HPV16 E7-Dependent Transformation Activates NHE1 through a PKA-RhoA-Iinduced Inhibition of p38alpha

Background: Neoplastic transformation originates from a large number of different genetic alterations. Despite this genetic variability, a common phenotype to transformed cells is cellular alkalinization. We have previously shown in human keratinocytes and a cell line in which transformation can be turned on and followed by the inducible expression of the E7 oncogene of human papillomavirus type 16 (HPV16), that intracellular alkalinization is an early and essential physiological event driven by the up-regulation of the Na/H-+(+) exchanger isoform 1 (NHE1) and is necessary for the development of other transformed phenotypes and the in vivo tumor formation in nude mice.Methodology: Here, we utilize these model systems to elucidate the dynamic sequence of alterations of the upstream signal transduction systems leading to the transformation-dependent activation of NHE1.Principal Findings: We observe that a down-regulation of p38 MAPK activity is a fundamental step in the ability of the oncogene to transform the cell. Further, using pharmacological agents and transient transfections with dominant interfering, constitutively active, phosphorylation negative mutants and siRNA strategy to modify specific upstream signal transduction components that link HPV16 E7 oncogenic signals to up-regulation of the NHE1, we demonstrate that the stimulation of NHE1 activity is driven by an early rise in cellular cAMP resulting in the down-stream inhibition of p38 MAPK via the PKA-dependent phosphorylation of the small G-protein, RhoA, and its subsequent inhibition.Conclusions: All together these data significantly improve our knowledge concerning the basic cellular alterations involved in oncogene-driven neoplastic transformation

Robot assisted radical cystectomy with totally intracorporeal urinary diversion: initial, single-surgeon's experience after a modified modular training

BACKGROUND: To report the perioperative and early functional outcomes of patients undergoing Robot-assisted radical cystectomy (RARC) with totally intracorporeal urinary diversion performed by a single surgeon after a modified modular training. METHODS: The surgeon (A.P.) attained a 30-days modified modular training at a referring Centre mentored by a worldwide-recognized robotic surgeon (P.W.). The training program consisted of: a) e-learning based on 10 hours of theoretical lessons made by the mentor; b) video-session concerning the different steps of the procedure, c) step-by-step in vivo modular training. Demographics, intraoperative data and post-operative complications were recorded for each patient. RESULTS: Twenty-four consecutive patients were prospectively evaluated. Median age was 68.5 years (IQR 59-75). Thirteen (54.2%) and 11 (45.8%) patients received RARC with orthotopic neobladder (ONB) and ileal conduit (IC), respectively. Overall mean (\ub1SD) operative time was 392 (\ub1 34.8) minutes. The median number of lymph node retrieved was 30 (IQR 24-42), the mean intraoperative estimated blood loss (EBL) was 403 mL (\ub1 60) with average hospitalization of 7.8 days (\ub1 2.2). All procedures were completed successfully without open conversion. A statistically significant difference in terms of overall operative time (OT) and urinary diversion operative time (UDOT) was found in favour of IC group compared to ONB group (p=0.002). Overall complication rate was 33%, 7 out of 9 (88%) were graded as minor (Clavien 1-2). Two (22%) major complications (Clavien 3-5) occurred solely on ONB group. CONCLUSIONS: Robot-assisted radical cystectomy with totally intracorporeal urinary diversion is a challenging procedure with a steep learning curve. An adequate modular training with an experienced mentor and a skilled robotic team could be essential to reach these optimal results. Further studies investigating the impact of modular learning curve and a dedicated menthorship on operative and functional outcomes after RARC are needed

Perioperative outcomes of patients undergoing urological elective surgery during the COVID-19 pandemic: a national overview across 28 Italian institutions

Introduction The aim of this study was to assess the safety of elective urological surgery performed during the pandemic by estimating the prevalence of COVID-19-like symptoms in the postoperative period and its correlation with perioperative and clinical factors.Material and methods In this multicenter, observational study we recorded clinical, surgical and postoperative data of consecutive patients undergoing elective urological surgery in 28 different institutions across Italy during initial stage of the COVID-19 pandemic (between February 24 and March 30, 2020, inclusive).Results A total of 1943 patients were enrolled. In 12%, 7.1%, 21.3%, 56.7% and 2.6% of cases an open, laparoscopic, robotic, endoscopic or percutaneous surgical approach was performed, respectively. Overall, 166 (8.5%) postoperative complications were registered, 77 (3.9%) surgical and 89 (4.6%) medical. Twenty-eight (1.4%) patients were readmitted to hospital after discharge and 13 (0.7%) died. In the 30 days following discharge, fever and respiratory symptoms were recorded in 101 (5.2%) and 60 (3.1%) patients. At multivariable analysis, not performing nasopharyngeal swab at hospital admission (HR 2.3; CI 95% 1.01-5.19; p = 0.04) was independently associated with risk of developing postoperative medical complications. Number of patients in the facility was confirmed as an independent predictor of experiencing postoperative respiratory symptoms (p = 0.047, HR:1.12; CI95% 1.00-1.05), while COVID-19-free type of hospitalization facility was a strong independent protective factor (p = 0.02, HR:0.23, CI95% 0.07-0.79).Conclusions Performing elective surgery during the COVID-19 pandemic does not seem to affect perioperative outcomes as long as proper preventive measures are adopted, including nasopharyngeal swab before hospital admission and hospitalization in dedicated COVID-19-free facilities

The Intraoperative Complications Assessment and Reporting with Universal Standards (ICARUS) Global Surgical Collaboration Project: Development of Criteria for Reporting Adverse Events During Surgical Procedures and Evaluating Their Impact on the Postoperative Course

Background: Intraoperative adverse events (iAEs) are surgical and anesthesiologic complications. Despite the availability of grading criteria, iAEs are infrequently reported in the surgical literature and in cases for which iAEs are reported, these events are described with significant heterogeneity. Objective: To develop Intraoperative Complications Assessment and Reporting with Universal Standards (ICARUS) Global Surgical Collaboration criteria to standardize the assessment, reporting, and grading of iAEs. The ultimate aim is to improve our understanding of the nature and frequency of iAEs and our ability to counsel patients regarding surgical procedures. Design, setting, and participants: The present study involved the following steps: (1) collecting criteria for assessing, reporting, and grading of iAEs via a comprehensive umbrella review; (2) collecting additional criteria via a survey of a panel of experienced surgeons (first round of a modified Delphi survey); (3) creating a comprehensive list of reporting criteria; (4) combining criteria acquired in the first two steps; and (5) establishing a consensus on clinical and quality assessment utility as determined in the second round of the Delphi survey. Outcome measurements and statistical analysis: Panel inter-rater agreement and consistency were assessed as the overall percentage agreement and Cronbach's α. Results and limitations: The umbrella review led to nine common criteria for assessing, grading, and reporting iAEs, and review of iAE grading systems led to two additional criteria. In the first Delphi round, 35 surgeons responded and two criteria were added. In the second Delphi round, 13 common criteria met the threshold for final guideline inclusion. All 13 criteria achieved the consensus minimum of 70%, with agreement on the usefulness of the criteria for clinical and quality improvement ranging from 74% to 100%. The mean inter-rater agreement was 89.0% for clinical improvement and 88.6% for quality improvement. Conclusions: The ICARUS Global Collaboration criteria might aid in identifying important criteria when reporting iAEs, which will support all those involved in patient care and scientific publishing. Patient summary: We consulted a panel of experienced surgeons to develop a set of guidelines for academic surgeons to follow when publishing surgical studies. The surgeon panel proposed a list of 13 criteria that may improve global understanding of complications during specific procedures and thus improve the ability to counsel patients on surgical risk

Urology in the time of coronavirus: reduced access to urgent and emergent urological care during the coronavirus disease 2019 outbreak in Italy

The coronavirus disease 2019 (COVID-19) pandemic has put a substantial burden on the Italian healthcare system, resulting in the restructuring of hospitals to care for COVID-19 patients. However, this has likely impacted access to care for patients experiencing other conditions. We aimed to quantify the impact of COVID-19 on access to care for patients with urgent/emergent urological conditions throughout Italy

The dramatic COVID 19 outbreak in Italy is responsible of a huge drop of urological surgical activity: a multicenter observational study

Objective To describe the trend in surgical volume in urology in Italy during the coronavirus disease 2019 (COVID-19) outbreak, as a result of the abrupt reorganisation of the Italian national health system to augment care provision to symptomatic patients with COVID-19. Methods A total of 33 urological units with physicians affiliated to the AGILE consortium (Italian Group for Advanced Laparo-Endoscopic Surgery; ) were surveyed. Urologists were asked to report the amount of surgical elective procedures week-by-week, from the beginning of the emergency to the following month. Results The 33 hospitals involved in the study account overall for 22 945 beds and are distributed in 13/20 Italian regions. Before the outbreak, the involved urology units performed overall 1213 procedures/week, half of which were oncological. A month later, the number of surgeries had declined by 78%. Lombardy, the first region with positive COVID-19 cases, experienced a 94% reduction. The decrease in oncological and non-oncological surgical activity was 35.9% and 89%, respectively. The trend of the decline showed a delay of roughly 2 weeks for the other regions. Conclusion Italy, a country with a high fatality rate from COVID-19, experienced a sudden decline in surgical activity. This decline was inversely related to the increase in COVID-19 care, with potential harm particularly in the oncological field. The Italian experience may be helpful for future surgical pre-planning in other countries not so drastically affected by the disease to date