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Avallone A.,Multidisciplinary Treatment Unit | Piccirillo M.C.,Clinical Trials Unit | Aloj L.,Nuclear Medicine Unit | Nasti G.,Gastrointestinal Medical Oncology Unit | And 28 more authors.
BMC Cancer | Year: 2016

Background: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. Methods/Design: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80 % statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [18F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. Discussion: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 Trial registration: ClinicalTrials.gove number, NCT01718873 © 2016 Avallone et al.


Pivonello C.,University of Naples Federico II | Negri M.,Futura Medical | De Martino M.C.,University of Naples Federico II | Napolitano M.,Immunology Oncology Unit | And 9 more authors.
Oncotarget | Year: 2016

Deregulation of mTOR and IGF pathways is frequent in hepatocellular carcinoma (HCC), thus mTOR and IGF1R represent suitable therapeutic targets in HCC. The aim of this study was to evaluate the effects of mTOR inhibitors (mTORi) and OSI-906, blocker of IGF1R/IR, on HCC cell proliferation, viability, migration and invasion, and alpha-fetoprotein (α-FP) secretion. In HepG2 and HuH-7 we evaluated, the expression of mTOR and IGF pathway components; the effects of Sirolimus, Everolimus, Temsirolimus and OSI-906 on cell proliferation; the effects of Sirolimus, OSI-906, and their combination, on cell secretion, proliferation, viability, cell cycle, apoptosis, invasion and migration. Moreover, intracellular mechanisms underlying these cell functions were evaluated in both cell lines. Our results show that HepG2 and HuH-7 present with the same mRNA expression profile with high levels of IGF2. OSI-906 inhibited cell proliferation at high concentration, while mTORi suppressed cell proliferation in a dose-time dependent manner in both cell lines. The co-treatment showed an additive inhibitory effect on cell proliferation and viability. This effect was not related to induction of apoptosis, but to G0/G1 phase block. Moreover, the co-treatment prevented the Sirolimus-induced AKT activation as escape mechanism. Both agents demonstrated to be differently effective in inhibiting α-FP secretion. Sirolimus, OSI-906, and their combination, blocked cell migration and invasion in HuH-7. These findings indicate that, co-targeting of IGF1R/IR and mTOR pathways could be a novel therapeutic approach in the management of HCC, in order to maximize antitumoral effect and to prevent the early development of resistance mechanisms.


Di Francesco F.,Hepatobiliary Surgery Unit | Del Prete L.,University of Rome Tor Vergata | Grimaldi C.,Hepatobiliary Surgery Unit | Monti L.,Hepatobiliary Radiology Unit | And 2 more authors.
Journal of Pediatric Surgery | Year: 2015

Background The association of pancreatitis and portal vein thrombosis (PVT) is extremely rare in children. We report on 3 cases which suggest that there may be a causal relation between the two. Methods Clinical characteristics and evolution of 3 children with this particular condition were analyzed retrospectively. In this group of patients, the strategy consisted in opting for early surgical decompression of the portal hypertension, which was followed by a favorable outcome, not only in terms of complications related to the portal hypertension but also of a contemporaneous spontaneous regression of the concurrent pancreatic disease, in absence of any other specific management of the latter problem. Results and conclusions Combined PVT and pancreatitis is exceptional in children. Although this series is small, it provides insight and some evidence that the pancreatic disease might be secondary to the cavernomatous transformation of the regional venous system. More interestingly, it suggests that the appropriate management strategy should be to rapidly relieve portal hypertension after resolution of the acute phase of pancreatitis. © 2015 Elsevier Inc. All rights reserved.


Ratti F.,Hepatobiliary Surgery Unit | Barkhatov L.I.,University of Oslo | Tomassini F.,Ghent University | Cipriani F.,Hepatobiliary Surgery Unit | And 6 more authors.
Surgical Endoscopy and Other Interventional Techniques | Year: 2015

Background: Laparoscopy was suggested as gold standard for left lateral sectionectomy (LLS), thanks to recognized benefits compared to open approach. Aim of this study was to define learning curve (LC) of laparoscopic LLS (LLLS) using operative time (OT) as tool to analyze outcome of procedures performed by four experienced surgeons. Reproducibility and safety of LC in LLLS among independent surgeons were also analyzed as essential features of “standard procedure” concept. Methods: LLLS performed by four experienced surgeons was collected. Multivariate analysis was carried out to screen factors affecting OT. A cumulative LC was created calculating median OT. Skewness of OT was analyzed, and ROC curve was carried out to identify the cutoff for LC. The impact of LC on outcomes (morbidity and mortality, blood loss, conversions, surgical margins and length of stay) was determined. Results: A total of 245 LLLSs were collected. Conversion rate was 1.2 %. Median OT was 141 min, blood loss 100 mL, morbidity 11.4 % and mortality 0.4 %. “Associated procedures” was the only independent factor affecting OT. The skewness of the OT was calculated, and the cutoff point for LC was determined after 15 LLLSs. LLLS performed during and after LC period had similar outcomes. Conclusion: LLLS is feasible with low morbidity, mortality and conversion rate. LC in LLLS is shorter compared to minor liver resections. Furthermore, it is reproducible and safe since it does not negatively affect clinical outcome. A reproducible, safe and short LC contributes to considering laparoscopy as the gold standard approach to perform LLS. © 2015 Springer Science+Business Media New York


Ratti F.,Hepatobiliary Surgery Unit | Catena M.,Hepatobiliary Surgery Unit | Di Palo S.,Gastrointestinal Surgery Unit | Staudacher C.,Gastrointestinal Surgery Unit | Aldrighetti L.,Hepatobiliary Surgery Unit
World Journal of Surgery | Year: 2015

Background: Safety and efficacy of simultaneous resections for patients with colorectal cancer and synchronous liver metastases have been widely reported, while the topic of approach (laparoscopic or open) to hepatic and colorectal resection is still a debated issue. The aim of this study was to assess short-term outcome of combined resection of left colon or rectum cancer and liver metastases, comparing the results of the primary tumor resection performed by laparoscopic or open approach. Study design: From January 2004 to March 2014, 106 patients underwent combined resection of colorectal cancer and synchronous liver metastases. Sixty-nine patients underwent laparoscopic colorectal resection (laparoscopic colorectal surgery, LCS Group), and were compared with 37 patients undergoing colorectal resection by laparotomy (totally open surgery, TOS Group). Hepatic resection was performed by open approach in all the patients. Results: Groups were comparable in terms of patients and disease characteristics, extent of liver resection, and length of surgery. In LCS Group, blood loss (400 vs. 650 mL, p < 0.001) and rate of intraoperative transfusions (19.3 vs. 47.2 %, p = 0.04) were lower compared to TOS Group. LCS Group was associated with reduced postoperative morbidity (24.6 vs. 44.4 %, p = 0.039), and shorter postoperative median hospital stay (9 vs. 13 days, p < 0.001). LCS and TOS Groups had comparable oncologic radicality in terms of primary tumor lymphadenectomy (median number of removed nodes 19 and 20, respectively, p NS) and rate of R1 colorectal resections (two patients in both Groups). Multivariate analysis revealed significant correlation morbidity with preoperative chemotherapy, blood loss, and approach to primary tumor. Conclusions: Laparoscopic resection of colorectal cancer in patients undergoing simultaneous open resection of liver metastases is associated with a reduction of blood loss, morbidity, and postoperative hospital stay, without affecting oncologic radicality. Outcome is mainly conditioned by approach to intestinal surgery, rather than the extent of liver resection. © 2015 Société Internationale de Chirurgie.

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