Minimally invasive transperitoneal partial versus radical nephrectomy in obese patients: perioperative and long-term functional outcomes from a large perspective contemporary series (RECORd2 project).

BACKGROUND: The aim of this study is to evaluate the perioperative and long-term functional outcomes of laparoscopic (LPN) and robot-assisted partial nephrectomy (RAPN) in comparison to laparoscopic radical nephrectomy (LRN) in obese patients diagnosed with renal cell carcinoma. METHODS: Clinical data of 4325 consecutive patients from The Italian REgistry of COnservative and Radical Surgery for cortical renal tumor Disease (RECORD 2 Project) were gathered. Only patients treated with transperitoneal LPN, RAPN, or LRN with Body Mass Index (BMI) ≥30 kg/m2, clinical T1 renal tumor and preoperative estimated glomerular filtration rate (eGFR) ≥60 mL/min, were included. Perioperative, and long-term functional outcomes were examined. RESULTS: Overall, 388 patients were included, of these 123 (31.7%), 120 (30.9%) and 145 (37.4%) patients were treated with LRN, LPN, and RAPN, respectively. No significant difference was observed in preoperative characteristics. Overall, intra and postoperative complication rates were comparable among the groups. The LRN group had a significantly increased occurrence of acute kidney injury (AKI) compared to LPN and RAPN (40.6% vs. 15.3% vs. 7.6%, P=0.001). Laparoscopic RN showed a statistically significant higher renal function decline at 60-month follow-up assessment compared to LPN and RAPN. A significant renal function loss was recorded in 30.1% of patients treated with LRN compared to 16.7% and 10.3% of patients treated with LPN and RAPN (P=0.01). CONCLUSIONS: In obese patients, both LPN and RAPN showcased comparable complication rates and higher renal function preservation than LRN. These findings highlighted the potential benefits of minimally invasive PN over radical surgery in the context of obese individuals.

Is it safe to defer prostate cancer treatment? Assessing the impact of surgical delay on the risk of pathological upstaging after robot-assisted radical prostatectomy.

INTRODUCTION: We sought to investigate whether surgical delay may be associated with pathological upstaging in patients treated with robot assisted radical prostatectomy (RARP) for localized and locally advanced prostate cancer (PCa). MATERIALS AND METHODS: Consecutive firstly-diagnosed PCa patients starting from March 2020 have been enrolled. All the patients were categorized according to EAU risk categories for PCa risk. Uni- and multivariate analysis were fitted to explore clinical and surgical predictors of pathological upstaging to locally advanced disease (pT3/pT4 - pN1 disease). RESULTS: Overall 2017 patients entered the study. Median age at surgery was 68 (IQR 63-73) years. Overall low risk, intermediate risk, localized high risk and locally advanced disease were recorded in 368 (18.2 %), 1071 (53.1 %), 388 (19.2 %) and 190 (9.4 %), respectively. Median time from to diagnosis to treatment was 51 (IQR 29-70) days. Time to surgery was 56 (IQR 32-75), 52 (IQR 30-70), 45 (IQR 24-60) and 41 (IQR 22-57) days for localized low, intermediate and high risk and locally advanced disease, respectively. Considering 1827 patients with localized PCa, at multivariate analysis ISUP grade group ≥4 on prostate biopsy (HR: 1.30; 95 % CI 1.07-1.86; p = 0.02) and surgical delay only in localized high-risk disease (HR: 1.02; 95 % CI 1.01-1.54; p = 0.02) were confirmed as independent predictors of pathological upstaging to pT3-T4/pN1 disease at final histopathological examination. CONCLUSIONS: In localized high-risk disease surgical delay could be associated with a higher risk of adverse pathologic findings.

Select DYRK1A Inhibitors Enhance Both Proliferation and Differentiation in Human Pancreatic Beta Cells.

The small molecule DYRK1A inhibitor, harmine, induces human beta cell proliferation, expands beta cell mass, enhances expression of beta cell phenotypic genes, and improves human beta cell function i n vitro and in vivo . It is unknown whether the "pro-differentiation effect" is a DYRK1A inhibitor class-wide effect. Here we compare multiple commonly studied DYRK1A inhibitors. Harmine, 2-2c and 5-IT increase expression of PDX1, MAFA, NKX6.1, SLC2A2, PCSK1, MAFB, SIX2, SLC2A2, SLC30A8, ENTPD3 in normal and T2D human islets. Unexpectedly, GNF4877, CC-401, INDY, CC-401 and Leucettine fail to induce expression of these essential beta cell molecules. Remarkably, the pro-differentiation effect is independent of DYRK1A inhibition: although silencing DYRK1A induces human beta cell proliferation, it has no effect on differentiation; conversely, harmine treatment enhances beta cell differentiation in DYRK1A-silenced islets. A careful screen of multiple DYRK1A inhibitor kinase candidate targets was unable to identify pro-differentiation pathways. Overall, harmine, 2-2c and 5-IT are unique among DYRK1A inhibitors in their ability to enhance both beta cell proliferation and differentiation. While beta cell proliferation is mediated by DYRK1A inhibition, the pro-differentiation effects of harmine, 2-2c and 5-IT are distinct, and unexplained in mechanistic terms. These considerations have important implications for DYRK1A inhibitor pharmaceutical development.

3D virtual model for robot-assisted partial nephrectomy in highly-complex cases (PADUA ⩾ 10).

PURPOSE: To compare two cohorts of patients submitted to robot-assisted partial nephrectomy (RAPN) for highly-complex renal masses (PADUA ⩾ 10) with versus without the use of 3DVMs. MATERIALS AND METHODS: We screened a prospective consecutive cohort of 152 patients submitted to RAPN with 3DVM and 1264 patients submitted to RAPN without 3DVM between 2019 and 2022. Only PADUA ⩾ 10 cases were considered eligible for analysis. Propensity score matching (PSM) analysis was applied. Primary endpoint was to evaluate whereas RAPNs with 3DVM were superior in terms of functional outcomes at 12-month. Secondary outcomes were to compare perioperative and oncological outcomes. Multivariable logistic regression analyses (MVA) tested the associations of clinically significant eGFR drop and 3DVMs. Subgroups analysis was performed for PAUDA-risk categories. RESULTS: Thirty seven patients for each group were analyzed after PSM. RAPN with 3DVM presented a higher rate of selective/no clamping procedure (32.5% vs 16.2%, p = 0.03) and a higher enucleation rate (43.2% vs 29.8%, p = 0.04). Twelve-month functional preservation performed better within 3DVM group in terms of creatinine serum level (median 1.2 [IQR 1.1-1.4] vs 1.6 [IQR 1.1-1.8], p = 0.03) and eGFR (median 64.6 [IQR 56.2-74.1] vs 52.3 [IQR 49.2-74.1], p = 0.03). MVA confirmed 3DVM as a protective factor for clinically significant eGFR drop in this subgroup of patients. CONCLUSIONS: RAPN performed with the use of 3DVM assistance for PADUA ⩾ 10 cases resulted in lower incidence of global ischemia and higher rate of enucleations. The positive impact of such technology was found at 12-month follow-up.

Step by step technique of Stentless Florence Robotic Intracorporeal Neobladder (FloRIN), does the ureteral management influence functional outcomes?

INTRODUCTION: Benefits and harms of avoid the sent placement during IntraCorporeal Neobladder configuration are still debated. Our objective was to describe the step-by-step technique of Florence intracorporeal neobladder (FloRIN) configuration performed with stentless procedure focusing on perioperative and mid-term functional outcomes. MATERIALS AND METHODS: In this single institution prospective randomized 1:1 series all consecutive patients underwent Robot-Assisted Radical Cystectomy (RARC) and FloRIN reconfiguration from January 2021 to March 2021 were enrolled. Functional perioperative and mid-term outcomes were gathered. Postoperative complications were graded according to Clavien-Dindo classification and divided in early (<30 days from discharge) and delayed (>30 days). RESULTS: Overall, 10 patients were included in the analysis. Of these, the 50.0% was treated with Stentless FloRIN. In terms of baseline features, no differences were recorded between the two groups. Median age was 65 and 66 years while median BMI was 27 and 25 in the stentless and in the stent group, respectively. Concerning intraoperative variables, no intraoperative complications as well as open conversion occurred among both groups. As regard introperative features, a shorter console time was associated with stentless procedure (331 min vs 365 min). In terms of perioperative outcomes, canalization and time to drainage removal didn't differ between groups while length of hospital stay was significantly lower in stentless group 10 days versus 14 days. Early and delayed postoperative complication rate was not influenced by the ureteral management at a preliminary assessment with comparable rates of Clavien Dindo ⩾ 3a between the two groups. Mid-term functional outcomes did not differ between groups in terms of kidney function loss. CONCLUSIONS: FloRIN with Stentless technique showed functional and perioperative preliminary outcomes comparable with the standard ureteral management strategy. Further series with longer functional follow-up assessment will be needed to confirm our preliminary results.

Three-dimensional virtual model for robot-assisted partial nephrectomy: a propensity-score matching analysis with a contemporary control group.

PURPOSE: To compare two cohorts of patients submitted to robot-assisted partial nephrectomy (RAPN) with vs without the use of three-dimensional virtual models (3DVMs). METHODS: We screened a prospective consecutive cohort of 152 patients submitted to RAPN with 3DVM and 1264 patients submitted to RAPN without 3DVM between 2019 and 2022. Propensity score matching analysis (PSMA) was applied. Primary endpoint was to evaluate whereas RAPNs with 3DVM were superior in terms of functional outcomes at 12-month. Secondary endopoints were to compare perioperative and oncological outcomes. Multivariable logistic regression analyses (MVA) tested the associations of clinically significant eGFR drop and 3DVMs. Subgroups analysis was performed for PAUDA-risk categories. RESULTS: 100 patients for each group were analyzed after PSMA. RAPN with 3DVM presented a higher rate of selective/no clamping procedure (32% vs 16%, p = 0.03) and a higher enucleation rate (40% vs 29%, p = 0.04). As concern to primary endopoint, 12-month functional preservation performed better within 3DVM group in terms of creatinine serum level (median 1.2 [IQR 1.1-1.4] vs 1.6 [IQR 1.1-1.8], p = 0.03) and eGFR (median 64.6 [IQR 56.2-74.1] vs 52.3 [IQR 49.2-74.1], p = 0.03). However, this result was confirmed only in the PADUA ≥ 10 renal masses. Regarding secondary endpoints, no significative difference emerged between the two cohorts. MVA confirmed 3DVM as a protective factor for clinically significant eGFR drop only in high-risk (PADUA ≥ 10) masses. CONCLUSIONS: RAPN performed with the use of 3DVM assistance resulted in lower incidence of global ischemia and higher rate of enucleations. The positive impact of such technology was found at 12-month only in high-risk renal masses.

NRF2 is required for neonatal mouse beta cell growth by maintaining redox balance and promoting mitochondrial biogenesis and function.

AIMS/HYPOTHESIS: All forms of diabetes result from insufficient functional beta cell mass. Due to the relatively limited expression of several antioxidant enzymes, beta cells are highly vulnerable to pathological levels of reactive oxygen species (ROS), which can lead to the reduction of functional beta cell mass. During early postnatal ages, both human and rodent beta cells go through a burst of proliferation that quickly declines with age. The exact mechanisms that account for neonatal beta cell proliferation are understudied but mitochondrial release of moderated ROS levels has been suggested as one of the main drivers. We previously showed that, apart from its conventional role in protecting beta cells from oxidative stress, the nuclear factor erythroid 2-related factor 2 (NRF2) is also essential for beta cell proliferation. We therefore hypothesised that NRF2, which is activated by ROS, plays an essential role in beta cell proliferation at early postnatal ages. METHODS: Beta cell NRF2 levels and beta cell proliferation were measured in pancreatic sections from non-diabetic human cadaveric donors at different postnatal ages, childhood and adulthood. Pancreatic sections from 1-, 7-, 14- and 28-day-old beta cell-specific Nrf2 (also known as Nfe2l2)-knockout mice (ßNrf2KO) or control (Nrf2lox/lox) mice were assessed for beta cell NRF2 levels, beta cell proliferation, beta cell oxidative stress, beta cell death, nuclear beta cell pancreatic duodenal homeobox protein 1 (PDX1) levels and beta cell mass. Seven-day-old ßNrf2KO and Nrf2lox/lox mice were injected daily with N-acetylcysteine (NAC) or saline (154 mmol/l NaCl) to explore the potential contribution of oxidative stress to the phenotypes seen in ßNrf2KO mice at early postnatal ages. RNA-seq was performed on 7-day-old ßNrf2KO and Nrf2lox/lox mice to investigate the mechanisms by which NRF2 stimulates beta cell proliferation at early postnatal ages. Mitochondrial biogenesis and function were determined using dispersed islets from 7-day-old ßNrf2KO and Nrf2lox/lox mice by measuring MitoTracker intensity, mtDNA/gDNA ratio and ATP/ADP ratio. To study the effect of neonatal beta cell-specific Nrf2 deletion on glucose homeostasis in adulthood, blood glucose, plasma insulin and insulin secretion were determined and a GTT was performed on 3-month-old ßNrf2KO and Nrf2lox/lox mice fed on regular diet (RD) or high-fat diet (HFD). RESULTS: The expression of the master antioxidant regulator NRF2 was increased at early postnatal ages in both human (1 day to 19 months old, 31%) and mouse (7 days old, 57%) beta cells, and gradually declined with age (8% in adult humans, 3.77% in adult mice). A significant correlation (R2=0.568; p=0.001) was found between beta cell proliferation and NRF2 levels in human beta cells. Seven-day-old ßNrf2KO mice showed reduced beta cell proliferation (by 65%), beta cell nuclear PDX1 levels (by 23%) and beta cell mass (by 67%), and increased beta cell oxidative stress (threefold) and beta cell death compared with Nrf2lox/lox control mice. NAC injections increased beta cell proliferation in 7-day-old ßNrf2KO mice (3.4-fold) compared with saline-injected ßNrf2KO mice. Interestingly, RNA-seq of islets isolated from 7-day-old ßNrf2KO mice revealed reduced expression of mitochondrial RNA genes and genes involved in the electron transport chain. Islets isolated from 7-day old ßNrf2KO mice presented reduced MitoTracker intensity (by 47%), mtDNA/gDNA ratio (by 75%) and ATP/ADP ratio (by 68%) compared with islets from Nrf2lox/lox littermates. Lastly, HFD-fed 3-month-old ßNrf2KO male mice displayed a significant reduction in beta cell mass (by 35%), a mild increase in non-fasting blood glucose (1.2-fold), decreased plasma insulin (by 14%), and reduced glucose tolerance (1.3-fold) compared with HFD-fed Nrf2lox/lox mice. CONCLUSIONS/INTERPRETATION: Our study highlights NRF2 as an essential transcription factor for maintaining neonatal redox balance, mitochondrial biogenesis and function and beta cell growth, and for preserving functional beta cell mass in adulthood under metabolic stress. DATA AVAILABILITY: Sequencing data are available in the NCBI Gene Expression Omnibus, accession number GSE242718 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242718 ).

Stentless florence robotic intracorporeal neobladder (FloRIN), a feasibility prospective randomized clinical trial.

INTRODUCTION: Aim of the study was to evaluate perioperative, postoperative and mid-term functional outcomes of Florence intracorporeal neobladder (FloRIN) configuration technique performed with stentless procedure. MATERIALS AND METHODS: This single institution randomized 1:1 prospective series included consecutive patients treated with Robot-Assisted Radical Cystectomy (RARC) and FloRIN reconfiguration from January 2021 to February 2022. Postoperative complications were graded according to Clavien Dindo classification and divided in early (<30 days from discharge) and delayed (>30 days). RESULTS: Overall, 63 patients were included in the analysis. Among these 32 (50.8 %) were treated with RARC + stentless FloRIN while 31 (49.2 %) underwent stent placement procedure. No differences were found in terms of baseline characteristics between the two groups. Stentless procedure was associated with significant shorter console time 328 vs 374 min (p = 0.04) and lower estimated blood loss (EBL) 330 vs 350 ml (p = 0.04) comparing to stent group. As regards perioperative features, no significant differences were recorded in terms of canalization (p = 0.58) and time to drainage removal (p = 0.11) while a shorter length of hospital stay was found in case of stentless procedure (p = 0.04). Early postoperative complications Clavien ≥ 3a occurred in 9.3 % and 12.9 % of patients while delayed major complications were recorded in the 3.1 % and 9.6 % of patients treated with stentless and stent FloRIN, respectively (p = 0.09). As regards the mid-term functional outcomes, no differences were found in terms of kidney function loss in both 3rd and 6th month assessment (p = 0.13 and p = 0.14, respectively). CONCLUSIONS: In conclusion, Stentless FloRIN is a feasible and safe IntraCorporeal Neobladder technique, as confirmed by the worthy functional and perioperative outcomes achieved in comparison with the standard FloRIN ureteral management strategy.

Development and internal validation of a nomogram predicting 3-year chronic kidney disease upstaging following robot-assisted partial nephrectomy.

PURPOSE: Aim of the present study was to develop and validate a nomogram to accurately predict the risk of chronic kidney disease (CKD) upstaging at 3 years in patients undergoing robot-assisted partial nephrectomy (RAPN). METHODS: A multi-institutional database was queried to identify patients treated with RAPN for localized renal tumor (cT1-cT2, cN0, cM0). Significant CKD upstaging (sCKD-upstaging) was defined as development of newly onset CKD stage 3a, 3b, and 4/5. Model accuracy was calculated according to Harrell C-index. Subsequently, internal validation using bootstrapping and calibration was performed. Then nomogram was depicted to graphically calculate the 3-year sCKD-upstaging risk. Finally, regression tree analysis identified potential cut-offs in nomogram-derived probability. Based on this cut-off, four risk classes were derived with Kaplan-Meier analysis tested this classification. RESULTS: Overall, 965 patients were identified. At Kaplan-Meier analysis, 3-year sCKD-upstaging rate was 21.4%. The model included baseline (estimated glomerular filtration rate) eGFR, solitary kidney status, multiple lesions, R.E.N.A.L. nephrometry score, clamping technique, and postoperative acute kidney injury (AKI). The model accurately predicted 3-year sCKD-upstaging (C-index 84%). Based on identified nomogram cut-offs (7 vs 16 vs 26%), a statistically significant increase in sCKD-upstaging rates between low vs intermediate favorable vs intermediate unfavorable vs high-risk patients (1.3 vs 9.2 vs 22 vs 54.2%, respectively, p < 0.001) was observed. CONCLUSION: Herein we introduce a novel nomogram that can accurately predict the risk of sCKD-upstaging at 3 years. Based on this nomogram, it is possible to identify four risk categories. If externally validated, this nomogram may represent a useful tool to improve patient counseling and management.

Transcriptional activation of the Myc gene by glucose in ß-cells requires a ChREBP-dependent 3-D chromatin interaction between the Myc and Pvt1 genes.

OBJECTIVE: All forms of diabetes result from insufficient functional ß-cell mass. Thus, achieving the therapeutic goal of expanding ß-cell mass requires a better mechanistic understanding of how ß-cells proliferate. Glucose is a natural ß-cell mitogen that mediates its effects in part through the glucose-responsive transcription factor, carbohydrate response element binding protein (ChREBP) and the anabolic transcription factor, MYC. However, mechanistic details by which glucose activates Myc at the transcriptional level are poorly understood. METHODS: Here, siRNA was used to test the role of ChREBP in the glucose response of MYC, ChIP and ChIPseq to identify potential regulatory binding sites, chromatin conformation capture to identify DNA/DNA interactions, and an adenovirus was constructed to expresses x-dCas9 and an sgRNA that specifically disrupts the recruitment of ChREBP to a specific targeted ChoRE. RESULTS: We found that ChREBP is essential for glucose-mediated transcriptional induction of Myc, and for increases in Myc mRNA and protein abundance. Further, ChIPseq revealed that the carbohydrate response element (ChoRE) nearest to the Myc transcriptional start site (TSS) is immediately upstream of the gene encoding the lncRNA, Pvt1, 60,000 bp downstream of the Myc gene. Chromatin Conformation Capture (3C) confirmed a glucose-dependent interaction between these two sites. Transduction with an adenovirus expressing x-dCas9 and an sgRNA specifically targeting the highly conserved Pvt1 ChoRE, attenuates ChREBP recruitment, decreases Myc-Pvt1 DNA/DNA interaction, and decreases expression of the Pvt1 and Myc genes in response to glucose. Importantly, isolated and dispersed rat islet cells transduced with the ChoRE-disrupting adenovirus also display specific decreases in ChREBP-dependent, glucose-mediated expression of Pvt1 and Myc, as well as decreased glucose-stimulated ß-cell proliferation. CONCLUSIONS: The mitogenic glucose response of Myc is mediated via glucose-dependent recruitment of ChREBP to the promoter of the Pvt1 gene and subsequent DNA looping with the Myc promoter.

Structure-Function Analysis of p57KIP2 in the Human Pancreatic Beta Cell Reveals a Bipartite Nuclear Localization Signal.

Mutations in CDKN1C, encoding p57KIP2, a canonical cell cycle inhibitor, underlie multiple pediatric endocrine syndromes. Despite this central role in disease, little is known about the structure and function of p57KIP2 in the human pancreatic beta cell. Since p57KIP2 is predominantly nuclear in human beta cells, we hypothesized that disease-causing mutations in its nuclear localization sequence (NLS) may correlate with abnormal phenotypes. We prepared RIP1 insulin promoter-driven adenoviruses encoding deletions of multiple disease-associated but unexplored regions of p57KIP2 and performed a comprehensive structure-function analysis of CDKN1C/p57KIP2. Real-time polymerase chain reaction and immunoblot analyses confirmed p57KIP2 overexpression, construct size, and beta cell specificity. By immunocytochemistry, wild-type (WT) p57KIP2 displayed nuclear localization. In contrast, deletion of a putative NLS at amino acids 278-281 failed to access the nucleus. Unexpectedly, we identified a second downstream NLS at amino acids 312-316. Further analysis showed that each individual NLS is required for nuclear localization, but neither alone is sufficient. In summary, p57KIP2 contains a classical bipartite NLS characterized by 2 clusters of positively charged amino acids separated by a proline-rich linker region. Variants in the sequences encoding these 2 NLS sequences account for functional p57KIP2 loss and beta cell expansion seen in human disease.

Redo Partial Nephrectomy for Local Recurrence After Previous Nephron-sparing Surgery. Surgical Insights and Oncologic Results from a High-volume Robotic Center.

Background: The role of redo partial nephrectomy (PN) for recurrent renal cell carcinoma (RCC) is still overlooked. Objective: To report our experience of salvage PN for local recurrence after previous nephron-sparing surgery (NSS). Design setting and participants: We prospectively gathered data from patients treated with robotic redo PN for locally recurrent RCC after previous NSS from January 2017 to January 2023. The type of surgical resection technique was assigned to the pathologic specimen according to the surface-intermediate-base (SIB) score. Surgical procedure: Redo PN was performed by using the Si Da Vinci robotic platform. Measurements: Operative time, warm ischemia time, and intra- and postoperative complications were recorded. The severity of postoperative complications and tumor stage were evaluated. Results and limitations: Overall, 26 patients entered the study. The median clinical diameter was 3.5 (interquartile range [IQR] 2.2-4.9) cm and the median Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) score was 8 (IQR 7-9). In 14 (53.8%) cases, recurrence was at the level of previous tumor resection bed. The median operative time was 177 (IQR 148-200) min, and hilar clamping was performed in 14 (53.8%) cases with a median warm ischemia time of 16 (14.5-22) min. Pure enucleation (SIB score 0-1), hybrid enucleation (SIB score 2), and pure enucleoresection (SIB score 3) were recorded in 13 (50%), eight (30.8%), and five (19.2%) cases, respectively. The totality of recurrent RCC far from previous tumor resection bed received a SIB score of 0-1, while in 57.1% and 35.8% of recurrent RCC on previous tumor resection a hybrid enucleation and a pure enucleoresection were performed, respectively. At a median follow-up of 37 (IQR 16-45) mo, five (19%) patients experienced disease recurrence, being local and systemic in three (11.5%) and two (7.7%) patients, respectively. Conclusions: Our study highlights the feasibility and safety of redo PN for the treatment of locally recurrent RCCs after NSS, either on previous tumor resection bed or elsewhere in the kidney. Patient summary: Robotic redo partial nephrectomy is a challenging procedure. The surgeon needs to tailor the surgical strategy and tumor resection technique case by case, given the heterogeneity of clinical scenarios and the need to achieve maximal functional preservation while ensuring oncologic efficacy.

Predictors of early catheter replacement after HoLEP. Results from a high-volume laser center

ABSTRACT Introduction: The aim of the study was to investigate clinical and surgical factors associated with early catheter replacement in patients treated with Holmium Laser Enucleation of the Prostate (HoLEP). Materials and Methods: Data of patients treated with HoLEP at our Institution by a single surgeon from March 2017 to January 2021 were collected. Preoperative variables, including non-invasive uroflowmetry and abdominal ultrasonography (US), were recorded. Bladder wall modifications (BWM) at preoperative US were defined as the presence of single or multiple bladder diverticula or bladder wall thickening ≥5 mm. Clinical symptoms were assessed using validated questionnaires. Only events occurred within the first week after catheter removal were considered. Results: Overall, 305 patients were included, of which 46 (15.1%) experienced early catheter replacement. Maintenance of anticoagulants/antiplatelets (AC/AP) therapy at surgery (p=0.001), indwelling urinary catheter (p=0.02) and the presence of BWM (p=0.001) were more frequently reported in patients needing postoperative re-catheterization. Intraoperative complications (p=0.02) and median lasing time (p=0.02) were significantly higher in this group. At univariate analysis, indwelling urinary catheter (p=0.02), BWM (p=0.01), ongoing AC/AP therapy (p=0.01) and intraoperative complications (p=0.01) were significantly associated with early catheter replacement. At multivariate analysis, indwelling urinary catheter (OR: 1.28; p=0.02), BWM (OR: 2.87; p=0.001), and AC/AP therapy (OR: 2.21; p=0.01) were confirmed as independent predictors of catheter replacement. Conclusions: In our experience the presence of indwelling urinary catheter before surgery, BWM and the maintenance of AC/AP therapy were shown to be independent predictors of early catheter replacement after HoLEP.

Predictors of early catheter replacement after HoLEP. Results from a high-volume laser center.

INTRODUCTION: The aim of the study was to investigate clinical and surgical factors associated with early catheter replacement in patients treated with Holmium Laser Enucleation of the Prostate (HoLEP). MATERIALS AND METHODS: Data of patients treated with HoLEP at our Institution by a single surgeon from March 2017 to January 2021 were collected. Preoperative variables, including non-invasive uroflowmetry and abdominal ultrasonography (US), were recorded. Bladder wall modifications (BWM) at preoperative US were defined as the presence of single or multiple bladder diverticula or bladder wall thickening 5 mm. Clinical symptoms were assessed using validated questionnaires. Only events occurred within the first week after catheter removal were considered. RESULTS: Overall, 305 patients were included, of which 46 (15.1%) experienced early catheter replacement. Maintenance of anticoagulants/antiplatelets (AC/AP) therapy at surgery (p=0.001), indwelling urinary catheter (p=0.02) and the presence of BWM (p=0.001) were more frequently reported in patients needing postoperative re-catheterization. Intraoperative complications (p=0.02) and median lasing time (p=0.02) were significantly higher in this group. At univariate analysis, indwelling urinary catheter (p=0.02), BWM (p=0.01), ongoing AC/AP therapy (p=0.01) and intraoperative complications (p=0.01) were significantly associated with early catheter replacement. At multivariate analysis, indwelling urinary catheter (OR: 1.28; p=0.02), BWM (OR: 2.87; p=0.001), and AC/AP therapy (OR: 2.21; p=0.01) were confirmed as independent predictors of catheter replacement. CONCLUSIONS: In our experience the presence of indwelling urinary catheter before surgery, BWM and the maintenance of AC/AP therapy were shown to be independent predictors of early catheter replacement after HoLEP.

Holmium laser enucleation of the prostate (HoLEP) is safe and effective in patients with high comorbidity burden

ABSTRACT Introduction We assessed the efficacy and safety of holmium laser enucleation of the prostate (HoLEP) in patients with high comorbidity burden. Materials and methods Data from patients treated with HoLEP at our academic referral center from March 2017 to January 2021 were prospectively collected. Patients were divided according to their CCI (Charlson Comorbidity Index). Perioperative surgical data and 3-month functional outcomes were collected. Results Out of 305 patients included, 107 (35.1%) and 198 (64.9%) were classified as CCI ≥ 3 and < 3, respectively. The groups were comparable in terms of baseline prostate size, symptoms severity, post-void residue and Qmax. The amount of energy delivered during HoLEP (141.3 vs. 118.0 KJ, p=0.01) and lasing time (38 vs 31 minutes, p=0.01) were significantly higher in patients with CCI ≥ 3. However, median enucleation, morcellation and overall surgical time were comparable between the two groups (all p>0.05). Intraoperative complications rate (9.3% vs. 9.5%, p=0.77), median time to catheter removal and hospital stay were comparable between the two cohorts. Similarly, early (30 days) and delayed (>30 days) surgical complications rates were not significantly different between the two groups. At 3-month follow up, functional outcomes using validated questionnaires did not differ between the two groups (all p>0.05). Conclusions HoLEP represents a safe and effective treatment option for BPH also in patients with high comorbidity burden.

Holmium laser enucleation of the prostate (HoLEP) is safe and effective in patients with high comorbidity burden.

INTRODUCTION: We assessed the efficacy and safety of holmium laser enucleation of the prostate (HoLEP) in patients with high comorbidity burden. MATERIALS AND METHODS: Data from patients treated with HoLEP at our academic referral center from March 2017 to January 2021 were prospectively collected. Patients were divided according to their CCI (Charlson Comorbidity Index). Perioperative surgical data and 3-month functional outcomes were collected. RESULTS: Out of 305 patients included, 107 (35.1%) and 198 (64.9%) were classified as CCI ≥ 3 and < 3, respectively. The groups were comparable in terms of baseline prostate size, symptoms severity, post-void residue and Qmax. The amount of energy delivered during HoLEP (141.3 vs. 118.0 KJ, p=0.01) and lasing time (38 vs 31 minutes, p=0.01) were significantly higher in patients with CCI ≥ 3. However, median enucleation, morcellation and overall surgical time were comparable between the two groups (all p>0.05). Intraoperative complications rate (9.3% vs. 9.5%, p=0.77), median time to catheter removal and hospital stay were comparable between the two cohorts. Similarly, early (30 days) and delayed (>30 days) surgical complications rates were not significantly different between the two groups. At 3-month follow up, functional outcomes using validated questionnaires did not differ between the two groups (all p>0.05). CONCLUSIONS: HoLEP represents a safe and effective treatment option for BPH also in patients with high comorbidity burden.

Patterns and Predictors of Optimal Surgical and Functional Outcomes after Holmium Laser Enucleation of the Prostate (HoLEP): Introducing the Concept of "Trifecta".

PURPOSE: The present study sought to provide reproducible and patient-oriented metrics to assess the rate of "successful" outcomes (Trifecta) following holmium laser enucleation of the prostate (HoLEP). Clinical and surgical predictors of failure to achieve Trifecta were investigated. MATERIALS AND METHODS: We queried our prospectively collected database of all patients treated with HoLEP between March 2017 and January 2021. Trifecta was defined as the contemporary presence of: (1) no postoperative complication within 3 months; (2) no urinary incontinence at 3-months follow-up; and (3) 3-month postoperative max flow-rate >15 mL/s. Cases were grouped according to Trifecta achievement. All surgical procedures were carried out by a single surgeon. Surgical experience was divided into two different eras according to the number of procedures conducted (surgical era). Multivariate logistic regression analysis was performed to assess predictors of Trifecta failure. RESULTS: Overall 305 patients were included. Of these, 192 patients (63.0%) achieved Trifecta. Preoperative patient-related features were comparable between the two groups, except for a higher post-void residual (PVR) in non-Trifecta patients (median 180 vs. 130 mL, p=0.003). A significant proportion of Trifecta patients (88.5%) were treated in the second surgical era and in 126 (65.6%) cases an en-bloc enucleation was performed. Multivariate analysis confirmed PVR ≥250 mL, first surgical era and standard three-lobes enucleation technique as independent predictors of Trifecta failure. CONCLUSIONS: In our experience the rate of "successful" HoLEP, defined according to our newly introduced Trifecta metric, was 63.0%. We demonstrated that surgical strategy together with rising experience and baseline PVR are key elements to forecast the outcomes.

Prognostic features of upstaged pT3a renal tumors with fat invasion after robot-assisted partial nephrectomy: is it time for a new subclassification?

INTRODUCTION: The clinical management of pT3a pathologic-upstaged renal cell carcinoma (RCC) patients is actually controversial. Aim of this study was i) to assess the impact of pT3a upstaging on oncologic outcomes after robot-assisted partial nephrectomy (RAPN) for cT1-T2 RCC; ii) to explore clinical and surgical predictors of pT3a upstaging; iii) to evaluate the differential impact of perinephric fat invasion (PFI) or sinus fat invasion (SFI) on survival outcomes after RAPN in case of upstaged pT3a RCC. MATERIALS AND METHODS: Clinical and surgical data from consecutive RCCs treated with RAPN in a single referral centre between January 2017 and June 2021 were prospectively collected and retrospectively reviewed. Pathological upstaging to pT3a tumors with fat invasion was further stratified in SFI or PFI. Uni- and multivariable analysis were fitted to explore clinical and surgical predictors of disease recurrence. RESULTS: Overall, 1852 patients were enrolled and 179 (9.7%) with pT3a upstaging were found. Median age was 65 (IQR 56-73) years with a median BMI of 25.6 (23.6-29.0). At a median follow up of 26 (9-38) months, 76 (4.1%) patients showed disease recurrence. Multivariable analysis confirmed PADUA score ≥10 (OR 1.76, CI 95% 1.18-1.91, p = 0.001), age at surgery (OR 1.04, CI 95% 1.01-1.06, p = 0.01), clinical tumor diameter (OR 1.31, CI 95% 1.17-1.47, p = 0.001), tumor necrosis (OR 1.54, CI 95% 1.08-1.88, p = 0.001) and nucleolar grading ≥3 (OR 1.27, CI 95% 1.01-1.44, p = 0.001) as independent predictors of pT3a upstaging. Multivariate Cox regression model showed pathological sinus fat invasion as an independent predictor of disease recurrence (HR 3.43, CI 95% 1.51-7.77, p = 0.003) in pT3a upstaged group. CONCLUSION: In pathologically upstaged pT3a RCCs, sinus fat invasion was confirmed as independent predictor of disease relapse. In this light, the definition of novel risk categories in the pT3a patients setting should be encouraged.

T3 and glucose increase expression of phosphoenolpyruvate carboxykinase (PCK1) leading to increased ß-cell proliferation.

OBJECTIVES: Thyroid hormone (T3) and high glucose concentrations are critical components of ß-cell maturation and function. In the present study, we asked whether T3 and glucose signaling pathways coordinately regulate transcription of genes important for ß-cell function and proliferation. METHODS: RNA-seq analysis was performed on cadaveric human islets from five different donors in response to low and high glucose concentrations and in the presence or absence of T3. Gene expression was also studies in sorted human ß-cells, mouse islets and Ins-1 cells by RT-qPCR. Silencing of the thyroid hormone receptors (THR) was conducted using lentiviruses. Proliferation was assessed by ki67 immunostaining in primary human/mouse islets. Chromatin immunoprecipitation and proximity ligation assay were preformed to validate interactions of ChREBP and THR. RESULTS: We found glucose-mediated expression of carbohydrate response element binding protein alpha and beta (ChREBPα and ChREBPß) mRNAs and their target genes are highly dependent on T3 concentrations in rodent and human ß-cells. In ß-cells, T3 and glucose coordinately regulate the expression of ChREBPß and PCK1 (phosphoenolpyruvate carboxykinase-1) among other important genes for ß-cell maturation. Additionally, we show the thyroid hormone receptor (THR) and ChREBP interact, and their relative response elements are located near to each other on mutually responsive genes. In FACS-sorted adult human ß-cells, we found that high concentrations of glucose and T3 induced the expression of PCK1. Next, we show that overexpression of Pck1 together with dimethyl malate (DMM), a substrate precursor, significantly increased ß-cell proliferation in human islets. Finally, using a Cre-Lox approach, we demonstrated that ChREBPß contributes to Pck1-dependent ß-cell proliferation in mouse ß-cells. CONCLUSIONS: We conclude that T3 and glucose act together to regulate ChREBPß, leading to increased expression and activity of Pck1, and ultimately increased ß-cell proliferation.