IRCCS San Raffaele Hospital

San Raffaele Cimena, Italy

IRCCS San Raffaele Hospital

San Raffaele Cimena, Italy
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Kooijmans S.A.A.,University Utrecht | Schiffelers R.M.,University Utrecht | Zarovni N.,Estonia and Exosomics Siena S.p.A | Vago R.,IRCCS San Raffaele Hospital | Vago R.,Vita-Salute San Raffaele University
Pharmacological Research | Year: 2016

Exosomes are naturally secreted nanovesicles that have recently aroused a great interest in the scientific and clinical community for their roles in intercellular communication in almost all physiological and pathological processes. These 30–100 nm sized vesicles are released from the cells into the extracellular space and ultimately into biofluids in a tightly regulated way. Their molecular composition reflects their cells of origin, may confer specific cell or tissue tropism and underlines their biological activity. Exosomes and other extracellular vesicles (EVs) carry specific sets of proteins, nucleic acids (DNA, mRNA and regulatory RNAs), lipids and metabolites that represent an appealing source of novel noninvasive markers through biofluid biopsies. Exosome-shuttled molecules maintain their biological activity and are capable of modulating and reprogramming recipient cells. This multi-faceted nature of exosomes hold great promise for improving cancer treatment featuring them as novel diagnostic sensors as well as therapeutic effectors and drug delivery vectors. Natural biological activity including the therapeutic payload and targeting behavior of EVs can be tuned via genetic and chemical engineering. In this review we describe the properties that EVs share with conventional synthetic nanoparticles, including size, liposome-like membrane bilayer with customizable surface, and multifunctional capacity. We also highlight unique characteristics of EVs, which possibly allow them to circumvent some limitations of synthetic nanoparticle systems and facilitate clinical translation. The latter are in particular correlated with their innate stability, ability to cross biological barriers, efficiently deliver bioactive cargos or evade immune recognition. Furthermore, we discuss the potential roles for EVs in diagnostics and theranostics, and highlight the challenges that still need to be overcome before EVs can be applied to routine clinical practice. © 2016 Elsevier Ltd

Proietti S.,IRCCS San Raffaele Hospital | Giusti G.,IRCCS San Raffaele Hospital | Desai M.,Muljibhai Patel Urological Hospital | Ganpule A.P.,Muljibhai Patel Urological Hospital
European Urology Focus | Year: 2017

Context: In an effort to reduce morbidity related to percutaneous nephrolithotomy (PCNL), some investigators have progressively introduced miniaturised approaches. The development of miniaturised nephroscopes facilitated widespread dissemination of these techniques and a significant expansion of the role of PCNL in endourology. Objective: To discuss the different techniques comprising modern PCNL and identify the pros and cons of each of them. Evidence acquisition: Data for this review were identified through a search of PubMed, including studies published in the last 20 yr in core clinical journals in English. The search terms included "urolithiasis", "nephrolithiasis", or "urinary stones" in combination with "miniaturised PCNL", "mini-PCNL", "micro-PCNL", "minimally invasive PCNL", and "ultra-mini PCNL". Publications relevant to the subject were retrieved and critically appraised. Evidence synthesis: The indications for miniaturised PCNL have not been standardised yet. Even though data in the literature reveal limitations and conflicting results, these techniques seem promising in terms of effectiveness and safety for the treatment of renal stones. The development of miniaturised scopes facilitated knowledge of the physics behind the vacuum cleaner effect generated during procedures, and greater efficacy of holmium laser generators and surgeon skill have led to progressive expansion of the indications for miniaturised techniques. Well-designed, randomised, multi-institutional studies are needed to better understand the indications for these miniaturised techniques before considering them a standard procedure for potential replacement of conventional PCNL. Conclusions: Miniaturised PCNL represents a valuable new tool in the armamentarium of modern endourologists, capable of offering good outcomes with lower complications rates compared to the standard technique and higher cost effectiveness compared to flexible ureteroscopy. Patient summary: Miniaturised percutaneous nephrolithotomy represents a safe and effective alternative to standard techniques for the treatment of renal stones. Each patient needs to be considered individually and tailored surgical treatment has to be offered. Miniaturized percutaneous nephrolithotomy represent a safe and effective alternative to standard techniques for the treatment of renal stones. Each patient needs to be considered individually and a tailored surgical approach has to be offered. © 2017.

Gandaglia G.,IRCCS San Raffaele Hospital | Briganti A.,IRCCS San Raffaele Hospital | Clarke N.,The Christie and Salford Royal NHS Foundation Trusts | Karnes R.J.,Mayo Medical School | And 4 more authors.
European Urology | Year: 2017

Context: Prostate cancer (PCa) patients found to have adverse pathologic features following radical prostatectomy (RP) are less likely to be cured with surgery alone. Objective: To analyze the role of postoperative radiotherapy (RT) in patients with aggressive PCa. Evidence acquisition: We performed a systematic literature review of the Medline and EMBASE databases. The search strategy included the terms radical prostatectomy, adjuvant radiotherapy, and salvage radiotherapy, alone or in combination. We limited our search to studies published between January 2009 and August 2016. Evidence synthesis: Three randomized trials demonstrated that immediate RT after RP reduces the risk of recurrence in patients with aggressive PCa. However, immediate postoperative RT is associated with an increased risk of acute and late side effects ranging from 15% to 35% and 2% to 8%, respectively. Retrospective studies support the oncologic efficacy of initial observation followed by salvage RT administered at the first sign of recurrence; however, the impact of this delay on long-term control remains uncertain. Hopefully, ongoing randomized trials will shed light on the role of adjuvant RT versus observation. ±. salvage RT in individuals with adverse features at RP. Accurate patient selection based on clinical characteristics and molecular profile is crucial. Dose escalation, whole-pelvis RT, novel techniques, and the use of hormonal therapy might improve the outcomes of postoperative RT. Conclusions: Immediate RT reduces the risk of recurrence after RP in patients with aggressive disease. However, this approach is associated with an increase in the incidence of short- and long-term side effects. Observation followed by salvage RT administered at the first sign of recurrence might be associated with durable cancer control, but prospective randomized comparison with adjuvant RT is still awaited. Dose escalation, refinements in the technique, and the concomitant use of hormonal therapies might improve outcomes of patients undergoing postoperative RT. Patient summary: Postoperative radiotherapy has an impact on oncologic outcomes in patients with aggressive disease characteristics. Salvage radiotherapy administered at the first sign of recurrence might be associated with durable cancer control in selected patients but might compromise cure in others. Adjuvant radiotherapy reduces the risk of recurrence after radical prostatectomy in patients with aggressive disease characteristics. However, it may be associated with a higher risk of Grade 2 and 3 genitourinary effects at long-term follow-up. Observation followed by salvage radiotherapy administered at the first sign of recurrence might be associated with durable cancer control in selected patients but may compromise cure in others. © 2017 European Association of Urology.

Sigismondi C.,IRCCS San Raffaele Hospital | Gadducci A.,University of Pisa | Lorusso D.,Catholic University of the Sacred Heart | Candiani M.,IRCCS San Raffaele Hospital | And 4 more authors.
Gynecologic Oncology | Year: 2012

Objective: To evaluate clinicopathologic features and to investigate the outcome of patients with ovarian Sertoli-Leydig cell tumors (SLCTs). Methods: Data concerning 21 patients treated in 11 MITO centers were retrospectively reviewed. Results: Median age was 37 (range 16-76). FIGO stage was: 17 (81%) IA, 1 (4.8%) IC, 1 (4.8%) IIB and 2 (9.5%) IIIC. Five patients (23.8%) had G1 tumor, ten (47.6%) had G2, and six (28.6%) had G3. Fertility-sparing operation was performed in 11 patients, while hysterectomy with bilateral salpingo-oophorectomy was executed in 10 patients; five patients received adjuvant chemotherapy (G2-3). Seven patients (33.3%) relapsed with a median time to recurrence of 14 months. Six recurrent patients had G2-3 disease, while one had G1. Four patients had stage IA disease, one IC and 2 stage IIIC. Patients with stage IA disease did not receive adjuvant chemotherapy. Two patients had pelvic recurrence, 4 abdominal (one with lymph nodal involvement), one on the contralateral ovary and the trocar access. Five patients underwent salvage surgery plus chemotherapy, while one received only salvage chemotherapy and one palliation. Five patients died of disease, four had received first treatment not in a MITO center. 5 year overall survival was 100% for patients with G1 disease and 77.8% for G2-3. 5 year overall survival was 92.3% for stage I and 33.3% for stage > I. Conclusions: The prognosis of patients with grade 1 SLCT is excellent without adjuvant chemotherapy. Patients with advanced stage or grade 2-3 tumors appear to benefit from postoperative chemotherapy. © 2012 Elsevier Inc. All rights reserved.

D'Addio F.,Harvard University | D'Addio F.,IRCCS San Raffaele Hospital | Vasquez A.V.,IRCCS San Raffaele Hospital | Nasr M.B.,Harvard University | And 8 more authors.
Diabetes | Year: 2014

Type 1 diabetes (T1D) is one of the major autoimmune diseases affecting children and young adults worldwide. To date, the different immunotherapies tested have achieved insulin independence in <5% of treated individuals. Recently, a novel hematopoietic stem cell (HSC)-based strategy has been tested in individuals with new-onset T1D. The aim of this study was to determine the effects of autologous nonmyeloablative HSC transplantation in 65 individuals with new-onset T1D who were enrolled in two Chinese centers and one Polish center, pooled, and followed up for 48 months. A total of 59% of individuals with T1D achieved insulin independence within the first 6 months after receiving conditioning immunosuppression therapy (with antithymocyte globulin and cyclophosphamide) and a single infusion of autologous HSCs, and 32% remained insulin independent at the last time point of their follow-up. All treated subjects showed a decrease in HbA1c levels and an increase in C-peptide levels compared with pretreatment. Despite a complete immune system recovery (i.e., leukocyte count) after treatment, 52% of treated individuals experienced adverse effects. Our study suggests the following: 1) that remission of T1D is possible by combining HSC transplantation and immunosuppression; 2) that autologous nonmyeloablative HSC transplantation represents an effective treatment for selected individuals with T1D; and 3) that safer HSC-based therapeutic options are required. © 2014 by the American Diabetes Association.

Serati M.,University of Insubria | Bauer R.,Ludwig Maximilians University of Munich | Cornu J.N.,University Paris - Sud | Cattoni E.,University of Insubria | And 6 more authors.
European Urology | Year: 2013

Background: Inside-out tension-free vaginal transobturator tape (TVT-O) is currently one of the most effective and popular procedures for the surgical treatment of female stress urinary incontinence (SUI), but data reporting long-term outcomes are scarce. Objective: To evaluate the efficacy and safety of TVT-O 5-yr implantation for management of pure SUI in women. Design, setting, and participants: A prospective observational study was conducted in four tertiary reference centers. Consecutive women presenting with urodynamically proven, pure SUI treated by TVT-O were included. Patients with mixed incontinence and/or anatomic evidence of pelvic organ prolapse were excluded. Intervention: TVT-O implantation without any associated procedure. Outcome measurements and statistical analysis: Data regarding subjective outcomes (International Consultation on Incontinence-Short Form [ICIQ-SF], Patient Global Impression of Improvement, patient satisfaction scores), objective cure (stress test) rates, and adverse events were collected during follow-up. Multivariable analyses were performed to investigate outcomes. Results and limitations: Of the 191 women included, 21 (11.0%) had previously undergone a failed anti-incontinence surgical procedure. Six (3.1%) patients were lost to follow-up. The 5-yr subjective and objective cure rates were 90.3% and 90.8%, respectively. De novo overactive bladder (OAB) was reported by 24.3% of patients at 5-yr follow-up. Median ICIQ-SF score significantly improved from 17 (interquartile range [IQR]:16-17) preoperatively to 0 (IQR: 0-2) (p < 0.0001). Failure of a previous anti-incontinence procedure was the only independent predictor of subjective recurrence of SUI (hazard ratio [HR]: 4.4; p = 0.009) or objective (HR: 3.7; p = 0.02). No predictive factor of de novo OAB was identified. Conclusions: TVT-O implantation is a highly effective option for the treatment of women with pure SUI, showing a very high cure rate and a low incidence of complications after 5-yr follow-up. © 2012 European Association of Urology.

Di Resta C.,Vita-Salute San Raffaele University | Pietrelli A.,CNR Institute of Biomedical Technologies | Pietrelli A.,University of Milan | Sala S.,IRCCS San Raffaele Hospital | And 6 more authors.
Human Molecular Genetics | Year: 2015

Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder that can lead to sudden death, with a prevalence of 1:5000 in Caucasian population and affecting mainly male patients in their third to fourth decade of life. BrS is inherited as an autosomal dominant trait; however, to date genetic bases have been only partially understood. Indeed most mutations are located in the SCN5A gene, encoding the alpha-subunit of the Na+ cardiac channel, but >70% BrS patients still remain genetically undiagnosed. Although 21 other genes have been associated with BrS susceptibility, their pathogenic role is still unclear. A recent nextgeneration sequencing study investigated the contribution of 45 arrhythmia susceptibility genes in BrS pathogenesis, observing a significant enrichment only for SCN5A. In our study, we evaluated the distribution of putative functional variants in a wider panel of 158 genes previously associated with arrhythmic and cardiac defects in a cohort of 91 SCN5A-negative BrS patients. In addition, to identify genes significantly enriched in BrS, we performed a mutation burden test by using as control dataset European individuals selected from the 1000Genomes project. We confirmed BrS genetic heterogeneity and identified new potential BrS candidates such as DSG2 and MYH7, suggesting a possible genetic overlap between different cardiac disorders. © The Author 2015.

Serati M.,University of Insubria | Ghezzi F.,University of Insubria | Cattoni E.,University of Insubria | Braga A.,University of Insubria | And 5 more authors.
European Urology | Year: 2012

Background: One of the most effective and popular current procedures for the surgical treatment of stress urinary incontinence (SUI) is tension-free midurethral slings. Objective: To evaluate the outcomes of women with retropubic tension-free vaginal tape (TVT) for urodynamic stress incontinence (USI) after 10-yr follow-up. Design, setting, and participants: This was a prospective observational study. Consecutive women with proven USI were treated with TVT. Patients with mixed incontinence and/or anatomic evidence of pelvic organ prolapse were excluded. Intervention: Standard retropubic TVT. Measurements: Patients underwent preoperative clinical and urodynamic evaluations. During follow-up examinations, women were assessed for subjective satisfaction and objective cure rates. Multivariable analyses were performed to investigate outcomes. Results and limitations: A total of 63 women were included. After 10 yr, 5 patients (8%) were lost or no longer evaluable. The 10-yr subjective, objective, and urodynamic cure rates were 89.7%, 93.1%, and 91.4%, respectively. These rates were stable across the whole study period (p > 0.99). De novo overactive bladder was reported by 30.1% and 18.9% of patients at 3-mo and 10-yr follow-up, respectively (p for trend = 0.19). A total of 84.2% of women with detrusor overactivity received antimuscarinic drugs, but 43.8% were nonresponders 12 wk later. At multivariable analysis, maximum detrusor pressure during the filling phase >9 cm H 2O (hazard ratio [HR]: 16.2; p = 0.01) and maximum detrusor pressure during the voiding phase ≤29 cm H 2O (HR: 8.0; p = 0.01) were independent predictors for the recurrence of SUI, as well as obesity was for the recurrence of objective SUI (HR: 17.1; p = 0.01) and of USI (HR: 8.9; p = 0.02), respectively. Intraoperatively, bladder perforation occurred in two cases; no severe bleeding or other complications occurred. Conclusions: The 10-yr results of this study seem to demonstrate that TVT is a highly effective option for the treatment of female SUI, recording a very high cure rate with low complications after a 10-yr follow-up. © 2012 European Association of Urology.

Serati M.,University of Insubria | Bogani G.,University of Insubria | Sorice P.,University of Insubria | Braga A.,University of Insubria | And 5 more authors.
European Urology | Year: 2014

Context Surgery represents the mainstay of treatment for pelvic organ prolapse (POP). Among different surgical procedures, abdominal sacrocolpopexy (SC) is the gold standard for apical or multicompartmental POP. Research has recently focused on the role of robot-assisted sacrocolpopexy (RASC). Objective To conduct a systematic review on the outcomes of RASC. Evidence acquisition PubMed, Scopus, and Web of Science databases as well as were searched for English-language literature on RASC. A total of 509 articles were screened; 50 (10%) were selected, and 27 (5%) were included. Studies were evaluated per the Grading of Recommendations, Assessment, Development, and Evaluation system and the European Association of Urology guidelines. Evidence synthesis Overall, data on 1488 RASCs were collected from 27 studies, published from 2006 to 2013. Objective and subjective cures ranged from 84% to 100% and from 92% to 95%, respectively. Conversion rate to open surgery was <1% (range: 0-5%). Intraoperative, severe postoperative complications, and mesh erosion rates were 3% (range: 0-19%), 2% (range: 0-8%), and 2% (range: 0-8%), respectively. Surgical-related outcomes have improved with increased experience, with an estimated learning curve of about 10-20 procedures. Laparoscopic SC is less costly than RASC, although the latter has lower costs than abdominal SC. Conclusions RASC is a safe and feasible procedure for POP; it allows the execution of complex surgical steps via minimally invasive surgery without medium- and long-term anatomic detriments. Further prospective studies are needed to confirm these findings. Patient summary We looked at the outcomes of robotic sacrocolpopexy for prolapse. We found that the use of robotic technology is safe and effective for the treatment of prolapse in women. © 2014 European Association of Urology.

Ratti F.,IRCCS San Raffaele Hospital | Schadde E.,University of Zürich | Masetti M.,Maggiore Hospital | Massani M.,Hepatopancreatobiliary Surgery Unit | And 7 more authors.
Annals of Surgical Oncology | Year: 2015

Background: Two-stage hepatectomy (TSH) is well established for the treatment of patients who have colorectal cancer liver metastases (CRLM) with a small liver remnant. The technique of associating liver partitioning and portal vein occlusion for staged hepatectomy (ALPPS) has been advocated as a novel tool to increase resectability. Using a case-match design, this study aimed to compare TSH and ALPPS for patients with CRLM.Methods: All patients undergoing ALPPS for CRLM at three major hepatobiliary centers in Italy (ALPPS group) were compared in a case-match analysis with patients undergoing TSH (TSH group) at a single institution. The groups were matched with a 1:3 ratio using propensity scores based on covariates representing severity of metastatic disease. The main end points of the study were feasibility of complete resection and intra- and postoperative outcomes.Results: The two treatments did not differ significantly in feasibility. Two patients in the TSH group dropped out compared with no patients in the ALPPS group. A comparable volume gain in future liver remnant (FLR) was obtained in the ALPPS and TSH groups (47 vs. 41 %, nonsignificant difference) but during a shorter interval in ALPPS group. The overall and major complication rate was significantly higher after stage 2 in the ALPPS group (Clavien ≥ 3a: 41.7 vs. 17.6 % in TSH group; p = 0.025).Conclusion: The feasibility of resection using ALPPS compared with TSH for CRLM was not significantly greater, but perioperative complications were increased. Therefore, ALPPS should be proposed to patients with caution and warnings. Currently, TSH remains the standard approach for performing R0 resection in patients with advanced CRLM and inadequate FLR. © 2014, Society of Surgical Oncology.

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