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IntroductionCystic Fibrosis (CF) is a genetic disease due to loss-of-function mutations of the CFTR channel. F508del is the most frequent mutation (70% of alleles in Italy), while other mutations have much lower frequency. Among them, G85E (0.4% frequency globally, 1.13% in Italy) emerges as a mutation characterized by a severe CFTR folding and trafficking defect.MethodsTo investigate the pharmacological responsiveness of the G85E-CFTR variant, we performed a functional and biochemical characterization in heterologous expression systems and ex vivo models based on patient-derived human nasal epithelial cells (HNEC).ResultsOur study demonstrated that treatment of primary airway cells with elexacaftor and tezacaftor causes a significant (although modest) rescue of CFTR function, that reaches 15%–25% of the activity measured in non-CF epithelia. A detrimental effect of chronic treatment with ivacaftor, further limiting G85E rescue, was also observed. A higher rescue of CFTR function, up to 25%–35% of the normal CFTR activity, with no evidence of negative effects upon chronic potentiator treatment, can be achieved by combining elexacaftor with ARN23765, a novel type 1 corrector endowed with very high potency. Importantly, dose-response relationships suggest that G85E might alter the binding of type 1 correctors, possibly affecting their affinity for the target.DiscussionIn conclusion, our studies suggest that novel combinations of modulators, endowed with higher efficacy leading to increased rescue of G85E-CFTR, are needed to improve the clinical benefit in patients for this variant.

Abstract. Background. Recently, an innovative tool called “proficiency score” was introduced to assess the learning curve for robot-assisted radical prostatectomy (RARP). However, the initial study only focused on patients with low-risk prostate cancer for whom pelvic lymph node dissection (PLND) was not required. To address this issue, we aimed to validate proficiency scores of a contemporary multicenter cohort of patients with high-risk prostate cancer treated with RARP plus extended PLND by trainee surgeons. Material and methods. Between 2010 and 2020, 4 Italian institutional prostate-cancer datasets were merged and queried for “RARP” and “high-risk prostate cancer.” High-risk prostate cancer was defined according to the most recent European Association of Urology guidelines as follows: prostate-specific antigen >20 ng/mL, International Society of Urological Pathology ≥4, and/or clinical stage (cT) ≥ 2c on preoperative imaging. The selected cohort (n = 144) included clinical cases performed by trainee surgeons (n = 4) after completing their RARP learning curve (50 procedures for low-risk prostate cancer). The outcome of interest, the proficiency score, was defined as the coexistence of all the following criteria: a comparable operation time to the interquartile range of the mentor surgeon at each center, absence of any significant perioperative complications Clavien-Dindo Grade 3–5, no perioperative blood transfusions, and negative surgical margins. A logistic binary regression model was built to identify the predictors of 1-year trifecta achievement in the trainee cohort. For all statistical analyses, a 2-sided p < 0.05 was considered significant. Results. A proficiency score was achieved in 42.3% patients. At univariable level, proficiency score was associated with 1-year trifecta achievement (odds ratio, 8.77; 95% confidence interval, 2.42–31.7; p = 0.001). After multivariable adjustments for age, nerve-sparing, and surgical technique, the proficiency score independently predicted 1-year trifecta achievement (odds ratio, 9.58; 95% confidence interval, 1.83–50.1; p = 0.007). Conclusions. Our findings support the use of proficiency scores in patients and require extended PLND in addition to RARP.

Introduction: To describe operatory room (OR) setting, trocar placement, surgical technique and perioperative outcomes of retroperitoneal (rRAPN) and transperitoneal (tRAPN) robot-assisted partial nephrectomy with the Hugo™ robot-assisted surgical (RAS) system. Patients and surgical procedure: We present our prospective, series of the first ten consecutive patients submitted to either rRAPN or tRAPN with the Hugo™ RAS system (Medtronic, Minneapolis, MN, USA) at ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, between April 2023 and June 2023. The outcomes of interest were to describe the OR setting, trocar placement and the performance of this novel robotic system. Pre, intra and post-operative variables were recorded. A descriptive analysis was performed. Results: Overall, ten patients underwent RAPN with the Hugo™ RAS system, of which two were rRAPN (one left and one right renal mass) and eight tRAPN (two left, five right, one bilateral). Median (interquartile range, IQR) tumor size was 2.75 cm, with a median PADUA score of 7 (7,9). Median time from first trocar placement to console was 20 (15, 23) minutes, median console time was 136 (100, 159) minutes, and median operative time was 185 (170, 232) minutes. No intra-operative complications were recorded. Four post-operative complications were reported: one patient developed acute kidney injury (AKI, Clavien-Dindo 1), one patient required a longer hospital stay due to chylous production from the drain after hilar lymphadenectomy (Clavien-Dindo 2) and two pneumothoraxes (Clavien-Dindo 3a). Median (IQR) hospital stay was 5 (3,7) days. At final pathology, clear cell RCC, papillary RCC, chromophobe RCC and oncocytoma were found in respectively seven (70 %), one (10 %), one (10 %), and one (10 %) patients, with T1a, T1b and T3a (perirenal fat invasion) stages in six (60 %), three (30 %) and one (10 %) patients, respectively. Conclusions: This video article illustrates the steps of both rRAPN and tRAPN with the Hugo™ RAS system. Our preliminary results demonstrate that both rRAPN and tRAPN are feasible with this novel robotic platform. Future large case series with long-term follow-up are needed to understand whether Hugo™ RAS system represents a true alternative to Intuitive platforms for nephron-sparing surgery.

The article discusses the feasibility, operative setup, and surgical outcomes of Retzius‐sparing robot‐assisted radical prostatectomy (RS‐RARP) using the Hugo robot‐assisted surgery system. The study evaluated 26 patients who underwent RS‐RARP with the Hugo system, reporting on patient characteristics, operative setup, complications, and outcomes. The findings suggest that RS‐RARP with the Hugo system is feasible and safe, with high rates of urinary continence recovery, but also highlight the need for a learning process due to higher positive surgical margin rates compared to other systems. Further research is needed to assess long-term outcomes and compare the Hugo system with other robotic platforms. [Extracted from the article]

Introduction: Cystic Fibrosis (CF) is a genetic disease due to loss-of-function mutations of the CFTR channel. F508del is the most frequent mutation (70% of alleles in Italy), while other mutations have much lower frequency. Among them, G85E (0.4% frequency globally, 1.13% in Italy) emerges as a mutation characterized by a severe CFTR folding and trafficking defect. Methods: To investigate the pharmacological responsiveness of the G85E-CFTR variant, we performed a functional and biochemical characterization in heterologous expression systems and ex vivo models based on patient-derived human nasal epithelial cells (HNEC). Results: Our study demonstrated that treatment of primary airway cells with elexacaftor and tezacaftor causes a significant (although modest) rescue of CFTR function, that reaches 15%–25% of the activity measured in non-CF epithelia. A detrimental effect of chronic treatment with ivacaftor, further limiting G85E rescue, was also observed. A higher rescue of CFTR function, up to 25%–35% of the normal CFTR activity, with no evidence of negative effects upon chronic potentiator treatment, can be achieved by combining elexacaftor with ARN23765, a novel type 1 corrector endowed with very high potency. Importantly, dose-response relationships suggest that G85E might alter the binding of type 1 correctors, possibly affecting their affinity for the target. Discussion: In conclusion, our studies suggest that novel combinations of modulators, endowed with higher efficacy leading to increased rescue of G85E-CFTR, are needed to improve the clinical benefit in patients for this variant. [ABSTRACT FROM AUTHOR]

Background: In patients with renal cell carcinoma (RCC) the role of the extent of tumor thrombus into the inferior vena cava (IVC) has never been addressed from a surgical and oncologic standpoint. This study aims to evaluate differences between level III–IV versus level I–II patients concerning peri- and postoperative morbidity, additional treatments and long-term oncological outcomes. Patients and Methods: Overall, 40 patients with RCC underwent radical nephrectomy (RN) with IVC thrombectomy at a single European institution between 2010 and 2023. Complications were reported according to the European Union (EAU) guidelines recommendations. Spider chart served as graphical depiction of surgical and oncologic outcomes. Results: Overall, 22 (55%) and 18 (45%) patients harbored level III–IV and I–II IVC thrombus. Level III–IV patients experienced significantly higher rates of intraoperative transfusions (68 vs 39%), but not significantly higher rates of intraoperative complications (32% vs 28%). Level III–IV patients had significantly higher rates of postoperative transfusions (82% vs 33%) and Clavien Dindo ≥3 complications (41% vs 15%). In level III–IV versus level I–II patients, median follow up was 482 and 1070 days, the rate of distant recurrence was 59% and 50%, the rate of systemic progression was 27% and 13%, and the rate of additional treatment/s was 64% and 61%, respectively (all p values > 0.05). Overall survival was 36% in level III–IV patients and 67% in level I–II (p = 0.001). Conclusions: Our findings suggest that patients with level III–IV RCC who are candidates for IVC thrombectomy should be counselled about the higher likelihood of postoperative severe adverse events and worse overall survival relative to level I–II counterparts. [ABSTRACT FROM AUTHOR]

Developmental and epileptic encephalopathies (DEEs) comprise a complex spectrum of neurological disorders characterized by neurodevelopmental delay and early‐onset seizures primarily caused by diverse genetic mutations. Traditional treatments have largely been symptomatic, focusing on seizure control without addressing the underlying genetic causes. The advent of gene therapy, particularly through antisense oligonucleotides (ASOs), offers a promising avenue toward targeted therapeutic interventions. ASOs by virtue of their ability to modulate gene expression at the mRNA level represent a sophisticated approach to counteract the effects of pathogenic mutations. This review delves into the recent advancements in ASO technology, highlighting its application in preclinical and clinical settings for DEEs. We present evidence of the efficacy of ASOs in ameliorating disease phenotypes in vitro and in vivo, alongside promising outcomes from ongoing clinical trials. The therapeutic landscape for DEEs is on the cusp of significant transformation, underscored by the potential of ASOs to offer precise, personalized, treatments that extend beyond symptomatic relief to potentially rectify the genetic underpinnings of these disorders. [ABSTRACT FROM AUTHOR]

Background: Retzius-sparing (RS) robot-assisted radical prostatectomy represents a valid surgical treatment option for prostate cancer (PCa) patients. However, the available evidence on the role of RS in high-risk (HR) PCa setting is sparse. Objective: To describe our RS technique for HR-PCa patients and to evaluate intra-, peri-, and postoperative oncological and functional outcomes. Design, setting, and participants: A total of 340 D’Amico HR-PCa patients underwent RS at a single high-volume centre between 2011 and 2020. Surgical procedure: Surgical procedures were performed by five experienced robotic surgeons. Measurements: Complications were collected according to the standardised methodology proposed by the European Association of Urology guidelines. Postoperative outcomes were evaluated in patients with complete follow-up data (n = 320). Biochemical recurrence (BCR) was defined as two consecutive prostate-specific antigen values of ≥0.2 ng/ml. Urinary continence (UC) recovery was defined as the use of zero or one safety pad. Kaplan-Meier and multivariable logistic and Cox regression models were performed. Results and limitations: Fourteen patients (4%) experienced intraoperative complications and 52 90-d complications occurred in 44 patients (14%), of whom 24 had Clavien-Dindo 3a/b. Final pathology reported 49% International Society of Urological Pathology (ISUP) grade 4–5, 55% ≥pT3a, and 28.8% positive surgical margins (PSMs; 9.4% focal and 19.4% extended PSMs). The median follow-up was 47 mo. Overall, 35.3% and 1.3% harboured BCR and died from PCa. At 4 yr of follow-up, BCR-free survival and additional treatment-free survival were 63.6% and 56.6%, respectively. ISUP 4–5 at biopsy (odds ratio [OR]: 2.6), prostate volume (OR: 1.03), partial or full nerve sparing (OR: 1.9), and full bladder neck preservation (OR: 2.2) were independent predictors of PSMs. Pathological ISUP 4–5 (hazard ratio [HR]: 1.5) and PSMs (HR: 2.3) were independent predictors of BCR. Pathological ISUP 4–5 (HR: 1.5), PSMs (HR: 2.4), pT ≥3b (HR: 1.8), and pN ≥1 (HR: 1.8) were independent predictors of additional treatment. Immediate UC recovery was recorded in 53% patients. The 1- and 2-yr UC recovery and erectile function recovery were, respectively, 84% and 85%, and 43% and 50%. Conclusions: RS in HR-PCa patients allows optimal intra-, peri-, and postoperative outcomes. The RS approach should be considered a valid surgical treatment option for HR-PCa patients in expert hands. Patient summary: Relying on the largest cohort of high-risk prostate cancer patients treated with Retzius sparing (RS), we observed that the RS approach is safe and allows optimal cancer control, without significantly compromising functional outcomes.

Background: Lombardy has been the first and one of the most affected European regions during the first and second waves of the novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]). Objective: To evaluate the impact of coronavirus disease 2019 (COVID-19) on all urologic activities over a 17-wk period in the three largest public hospitals in Lombardy located in the worst hit area in Italy, and to assess the applicability of the authorities’ recommendations provided for reorganising urology practice. Design, setting, and participants: A retrospective analysis of all urologic activities performed at three major public hospitals in Lombardy (Brescia, Bergamo, and Milan), from January 1 to April 28, 2020, was performed. Outcome measurements and statistical analysis: Join-point regression was used to identify significant changes in trends for all urologic activities. Average weekly percentage changes (AWPCs) were estimated to summarise linear trends. Uro-oncologic surgeries performed during the pandemic were tabulated and stratified according to the first preliminary recommendations by Stensland et al (Stensland KD, Morgan TM, Moinzadeh A, et al. Considerations in the triage of urologic surgeries during the COVID-19 pandemic. Eur Urol 2020;77:663–6) and according to the level of priority recommended by European Association of Urology guidelines. Results and limitations: The trend for 2020 urologic activities decreased constantly from weeks 8–9 up to weeks 11–13 (AWPC range –41%, –29.9%; p

IntroductionThe Italian Radical Cystectomy Registry (RIC) is an observational prospective study aiming to understand clinical variables and patient characteristics associated with short- and long-term outcomes among bladder cancer (BC) patients undergoing radical cystectomy (RC). Moreover, it compares the effectiveness of three RC techniques - open, robotic, and laparoscopic.MethodsFrom 2017 to 2020, 1400 patients were enrolled at one of the 28 centers across Italy. Patient characteristics, as well as preoperative, postoperative, and follow-up (3, 6, 12, and 24 months) clinical variables and outcomes were collected.ResultsPreoperatively, it was found that patients undergoing robotic procedures were younger (p

Abstract Background Bladder cancer is the ninth most common type of cancer worldwide. In the past, radical cystectomy via open surgery has been considered the gold-standard treatment for muscle invasive bladder cancer. However, in recent years there has been a progressive increase in the use of robot-assisted laparoscopic radical cystectomy. The aim of the current project is to investigate the surgical, oncological, and functional outcomes of patients with bladder cancer who undergo radical cystectomy comparing three different surgical techniques (robotic-assisted, laparoscopic, and open surgery). Pre-, peri- and post-operative factors will be examined, and participants will be followed for a period of up to 24 months to identify risks of mortality, oncological outcomes, hospital readmission, sexual performance, and continence. Methods We describe a protocol for an observational, prospective, multicenter, cohort study to assess patients affected by bladder neoplasms undergoing radical cystectomy and urinary diversion. The Italian Radical Cystectomy Registry is an electronic registry to prospectively collect the data of patients undergoing radical cystectomy conducted with any technique (open, laparoscopic, robotic-assisted). Twenty-eight urology departments across Italy will provide data for the study, with the recruitment phase between 1st January 2017-31st October 2020. Information is collected from the patients at the moment of surgical intervention and during follow-up (3, 6, 12, and 24 months after radical cystectomy). Peri-operative variables include surgery time, type of urinary diversion, conversion to open surgery, bleeding, nerve sparing and lymphadenectomy. Follow-up data collection includes histological information (e.g., post-op staging, grading, and tumor histology), short- and long-term outcomes (e.g., mortality, post-op complications, hospital readmission, sexual potency, continence etc). Discussion The current protocol aims to contribute additional data to the field concerning the short- and long-term outcomes of three different radical cystectomy surgical techniques for patients with bladder cancer, including open, laparoscopic, and robot-assisted. This is a comparative-effectiveness trial that takes into account a complex range of factors and decision making by both physicians and patients that affect their choice of surgical technique. Trial registration ClinicalTrials.gov , NCT04228198 . Registered 14th January 2020- Retrospectively registered.

Next-generation sequencing (NGS) has revolutionized the field of genomics and created new opportunities for basic research. We described the strategy for the NGS validation of the “dysglycaemia panel” composed by 44 genes related to glucose metabolism disorders (MODY, Wolfram syndrome) and familial renal glycosuria using Ion AmpliSeq technology combined with Ion-PGM. Anonymized DNA of 32 previously genotyped cases with 33 different variants were used to optimize the methodology. Standard protocol was used to generate the primer design, library, template preparation, and sequencing. Ion Reporter tool was used for data analysis. In all the runs, the mean coverage was over 200×. Twenty-nine out of thirty three variants (96.5%) were detected; four frameshift variants were missed. All point mutations were detected with high sensitivity. We identified three further variants of unknown significance in addition to pathogenic mutations previously identified by Sanger sequencing. The NGS panel allowed us to identify pathogenic variants in multiple genes in a short time. This could help to identify several defects in children and young adults that have to receive the genetic diagnosis necessary for optimal treatment. In order not to lose any pathogenic variants, Sanger sequencing is included in our analytical protocol to avoid missing frameshift variants.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006. After this, the pathophysiology of FOP has been further elucidated through the efforts of research groups worldwide. In 2015, a workshop was held to gather these groups and discuss the new challenges in FOP research. Here we present an overview and update on these topics.

Abstract Background Fibrodysplasia Ossificans Progressiva (FOP) is a rare autosomal dominant disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues leading to cumulative disability. The genetic cause of FOP are mutations in the ACVR1 gene that encodes a type I receptor of Bone Morphogenetic Proteins. The most recurrent mutation in FOP patients is R206H affecting the Glycine‐Serine rich domain and causing the hyper‐activation of the receptor and the responsivity to the non‐canonical ligand, Activin A. In the present study, we described a 3‐years old child with early and highly suggestive clinical features of FOP who was found negative for the recurrent p.R206H substitution. Methods Molecular screening of the whole ACVR1 coding sequence and functional characterization in transfection‐based assays. Results and Conclusions We identified a novel, de novo variant in the fifth ACVR1 coding exon (NM_001111067.4:c.772A>T; NP_001104537.1:p.(R258W)). This substitution, never reported in association with FOP, affects a conserved arginine residue in the kinase domain of the protein. In silico analysis predicted the pathogenicity of this substitution, demonstrated by in vitro assays showing that the p.R258W ACVR1 mutated receptor acquires the ability to transduce the aberrant Activin A‐mediated signaling, as observed for the gene variants associated with FOP.