA and to assign a PADUA score. Several expert surgeons performed the surgical procedures in each participating centre. Binary logistic regression was used to perform both univariable and multivariable analyses to identify predictors of postoperative complications. Linear regression analysis was used to identify independent predictors of absolute change in estimated glomerular filtration rate (eGFR; ACE). Results: The median (interquartile range) CSA value was 14.2 (7.4–25.1) cm2. A total of 349 tumours (65.7%) had a CSA ≤ 20 cm2 and the remaining 182 (34.3%) had a CSA > 20 cm2. PNs were performed using an open approach in 237 (44.6%) cases, a pure laparoscopic approach in 152 cases (28.6%), and a robot‐assisted approach in the remaining 142 cases (26.7%). Multivariable analyses found that only age (odds ratio [OR] 1.037, 95% confidence interval [CI] 1.018–1.057) and PADUA score (OR 1.289, 95%CI 1.132–1.469) were independent predictors of postoperative complications. Tumour CSA (OR 1.020, 95%CI 1.010–1.030) was found to be an independent predictor of postoperative complications only when PADUA score was removed from the model. Age (from −0.639 to −0.306; P < 0.001); body mass index (from 0.267 to 1.076; P = 0.001), age‐adjusted Charlson score (from −3.193 to −0.259; P = 0.02), preoperative eGFR value (from −0.939 to −0.862; P < 0.001) and tumour CSA (from −0.260 to −0.048; P = 0.005) were found to be independent predictors of ACE. Conclusions: Tumour CSA is an independent predictor of postoperative renal function. Conversely, at multivariable analysis, PADUA score outperformed tumour CSA to predict postoperative complications after PN. The complexity of The Leslie et al. formula for calculating tumour CSA is a potential limitation with regard to its diffusion and application in clinical practice. [ABSTRACT FROM AUTHOR]

The aim of the present review was to assess the prognostic impact of lymphovascular invasion (LVI) in transurethral resection (TUR) of bladder cancer (BCa) specimens on clinical outcomes. A systematic review and meta‐analysis of the available literature from the past 10 years was performed using MEDLINE, EMBASE and Cochrane library in August 2017. The protocol for this systematic review was registered on PROSPERO (Central Registration Depository: CRD42018084876) and is available in full on the University of York website. Overall, 33 studies (including 6194 patients) evaluating the presence of LVI at TUR were retrieved. LVI was detected in 17.3% of TUR specimens. In 19 studies, including 2941 patients with ≤cT1 stage only, LVI was detected in 15% of specimens. In patients with ≤cT1 stage, LVI at TUR of the bladder tumour (TURBT) was a significant prognostic factor for disease recurrence (pooled hazard ratio [HR] 1.97, 95% CI: 1.47–2.62) and progression (pooled HR 2.95, 95% CI: 2.11–4.13), without heterogeneity (I2 = 0.0%, P = 0.84 and I2 = 0.0%, P = 0.93, respectively). For patients with cT1–2 disease, LVI was significantly associated with upstaging at time of radical cystectomy (pooled odds ratio 2.39, 95% CI: 1.45–3.96), with heterogeneity among studies (I2 = 53.6%, P = 0.044). LVI at TURBT is a robust prognostic factor of disease recurrence and progression in non‐muscle invasive BCa. Furthermore, LVI has a strong impact on upstaging in patients with organ‐confined disease. The assessment of LVI should be standardized, reported, and considered for inclusion in the TNM classification system, helping clinicians in decision‐making and patient counselling. [ABSTRACT FROM AUTHOR]

Excess insulin secretion and hyperinsulinaemia contribute to the progression of type 2 diabetes. However, the mechanisms leading to insulin hypersecretion remain largely unknown. Based on our preliminary data, we examined whether triglycerides and very low‐density lipoprotein (VLDL) are independently associated with insulin secretion, and whether ethnicity/race modulates these associations. Fasting triglycerides and VLDL were measured in a multiethnic cohort of 630 non‐diabetic adolescents. Insulin secretion, β‐cell function parameters, insulin sensitivity and insulin clearance were estimated through a 3‐h oral glucose tolerance test. Metabolic assessments were repeated after 2 years in 239 subjects. Triglycerides and triglyceride‐rich VLDL (large and medium size fractions) were associated with both basal and glucose‐stimulated insulin secretion, after adjustment for age, sex, ethnicity, BMI z‐score, plasma glucose, and insulin sensitivity. Ethnicity per se had an impact on lipid profile and β‐cell function, but did not modulate the effect of triglycerides/VLDL on insulin secretion. At follow‐up, changes in triglyceride levels were proportional to changes in insulin secretion. These findings support the hypothesis that hypertriglyceridaemia is an important stimulus for β‐cell insulin release in young people under both fasting and fed conditions. [ABSTRACT FROM AUTHOR]

Aims: To investigate the physiological mechanisms leading to rapid improvement in diabetes after Roux‐en‐Y gastric bypass (RYGB) and specifically the contribution of the concurrent peri‐operative dietary restrictions, which may also alter glucose metabolism. Materials and methods: In order to assess the differential contributions of diet and surgery to the mechanisms leading to the rapid improvement in diabetes after RYGB we enrolled 10 patients with type 2 diabetes scheduled to undergo RYGB. All patients underwent a 10‐day inpatient supervised dietary intervention equivalent to the peri‐operative diet (diet‐only period), followed by, after a re‐equilibration (washout) period, an identical period of pair‐matched diet in conjunction with RYGB (diet and RYGB period). We conducted extensive metabolic assessments during a 6‐hour mixed‐meal challenge test, with stable isotope glucose tracer infusion performed before and after each intervention. Results: Similar improvements in glucose levels, β‐cell function, insulin sensitivity and post‐meal hepatic insulin resistance were observed with both interventions. Both interventions led to significant reductions in fasting and postprandial acyl ghrelin. The diet‐only intervention induced greater improvements in basal hepatic glucose output and post‐meal gastric inhibitory polypeptide (GIP) secretion. The diet and RYGB intervention induced significantly greater increases in post‐meal glucagon‐like peptide‐1 (GLP‐1), peptide YY (PYY) and glucagon levels. Conclusions: Strict peri‐operative dietary restriction is a main contributor to the rapid improvement in glucose metabolism after RYGB. The RYGB‐induced changes in the incretin hormones GLP‐1 and PYY probably play a major role in long‐term compliance with such major dietary restrictions through central and peripheral mechanisms. [ABSTRACT FROM AUTHOR]

Aim: To study the effects of angiotensin receptor blockers (ARBs) on insulin secretion in hypertensive patients with type 2 diabetes. Materials and methods: A total of 41 patients were enrolled in this open‐label, active comparator‐controlled, crossover study. After a 2‐week run‐in period with amlodipine, the participants were assigned to receive either fimasartan (60–120 mg daily) or amlodipine (5–10 mg daily) for 16 weeks. Thereafter, they were treated with the other drug for another 16 weeks. Physical examinations and laboratory tests were performed before and after each treatment. Results: Blood pressure, glycated haemoglobin and oral glucose tolerance test (OGTT) values were similar with each treatment. Fimasartan treatment significantly increased median (range) homeostatic assessment of β‐cell function values (49.9 [22.5–174.4] vs 46.9 [15.6–148.0]), area under the curve of insulin during OGTT (27 284 [9501–94 525] vs 26 818 [8112–76 704] pmol/L × min), insulinogenic index at 60 minutes (19.7 [3.0–131.2] vs 15.0 [2.4–103.8] pmol/mmol) and at 120 minutes (19.1 [1.9–85.5] vs 12.6 [−4.3–178.8] pmol/mmol) compared with those with amlodipine (all P < .05); however, acute insulin response and insulin resistance indices were similar for both agents. Conclusions: Compared with amlodipine, fimasartan increased late‐phase glucose‐stimulated insulin secretion in patients with type 2 diabetes and hypertension. This finding suggests that ARBs would be more beneficial in such patients compared with other classes of anti‐hypertensives. [ABSTRACT FROM AUTHOR]

To explore the effects of a single dose of the DPP‐4 inhibitor sitagliptin on glucose‐standardized insulin secretion and β‐cell glucose sensitivity after meal ingestion, 12 healthy and 12 drug‐naïve, well‐controlled type 2 diabetes (T2D) subjects (mean HbA1c 43 mmol/mol, 6.2%) received sitagliptin (100 mg) or placebo before a meal (525 kcal). β‐cell function was measured as the insulin secretory rate at a standardized glucose concentration and the β‐cell glucose sensitivity (the slope between glucose and insulin secretory rate). Incretin levels were also monitored. Sitagliptin increased standardized insulin secretion, in both healthy and T2D subjects, compared to placebo, but without increasing β‐cell glucose sensitivity. Sitagliptin also increased active glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) and reduced total (reflecting the secretion) GIP, but not total GLP‐1 levels. We conclude that a single dose of DPP‐4 inhibition induces dissociated effects on different aspects of β‐cell function and incretin hormones after meal ingestion in both healthy and well‐controlled T2D subjects. [ABSTRACT FROM AUTHOR]

Objective: To describe our step‐by‐step technique for robotic intracorporeal neobladder configuration, including the stages of conception, development and exploration of this surgical innovation, according to the Idea, Development, Exploration, Assessment, Long‐term follow‐up (IDEAL) Collaboration guidelines. Patients and Methods: The Florence robotic intracorporeal neobladder (FloRIN) was performed employing the following main surgical steps: isolation of 50 cm of ileum; bowel anastomosis; urethro‐ileal anastomosis creating an asymmetrical ‘U’‐shape (30 cm distally and 20 cm proximally to anastomosis), ileum detubularisation; posterior wall reconfiguration as an ‘L’; bladder neck reconstruction; anterior folding of the posterior plate to reach the 12 o'clock position; uretero‐enteral ‘orthotopic’ bilateral anastomosis. The conception and development of the FloRIN followed the IDEAL guidelines recommended stages: Phase 1 (simulation) involved the neobladder robotic configuration using silicone models. Phase 2a (development) aimed to reproduce the configuration in an open fashion in one patient, and then in the first three robotic procedures. Phase 2b (exploration) consisted of the technique standardisation in 15 consecutive robotic approaches. Phase 2a and 2b included urodynamics and imaging assessment of the patients treated. Results: From February 2016 to September 2017 FloRIN was performed in 18 patients. Comparing the first three (Phase 2a) with the subsequent 15 patients (Phase 2b), the median (interquartile range [IQR]) reconstruction operating time was 260 (220–340) vs 160 (150–210) min, respectively. Postoperative surgical complications occurred in four of the 18 patients (22.1%), including one surgical Clavien–Dindo Grade III and three Grade I, postoperative medical Clavien–Dindo Grade II complications occurred in three (16.7%) patients. On urodynamic examination (available in nine [50%] patients) the median (IQR) reservoir cystometric capacity, compliance, and post‐void residual were 240 (220–267) mL, 18 (12.5–19.8) mL/cmH2O, and 0 (0–50) mL, respectively. Ultrasonography showed no Grade ≥2 vesico‐ureteric reflux. Conclusion: We describe the FloRIN configuration, showing its technical feasibility with acceptable time efficiency. The first cases studied had good reservoir capacity, low pressure with no reflux, and complete voiding. [ABSTRACT FROM AUTHOR]

Aims To investigate the effect of exenatide on glucose disposal, insulin secretion, ß-cell function, lipolysis and hormone concentrations in non-diabetic, morbidly obese subjects under physiological conditions. Materials and methods Patients were assigned to exenatide 10 µg twice daily ( EXE, n = 15) or control ( CT, n = 15) for 3 months. Patients received a meal test/tracer study ( MTT) to measure endogenous glucose production ( EGP), rate of oral glucose appearance ( RaO), insulin secretion rate ( ISR), ß-cell function, hepatic insulin resistance ( HIR) and adipose tissue insulin resistance ( AT-IR) and insulin sensitivity ( IS). Results Post treatment, the EXE group showed a significant reduction in body weight ( P < .001). The postmeal time-course of glucose, insulin and ISR showed a lower peak between 60 and 180 minutes in phase with a reduction in RaO ( P < .01). After an initial similar suppression, EGP resumed at higher rates between 60 and 180 minutes ( P = .02) in EXE vs CT, while total RaO and EGP were similar throughout the MTT. In EXE, the postmeal glucagon, GLP1 and GIP responses were reduced ( P < .05). Fasting and postprandial lipolysis and ß-cell function were unaltered by active treatment. HIR, AT-IR and IS were all improved after exenatide treatment ( P < .05). Conclusions In morbidly obese non-diabetic subjects, exenatide causes weight loss, decreased postprandial glycaemia and glucagon response without changes in ß-cell function. These effects are consequent upon delayed oral glucose appearance in the circulation. Exenatide treatment is also associated with an improvement in hepatic, adipose tissue and whole-body IS with no influence on postprandial lipolysis. [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 To evaluate the efficacy of hemostatic agents, TachoSil and FloSeal, during partial nephrectomy using a large multicenter dataset. Methods Data of 1055 patients who underwent partial nephrectomy between January 2009 and December 2012 in 19 Italian centers were collected within an observational multicentric study ( RECORd Project). The decision whether or not to use hemostatic agents after renorrhaphy and the type of hemostatic agents applied was adopted according to the centers' and surgeons' preference. A Tri Match propensity score analysis was applied to balance three study groups (no hemostatic agents, TachoSil, FloSeal) for sex, age, surgical indication (elective/relative vs imperative), clinical stage ( cT1a vs cT1b), tumor exophyticity, approach (open vs minimally invasive), technique (standard partial nephrectomy vs simple enucleation), preoperative hemoglobin and creatinine. Postoperative complications and variation of hemoglobin and creatinine values between preoperative versus third postoperative day were compared. Results Tri Match analysis allowed us to obtain 66 well-balanced triplets. No differences were found in terms of outcomes between the study groups. Conclusions The present findings suggest that adding hemostatic agents to renorraphy during partial nephrectomy does not provide better surgical outcomes. [ABSTRACT FROM AUTHOR]

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]

The article focuses on a study which examines the surgical and postoperative outcomes of consecutive patients treated with robot-assisted pyeloplasty (RAP) for ureteropelvic junction obstruction and absence of drain placement in a tertiary referral health center. Results show that RAP can be considered as a safe minimally invasive treatment approach for ureteropelvic junction obstruction.

The article examines the efficacy of robot-assisted laparoscopic and open partial nephrectomy in patients with chronic kidney disease. Topics discussed include need for partial nephrectomy (PN) treatment of clinical T1 renal tumors in patients with chronic kidney disease; role of avoiding or reducing functional damage related to surgical modifiable parameters; and concludes that the patients undergoing RAPN have a significantly lower rate of overall complications and bleeding.