Paolo Massucco

Inhibition of MEK and PI3K/mTOR Suppresses Tumor Growth but Does Not Cause Tumor Regression in Patient-Derived Xenografts of RAS-Mutant Colorectal Carcinomas

Purpose: Gene mutations along the Ras pathway (KRAS, NRAS, BRAF, PIK3CA) occur in approximately 50% of colorectal cancers (CRC) and correlate with poor response to anti–EGF receptor (EGFR) therapies. We assessed the effects of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) and phosphoinositide 3-kinase (PI3K)/mTOR inhibitors, which neutralize the major Ras effectors, in patient-derived xenografts from RAS/RAF/PIK3CA-mutant metastatic CRCs (mCRC). Experimental Design: Forty mCRC specimens harboring KRAS, NRAS, BRAF, and/or PIK3CA mutations were implanted in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Each xenograft was expanded into four treatment arms: placebo, the MEK inhibitor AZD6244, the PI3K/mTOR inhibitor, BEZ235, or AZD6244 + BEZ235. Cases initially treated with placebo crossed over to AZD6244, BEZ235, and the anti-EGFR monoclonal antibody cetuximab. Results: At the 3-week evaluation time point, cotreatment of established tumors with AZD6244 + BEZ235 induced disease stabilization in the majority of cases (70%) but did not lead to overt tumor regression. Monotherapy was less effective, with BEZ235 displaying higher activity than AZD6244 (disease control rates, DCRs: AZD6244, 27.5%; BEZ235, 42.5%). Triple therapy with cetuximab provided further advantage (DCR, 88%). The extent of disease control declined at the 6-week evaluation time point (DCRs: AZD6244, 13.9%; BEZ235, 16.2%; AZD6244 + BEZ235, 34%). Cross-analysis of mice harboring xenografts from the same original tumor and treated with each of the different modalities revealed subgroups with preferential sensitivity to AZD6244 (12.5%), BEZ235 (35%), or AZD6244 + BEZ235 (42.5%); another subgroup (10%) showed equivalent response to any treatment. Conclusions: The prevalent growth-suppressive effects produced by MEK and PI3K/mTOR inhibition suggest that this strategy may retard disease progression in patients. However, data offer cautionary evidence against the occurrence of durable responses. Clin Cancer Res; 18(9); 2515–25. ©2012 AACR.

Asymptomatic Colorectal Cancer with Un-Resectable Liver Metastases: Immediate Colorectal Resection or Up-Front Systemic Chemotherapy?

BackgroundAbout 20% of patients with colorectal cancer have synchronous un-resectable liver metastases. Resection of colorectal cancer in patients with moderate-severe symptoms is mandatory before starting chemotherapy. Surgical treatment of asymptomatic colorectal cancers is still a matter of discussion.MethodsFrom January 2000 to December 2004, we prospectively collected data on 35 consecutive patients who were treated straightaway by chemotherapy without primary tumor resection. All patients underwent FOLFOX6 as first-line chemotherapy. The aim of the study was to evaluate the rate of surgical complications related to un-resected colorectal tumor.ResultsThe mean interval between diagnosis and start of chemotherapy was 23.1 days (95% CI: 17.3–28.8). Fifteen of the 35 patients (42.9%) were down-staged to surgery; the mean interval between chemotherapy start and colon-rectum cancer resection was 6.5 months (95% CI: 5.5–7.5). None of them developed complications related to the primary tumor during chemotherapy. Of the other 20 patients who did not undergo any curative surgery, 16 received a second line chemotherapy and 10 a third line: six patients are alive and without intestinal symptoms (mean follow up 22.5 months, 95% CI: 11.2–33.9). Only one patient (2.8%) developed clinical signs of intestinal occlusion 5.6 months from the start of chemotherapy and required urgent colostomy.ConclusionsThe rate of complications related to the non-resected colorectal tumor is very low using oxaliplatin as first line chemotherapy. Non-operative management of asymptomatic colorectal cancers with un-resectable liver metastases is a safe approach.

Liver resection for hilar cholangiocarcinoma: in-hospital mortality and longterm survival

BACKGROUND Extended surgical procedures are the only chance of longterm survival for patients with Klatskin tumors, but high mortality rates have been reported. The type of treatment for Bismuth type l-II carcinomas is still a matter of discussion. STUDY DESIGN We performed a single-unit, retrospective study analyzing 36 patients who underwent resectional surgery for Klatskin tumor. RESULTS An associated liver resection was performed in 88.9% of our patients; most of them had a major hepatectomy. The in-hospital mortality rate was 2.8%. Three- and 5-year survival rates were 40.8% and 27.2%, respectively. But the group of patients with Bismuth type I-II carcinomas undergoing hepatectomy had markedly better longterm outcomes than those undergoing hilar resection (p = 0.04): 54.5% versus 0% at 5 years, respectively; none of the patients who had only resection of bile duct confluence were alive at 2 years. Lymph node metastases were found in 38.8% of our patients; nodal involvement was not a major prognostic factor. CONCLUSIONS Achievement of low in-hospital mortality rates is possible in specialized surgical departments. Aggressive surgical approaches can allow better longterm results in the subset of Bismuth type I-II carcinomas.

Genetic and Expression Analysis of MET, MACC1, and HGF in Metastatic Colorectal Cancer: Response to Met Inhibition in Patient Xenografts and Pathologic Correlations

Purpose: We determined the gene copy numbers for MET, for its transcriptional activator MACC1 and for its ligand hepatocyte growth factor (HGF) in liver metastases from colorectal carcinoma (mCRC). We correlated copy numbers with mRNA levels and explored whether gain and/or overexpression of MET and MACC1 predict response to anti-Met therapies. Finally, we assessed whether their genomic or transcriptional deregulation correlates with pathologic and molecular parameters of aggressive disease. Experimental Design: One hundred three mCRCs were analyzed. Copy numbers and mRNA were determined by quantitative PCR (qPCR). Thirty nine samples were implanted and expanded in NOD (nonobese diabetic)/SCID (severe combined immunodeficient) mice to generate cohorts that were treated with the Met inhibitor JNJ-38877605. In silico analysis of MACC1 targets relied on genome-wide mapping of promoter regions and on expression data from two CRC datasets. Results: No focal, high-grade amplifications of MET, MACC1, or HGF were detected. Chromosome 7 polysomy and gain of the p-arm were observed in 21% and 8% of cases, respectively, and significantly correlated with higher expression of both Met and MACC1. Met inhibition in patient-derived xenografts did not modify tumor growth. Copy number gain and overexpression of MACC1 correlated with unfavorable pathologic features better than overexpression of Met. Bioinformatic analysis of putative MACC1 targets identified elements besides Met, whose overexpression cosegregated with aggressive forms of colorectal cancer. Conclusions: Experiments in patient-derived xenografts suggest that mCRCs do not rely on Met genomic gain and/or overexpression for growth. On the basis of pathologic correlations and bioinformatic analysis, MACC1 could contribute to CRC progression through mechanisms other than or additional to Met transcriptional upregulation. Clin Cancer Res; 17(10); 3146–56. ©2011 AACR.

Induction Gemcitabine and Oxaliplatin Therapy Followed by a Twice-Weekly Infusion of Gemcitabine and Concurrent External-Beam Radiation for Neoadjuvant Treatment of Locally Advanced Pancreatic Cancer A Single Institutional Experience

Chemoradiotherapy (CRT) may render curative resection feasible in patients with locally advanced pancreatic carcinoma (LAPC). The authors previously demonstrated the achievement of significant disease control and a median survival of 14 months by CRT in patients with LAPC. In this study, they evaluated the use of induction chemotherapy followed by a CRT neoadjuvant protocol.

Major liver resections for hepatocellular carcinoma on cirrhosis: Early and long-term outcomes

Since the lack of donors, liver resections continue to be the treatment of choice for cirrhotic patients with good liver function and resectable hepatocellular carcinoma (HCC). Moreover, over the past 2 decades, an increasing number of major hepatic resections have been performed. The aim of this study is to evaluate short‐ and long‐term outcomes of 55 cirrhotic patients undergoing major hepatic resection with particular attention to the survival of the patients with gross portal vein invasion or large size tumors. Twenty‐two patients (40%) required intra‐ or post‐operative blood transfusion. Medium tumor size was 66.6±29.2 mm; 7 patients had large size (> 10 cm) HCCs. A single node was present in 38 cases (69.1%). There was a gross portal vein tumor thrombus (PVTT) in 13 patients (23.6%). Resection was non‐curative in 4 cases. In‐hospital mortality and morbidity rates were 5.5% and 30.9%, respectively. The overall and disease‐free survival rates were 36.2% and 42.8%, respectively. Overall 5‐year survival rates of patients with large size tumors was 17.1%. Ten patients with a gross PVTT had an R0 resection with a 26.6% 5‐year survival rate. In conclusion, major hepatic resections for HCC can be performed with low mortality and morbidity rates. HCCs with PVTT or greater than 10 cm in size have very limited options of treatment; the favorable long‐term results of our study suggest that they should undergo surgery if a radical resection can be achieved. (Liver Transpl 2004;10:S64–S68.)

Outcome of Surgical Treatment for Chronic Calcifying Pancreatitis

Objective To evaluate the short and long-term results of surgical treatment of calcifying chronic pancreatitis in our center. Patients and methods We studied 55 consecutive patients operated on for chronic calcifying pancreatitis during a period of 12 years. The mean follow-up period was 6.2 years. Main outcome measures were operative mortality and morbidity, degree of pain control, diabetes onset, survival, and causes of death. Results The etiology was alcoholic in 48 patients and idiopathic in seven patients. A resection was performed in 78% of cases and a by-pass procedure was performed in 22%. Operative mortality was 3.6%; morbidity was 21.8%. A ductal adenocarcinoma was found in 3.6% of cases. The alcohol withdrawal rate was 78%. Complete pain control was achieved in 71.4% of the patients. Among diabetes, cirrhosis, type of surgery, smoking and alcohol abuse history, only alcohol withdrawal was associated with pain control (p < 0.03). A late reintervention was needed in only one patient in the by-pass group. Five and 10-year survival rates for the entire population were 80% and 61%, respectively. Among alcohol, cirrhosis, diabetes, and type of surgery, only the former was associated with survival (p < 0.003). Five-year actuarial survival was 55.6% for patients who continued drinking compared with 86.3% for ex-alcoholics. Conclusions Surgical resection should be performed when required by the anatomical conditions because it was associated with good long-term pain control and low postoperative and late morbidity. Alcohol withdrawal has a key role for effective control of pain and prolonged survival.

Laparoscopic vs open restorative proctocolectomy with IPAA for ulcerative colitis: Impact of surgical technique on creating a well functioning pouch

BACKGROUND Patients with ulcerative colitis are often young, and proctocolectomy with restorative ileo-pouch anal anastomosis is a crucial act that can improve or worsen the quality of the rest of their lives. The literature is scant on long-term functional outcomes after laparoscopy. The purpose of this study was to investigate results in terms of pouch function after standardized total laparoscopic technique compared with open intervention. MATERIALS AND METHODS This was a retrospective comparative study. Cases were collected from the prospectively-maintained database of the Unit of General and Oncologic Surgery, XXX, Torino, Italy. Patients treated between May 2005 and May 2015 with three-stage laparoscopic or open proctocolectomy and ileo-pouch anal anastomosis were enrolled. The primary study endpoint was the percentage of well-functioning pouches. Secondary endpoints were postoperative early and late outcomes such as morbidity and pouch survival. RESULTS Of the 78 patients identified, 48 underwent the open technique and 30 underwent laparoscopy. Median follow-up was 4 years. The overall complication rates were 19% and 13% (p = 0.5), and there were major complications (Clavien-Dindo III-IV) in 14.6% and 13.3% of patients in the open and laparoscopic groups, respectively (p = 0.8). Late complications occurred in 26 patients. Nine (18.8%) and 5 (16.7%) patients had pouchitis (p = 0.8), and 6 (12.5%) and 2 (6.7%) had cuffitis in the open and laparoscopic groups, respectively (p = 0.70). Pouch failure occurred in 2 patients (4.2%) in the open group and 2 (6.7%) in the laparoscopic group. The pouch was observed to be functioning very well in 18 patients (37.5%) in the open group and in 17 patients (56%) in the laparoscopic group (p = 0.09). The study was limited by its retrospective, nonrandomized design. CONCLUSION Our data demonstrated similar early and late results after total laparoscopic and open proctocolectomy, in particular concerning pouch function.