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Background: For borderline resectable colorectal cancer liver metastases (CLM), systemic treatment can help to achieve R0 resection and reduce the risk of relapse. We assessed the role of perioperative triplet chemotherapy in combination with cetuximab in patients with RAS wild type high recurrence risk and/or borderline resectable CLM., Patients and Methods: This was a monocenter, open-label phase II study. Borderline resectability was defined technically as tumor involvement of >1 hepatic vein, or >4 hepatic segments, need for 2-stage hepatectomy or radiofrequency ablation, and/or biologically (high risk): ≥4 metastatic nodules, or synchronous metastases. Patients were treated with 4 pre- and postoperative cycles of biweekly COI-E (cetuximab 500 mg/m 2 and irinotecan 180 mg/m 2 on day 1, oxaliplatin 85 mg/m 2 on day 2, and capecitabine 1000 mg/m 2 twice per day on days 2-6). The primary end point was overall response rate., Results: Forty patients were enrolled. Nine patients with KRAS mutation were excluded after amendment in 2010. In an extended RAS test we did not find additional RAS mutations. The final population was comprised of 31 patients with RAS wild type CLM (technically borderline resectable 39%; synchronous 84%; ≥4 metastatic nodules 29%). The overall response, R0 resection, and pathological response rates were 87%, 84%, and 33%, respectively. At a median follow-up of 4 years, median progression-free survival and overall survival were 17.8 and 62.5 months, respectively. Treatment toxicity was relevant but did not jeopardize the surgical plan., Conclusion: The COI-E regimen was associated with high response and R0 resection rates in patients with RAS wild type CLM with borderline resectability and/or high-risk features., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aim: To investigate death for liver failure and for tumor recurrence as competing events after hepatectomy of hepatocellular carcinoma., Methods: Data from 864 cirrhotic Child-Pugh class A consecutive patients, submitted to curative hepatectomy (1997-2013) at two tertiary referral hospitals, were used for competing-risk analysis through the Fine and Gray method, aimed at assessing in which circumstances the oncological benefit from tumour removal is greater than the risk of dying from hepatic decompensation. To accomplish this task, the average risk of these two competing events, over 5 years of follow-up, was calculated through the integral of each cumulative incidence function, and represented the main comparison parameter., Results: Within a median follow-up of 5.6 years, death was attributable to tumor recurrence in 63.5%, and to liver failure in 21.2% of cases. In the first 16 mo, the risk of dying due to liver failure exceeded that of dying due to tumor relapse. Tumor stage only affects death from recurrence; whereas hepatitis C infection, Model for End-stage Liver Disease score, extent of hepatectomy and portal hypertension influence death from liver failure ( P < 0.05 in all cases). The combination of these clinical and tumoral features identifies those patients in whom the risk of dying from liver failure did not exceed the tumour-related mortality, representing optimal surgical candidates. It also identifies those clinical circumstances where the oncological benefit would be borderline or even where the surgery would be harmful., Conclusion: Having knowledge of these competing events can be used to weigh the risks and benefits of hepatic resection in each clinical circumstance, separating optimal from non-optimal surgical candidates., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report.

Objectives: This phase II trial was aimed at assessing the safety and activity of capecitabine, oxaliplatin, and irinotecan (COI regimen) as a preoperative treatment for resectable gastric cancer (GC) or gastroesophageal junction (GEJ) cancer., Methods: Patients affected by T3-T4/N0-N+/M0 GC/GEJ cancer were treated with the COI regimen for 4 cycles followed by restaging and gastroresection with D2 lymphadenectomy. Four postoperative cycles were scheduled. The primary endpoint was pathological response rate according to Becker et al. [Cancer 2003;98:1521-1530]. The potential role of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) as a predictive biomarker of pathological tumor response was assessed in a subgroup of 19 evaluable patients., Results: Between January 2011 and October 2015, a total of 40 patients were enrolled. After the preoperative phase, 36 out of 40 patients (90%) were considered eligible for surgery: 12 patients (30%) achieved a pathological response. The most frequent grade 3/4 adverse events were diarrhea (27%), nausea (25%), and fatigue (17%). Grade 3 neutropenia occurred in 7.5% of patients. A lower standard uptake value at baseline FDG-PET/CT was associated with pathological response., Conclusion: COI combination is active with a manageable toxicity profile in patients with resectable GC or GEJ cancer. FDG-PET/CT imaging as a surrogate biomarker of pathological response in this setting appears fascinating but should be further investigated., (© 2017 S. Karger AG, Basel.)

Neoadjuvant chemotherapy (NACT) prior to liver resection is advantageous for patients with colorectal cancer liver metastases (CLM). Bevacizumab- or cetuximab-based NACT may affect patient outcome and curative resection rate, but comparative studies on differential tumour regression grade (TRG) associated with distinct antibodies-associated regimens are lacking. Ninety-three consecutive patients received NACT plus bevacizumab (n = 46) or cetuximab (n = 47) followed by CLM resection. Pathological response was determined in each resected metastasis as TRG rated from 1 (complete) to 5 (no response). Except for KRAS mutations prevailing in bevacizumab versus cetuximab (57 vs. 21 %, p = 0.001), patients characteristics were well balanced. Median follow-up was 31 months (IQR 17-48). Bevacizumab induced significantly better pathological response rates (TRG1-3: 78 vs. 34 %, p < 0.001) as well as complete responses (TRG1: 13 vs. 0 %, p = 0.012) with respect to cetuximab. Three-year progression-free survival (PFS) and overall survival (OS) were not significantly different in the two cohorts. At multivariable analysis, significant association with pathological response was found for number of resected metastases (p = 0.015) and bevacizumab allocation (p < 0.001), while KRAS mutation showed only a trend. Significant association with poorer PFS and OS was found for low grades of pathological response (p = 0.009 and p < 0.001, respectively), R2 resection or presence of extrahepatic disease (both p < 0.001) and presence of KRAS mutation (p = 0.007 and p < 0.001, respectively). Bevacizumab-based regimens, although influenced by the number of metastases and KRAS status, improve significantly pathological response if compared to cetuximab-based NACT. Possible differential impact among regimens on patient outcome has still to be elucidated.

Background: The operative approach to large retrohepatic tumors can be challenging because of the difficulty in exposing the inferior vena cava (IVC) and controlling bleeding. The anterior approach to the IVC associated with the hanging maneuver for liver transection, originally described in large hepatic tumors, may also facilitate removal of large masses set behind the liver., Methods: A prospective cohort of 10 patients with large retrohepatic tumors involving the IVC was selected according to restrictive criteria (ie, single low-grade tumor, sufficient liver remnant, normal hepatic function, absence of cholestasis, and symptoms secondary to lower vena cava obstruction). In all cases, the anterior approach and the hanging maneuver were applied intentionally to expose the IVC without any liver mobilization. Depending on tumor invasiveness, either IVC-preserving (n = 7) or IVC-removing (n = 3) strategies were applied. Our aim was to assess the safety of the technique and the possible benefits for patient outcome., Results: The cohort represented less than 1% of a series of 1,168 major hepatectomies performed in our unit between 2005 and 2011. The median age of the patients was 58; adrenal tumors and retroperitoneal sarcomas accounted for 70% of the series. Total vascular liver exclusion was necessary in 3 patients. Median operative time was 420 min. R0 resection was obtained in all cases, with no mortality and 40% overall morbidity. Overall survival was 83% at 5 years., Conclusion: The transhepatic, anterior approach to the IVC is a safe procedure that improves vascular control, facilitates vein repair or reconstruction, and allows potentially curative resection of large retrohepatic tumors. This approach should be the preferred choice to be adopted in properly selected patients., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background & Aims: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients., Methods: We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations were identified by Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC)., Results: We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. Copy number variation-based clustering was able to refine these molecular groups further. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P < .001)., Conclusions: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, activation of oncogenic pathways, and is associated with worse outcome. Different classes of ICC, based on molecular features, therefore might require different treatment approaches., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)