Patient and Context Factors in the Adoption of Active Surveillance for Low-Risk Prostate Cancer.

Importance: Although active surveillance for patients with low-risk prostate cancer (LRPC) has been recommended for years, its adoption at the population level is often limited. Objective: To make active surveillance available for patients with LRPC using a research framework and to compare patient characteristics and clinical outcomes between those who receive active surveillance vs radical treatments at diagnosis. Design, Setting, and Participants: This population-based, prospective cohort study was designed by a large multidisciplinary group of specialists and patients' representatives. The study was conducted within all 18 urology centers and 7 radiation oncology centers in the Piemonte and Valle d'Aosta Regional Oncology Network in Northwest Italy (approximate population, 4.5 million). Participants included patients with a new diagnosis of LRPC from June 2015 to December 2021. Data were analyzed from January to May 2023. Exposure: At diagnosis, all patients were informed of the available treatment options by the urologist and received an information leaflet describing the benefits and risks of active surveillance compared with active treatments, either radical prostatectomy (RP) or radiation treatment (RT). Patients choosing active surveillance were actively monitored with regular prostate-specific antigen testing, clinical examinations, and a rebiopsy at 12 months. Main Outcomes and Measures: Outcomes of interest were proportion of patients choosing active surveillance or radical treatments, overall survival, and, for patients in active surveillance, treatment-free survival. Comparisons were analyzed with multivariable logistic or Cox models, considering centers as clusters. Results: A total of 852 male patients (median [IQR] age, 70 [64-74] years) were included, and 706 patients (82.9%) chose active surveillance, with an increasing trend over time; 109 patients (12.8%) chose RP, and 37 patients (4.3%) chose RT. Median (IQR) follow-up was 57 (41-76) months. Worse prostate cancer prognostic factors were negatively associated with choosing active surveillance (eg, stage T2a vs T1c: odds ratio [OR], 0.51; 95% CI, 0.28-0.93), while patients who were older (eg, age ≥75 vs <65 years: OR, 4.27; 95% CI, 1.98-9.22), had higher comorbidity (Charlson Comorbidity Index ≥2 vs 0: OR, 1.98; 95% CI, 1.02-3.85), underwent an independent revision of the first prostate biopsy (OR, 2.35; 95% CI, 1.26-4.38) or underwent a multidisciplinary assessment (OR, 2.65; 95% CI, 1.38-5.11) were more likely to choose active surveillance vs active treatment. After adjustment, center at which a patient was treated continued to be an important factor in the choice of treatment (intraclass correlation coefficient, 18.6%). No differences were detected in overall survival between active treatment and active surveillance. Treatment-free survival in the active surveillance cohort was 59.0% (95% CI, 54.8%-62.9%) at 24 months, 54.5% (95% CI, 50.2%-58.6%) at 36 months, and 47.0% (95% CI, 42.2%-51.7%) at 48 months. Conclusions and Relevance: In this population-based cohort study of patients with LRPC, a research framework at system level as well as favorable prognostic factors, a multidisciplinary approach, and an independent review of the first prostate biopsy at patient-level were positively associated with high uptake of active surveillance, a practice largely underused before this study.

Risk factors for recurrence and complications after laparoscopic repair of incisional hernia using a double-layered ePTFE/PP mesh: results of a retrospective study.

BACKGROUND: The objective was to analyse, risk factors for recurrence (primary outcome) and complications (secondary outome) after the implantation of a double layer ePTFE (expanded PolytTetraFluoroEthylene) / PP (PolyPropylene) mesh to treat incisional hernias (IH) using the Intraperitoneal Onlay Mesh (IPOM) technique. METHODS: We included all elective laparoscopic IH repairs with intraperitoneal placement of a ePTFE / PP mesh (Relimesh® - Herniamesh S.r.l.) from January 1, 2010 to December 31, 2017 at Humanitas Mater Domini Clinical Institute in Castellanza (Italy) and at the Centre for Minimally Invasive Surgery of Nis (Serbia). Performance was defined as long-term recurrence rate. RESULTS: A total of 284 patients were enrolled. According to the European Hernia Society (EHS) hernias were classified as: W1 (<4 cm) 60.29%, W2 (≥4-10 cm) 35.02% and W3 (≥10 cm) 4.69%; medial 90.85%, lateral 6.69%, both medial and lateral 2.11%. Average follow-up was 48 (11-110) months. The 30-days complication rate was 4.23%. Hernia recurrence rate was 3.36%. Long-term complication rate was 6.34%. At multivariable analysis, an increased risk of short-term complications was associated to chronic obstructive pulmonary disease (COPD) (OR 7.59 [2.23-25.83], P=0.001); an increased risk of long-term complications was associated to diabetes (OR 6.21 [1.80-21.42], P=0.004), an increased risk of recurrence was correlated to COPD (OR 13.40 [1.36-131.9], P=0.026) and hernia defects larger than 6 cm (OR 19.2 [1.12-329.9], P=0.042). CONCLUSIONS: Elective laparoscopic IH repair with a double-layered ePTFE/PP mesh is safe and effective. Compliance with indications and preoperative patients evaluation are essential to improve outcomes.

Design and optimization of reaction chamber and detection system in dynamic labs-on-chip for proteins detection.

In this paper, the lab-on-chip section for a protein assay is designed and optimized. To avoid severe reliability problems related to activated surface stability, a dynamic assay approach is adopted: protein-to-protein neutralization is performed while proteins diffuse freely in the reaction chamber. The related refraction index change is detected via an integrated interferometer. The structure is also design to provide a functional test of the reference protein solution, which is generally required for qualification for medical uses.

Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors.

The histone deacetylases (HDACs) are able to regulate gene expression, and histone deacetylase inhibitors (HDACi) emerged as a new class of agents in the treatment of cancer as well as other human disorders such as neurodegenerative diseases. In the present investigation, we report on the synthesis and biological evaluation of compounds derived from the expansion of a HDAC inhibitor scaffold having N-hydroxy-3-phenyl-2-propenamide and N-hydroxy-3-(pyridin-2-yl)-2-propenamide as core structures and containing a phenyloxopropenyl moiety, either unsubstituted or substituted by a 4-methylpiperazin-1-yl or 4-methylpiperazin-1-ylmethyl group. The compounds were evaluated for their ability to inhibit nuclear HDACs, as well as for their in vitro antiproliferative activity. Moreover, their metabolic stability in microsomes and aqueous solubility were studied and selected compounds were further characterized by in vivo pharmacokinetic experiments. These compounds showed a remarkable stability in vivo, compared to hydroxamic acid HDAC inhibitors that have already entered clinical trials. The representative compound 30b showed in vivo antitumor activity in a human colon carcinoma xenograft model.

Regulatory effects of the mitochondrial energetic status on mitochondrial p66Shc.

p66(Shc) promotes apoptosis and controls the intracellular redox balance. A fraction of p66(Shc) exists within mitochondria, where it oxidizes cytochrome c to form hydrogen peroxide, which in turn induces mitochondrial permeability and apoptosis. However, cells tolerate p66(Shc) expression and accumulate oxidative damage under normal conditions, implying that the p66(Shc) functions must be tightly regulated. Here we review available knowledge on the regulation of p66(Shc) transcription, protein stabilization and post-translational modifications. In addition, we report novel investigations into the role of the mitochondrial import machinery on p66(Shc) activation, which highlight the energetic status of mitochondria as a crucial determinant of p66(Shc) function.

Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis.

Reactive oxygen species (ROS) are potent inducers of oxidative damage and have been implicated in the regulation of specific cellular functions, including apoptosis. Mitochondrial ROS increase markedly after proapoptotic signals, though the biological significance and the underlying molecular mechanisms remain undetermined. P66Shc is a genetic determinant of life span in mammals, which regulates ROS metabolism and apoptosis. We report here that p66Shc is a redox enzyme that generates mitochondrial ROS (hydrogen peroxide) as signaling molecules for apoptosis. For this function, p66Shc utilizes reducing equivalents of the mitochondrial electron transfer chain through the oxidation of cytochrome c. Redox-defective mutants of p66Shc are unable to induce mitochondrial ROS generation and swelling in vitro or to mediate mitochondrial apoptosis in vivo. These data demonstrate the existence of alternative redox reactions of the mitochondrial electron transfer chain, which evolved to generate proapoptotic ROS in response to specific stress signals.

The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential.

P66Shc regulates life span in mammals and is a critical component of the apoptotic response to oxidative stress. It functions as a downstream target of the tumor suppressor p53 and is indispensable for the ability of oxidative stress-activated p53 to induce apoptosis. The molecular mechanisms underlying the apoptogenic effect of p66Shc are unknown. Here we report the following three findings. (i) The apoptosome can be properly activated in vitro in the absence of p66Shc only if purified cytochrome c is supplied. (ii) Cytochrome c release after oxidative signals is impaired in the absence of p66Shc. (iii) p66Shc induces the collapse of the mitochondrial trans-membrane potential after oxidative stress. Furthermore, we showed that a fraction of cytosolic p66Shc localizes within mitochondria where it forms a complex with mitochondrial Hsp70. Treatment of cells with ultraviolet radiation induced the dissociation of this complex and the release of monomeric p66Shc. We propose that p66Shc regulates the mitochondrial pathway of apoptosis by inducing mitochondrial damage after dissociation from an inhibitory protein complex. Genetic and biochemical evidence suggests that mitochondria regulate life span through their effects on the energetic metabolism (mitochondrial theory of aging). Our data suggest that mitochondrial regulation of apoptosis might also contribute to life span determination.

Laparoscopic cholecystectomy with three trocars: 10 years experience.

Since 1992 we have performed laparoscopic cholecystectomy with 3 trocars (10, 10 and 5 mm) while most surgeons use 4. In our 10 years of experience a total of 1,243 cholecystectomies have been performed with the 3-trocar technique. The overall conversion rate is 0.75%. In 5.7% of cases we used a fourth trocar in order to avoid anatomical difficulties or to perform intraoperative cholangiography. All interventions are technically feasible, even in sclerotic cholecystitis and in emergency operations. We describe this technique which can be considered an economic and cosmetically satisfying alternative, that is safe and effective for the patient and easy to perform for the surgeon.

[The learning curve in laparoscopic resections of the colon and rectum: results and considerations]. / La curva di apprendimento nelle resezioni laparoscopiche del colon-retto: risultati e considerazioni.

A well-designed learning curve is essential for the success of laparoscopic colorectal surgery for cancer. The aim of this study was to evaluate the results and characteristics of the learning curve in laparoscopic colorectal surgery beginning with benign diseases and eventually going on to include colonic resections for cancer. A total of 60 laparoscopic resections were performed. In the first 33 cases only benign diseases (diverticular disease and polyps) were treated. The next 27 cases included resections for cancer, initially with the following exclusion criteria: obesity, previous abdominal surgery, emergency surgery for occlusion, voluminous tumours or infiltration of surrounding organs. Since January 2002 the only applicable exclusion criteria for laparoscopic resection have been emergency surgery for occlusion and invasion of adjacent organs. The following procedures were performed: 29 left hemicolectomies, 19 sigmoid resections, 7 segmentary resections, 3 abdomino-perineal resections and 2 right hemicolectomies. The conversion rate was 11.6%. The mean length of the segment removed was 21.5 cm. The mean number of lymph nodes harvested (for cancer) was 22.3. Major complications were observed in 3.3% and minor complications in 13.3%. The operative time decreased from a mean of 207 minutes to a mean of 170 minutes in the last group of 20 patients. Laparoscopic resections are safe and give the patient the opportunity to make a rapid recovery with less pain and a better outcome. We suggest performing laparoscopic colorectal resections initially for benign diseases (diverticular disease and polyps). This is needed in order to hone the technique. Resections for cancer can be undertaken only when the surgical team can guarantee an oncologically correct procedure in terms of lymphadenectomy, intraabdominal manipulation and extraction of the diseased segment from the abdomen.