Objective To determine the impact of RAS mutation status on survival and patterns of recurrence in patients undergoing curative resection of colorectal liver metastases (CLM) after preoperative modern chemotherapy. Summary Background Data RAS mutation has been reported to be associated with aggressive tumor biology. However, the effect of RAS mutation on survival and patterns of recurrence after resection of CLM remains unclear. Methods Somatic mutations were analyzed using mass spectroscopy in 193 patients who underwent single-regimen modern chemotherapy before resection of CLM. The relationship between RAS mutation status and survival outcomes was investigated. Results Detected somatic mutations included RAS (KRAS/NRAS) in 34 patients (18%), PIK3CA in 13 (7%), and BRAF in 2 (1%). At a median follow-up of 33 months, 3-year overall survival (OS) rates were 81% in patients with wild-type vs 52.2% in patients with mutant RAS (P=0.002); 3-year recurrence-free survival (RFS) rates were 33.5% with wild-type vs 13.5% with mutant RAS (P=0.001). Liver and lung recurrences were observed in 89 and 83 patients, respectively. Patients with RAS mutation had a lower 3-year lung RFS rate (34.6% vs 59.3%, P<0.001), but not a lower 3-year liver RFS rate (43.8% vs 50.2%, P=0.181). In multivariate analyses, RAS mutation predicted worse OS (hazard ratio [HR] 2.3, P=0.002), overall RFS (HR 1.9, P=0.005), and lung RFS (HR 2.0, P=0.01), but not liver RFS (P=0.181). Conclusions RAS mutation predicts early lung recurrence and worse survival after curative resection of CLM. This information may be used to individualize systemic and local tumor-directed therapies and follow-up strategies.

Background Standardized future liver remnant (sFLR) volume and degree of hypertrophy after portal vein embolization (PVE) have been recognized as significant predictors of surgical outcomes after major liver resection. However, regeneration rate of the FLR after PVE varies among individuals and its clinical significance is unknown. Study Design Degree of hypertrophy at initial volume assessment divided by number of weeks elapsed after PVE was defined as the kinetic growth rate (KGR). In 107 consecutive patients who underwent liver resection for colorectal liver metastases with a sFLR volume of greater than 20%, the ability of the KGR to predict overall and liver-specific postoperative morbidity and mortality was compared with sFLR volume and degree of hypertrophy. Results Using receiver operating characteristic analysis, the best cut-off values for sFLR volume, degree of hypertrophy, and KGR for predicting postoperative hepatic insufficiency were estimated as, respectively, 29.6%, 7.5%, and 2.0% per week. Among these, KGR was the most accurate predictor (area under the curve, 0.830 [0.736-0.923]; asymptotic significance, 0.002). KGR of less than 2% per week vs. ≥2% per week correlate with rates of hepatic insufficiency (21.6% vs. 0%, p = 0.0001) and liver-related 90-day mortality (8.1% vs. 0%, P=0.04). The predictive value of KGR was not influenced by sFLR volume or the timing of initial volume assessment when evaluated within 8 weeks after PVE. Conclusions KGR is a better predictor of postoperative morbidity and mortality after liver resection for small FLR than conventional measured volume parameters (sFLR volume and degree of hypertrophy).

Background The primary reported indication for the Associating Liver Partition with Portal vein Ligation for Staged hepatectomy (ALPPS) technique is in patients with very low future liver remnant volumes. Given the elevated incidence of major morbidity (40%) and liver-related mortality (12%) with ALPPS, we sought to determine the safety and efficacy of percutaneous portal vein embolization (PVE) in a similar patient population. Patients and Methods Tumor resectability and morbidity/mortality rates were reviewed for 144 consecutive liver tumor patients with future liver remnant to body weight ratios (LR/BW) less than 0.5%. All patients were referred for preoperative percutaneous right plus segment IV PVE using embolic microspheres, with planned reassessment of the LR/BW 30 days after PVE. Post-PVE outcomes were compared to reported outcomes for ALPPS. Results Percutaneous PVE was successfully performed in 141 of the 144 study patients (97.9%). Adequate regeneration was observed in 139 patients (98.5%) with median post-PVE LR/BW rising from 0.33% to 0.52% (p<0.0001), representing a per-patient median regeneration of 62% (range: 0.3 – 379%). In total, 104 patients underwent extended right hepatectomy (n=102) or right hepatectomy (n=2). The remaining 40 patients (27.8%) were not resectable due to short-interval disease progression (27 patients, 18.5%), insufficient liver regeneration (5 patients, 3.5%), and medical comorbidities (8 patients, 5.6%). After resection, the following outcomes were observed: major morbidity: 33.0% (34/104), liver insufficiency: 12.5% (13/104), and 90-day liver-related mortality: 5.8% (6/104). These oncologic and technical results compare favorably to those of ALPPS. Conclusion Based on its ability to select oncologically resectable patients and superior safety and efficacy profiles, percutaneous right+segment IV PVE and interval surgery remains the standard of care for patients with very low future liver remnant volumes.

Objective To determine the prognostic impact of tumor location in gallbladder cancer. Summary Background Data Depth of tumor is a strong predictor of survival after curative resection of gallbladder cancer. However, the gallbladder has a unique anatomical relationship with the liver, and the clinical significance of tumor location remains unclear. Methods For 437 patients with gallbladder cancer resected at 4 international institutions, clinicopathologic characteristics and their association with survival were analyzed. Tumor location was defined as “hepatic side” or “peritoneal side”, and the prognostic significance of tumor location was evaluated. Results Among the 252 patients with T2 disease, patients with tumors on the hepatic side (T2h, n=99) had higher rates of vascular invasion, neural invasion, and nodal metastasis than patients with tumors on the peritoneal side (T2p, n=153) (51% vs. 19%, 33% vs. 8%, and 40% vs. 17%, respectively, P<0.01 for all). After a median follow-up of 58.9 months, 3-year and 5-year survival rates were 52.1% and 42.6%, respectively, for T2h tumors and 73.7% and 64.7%, respectively, for T2p tumors (P=0.0006). No such differences were observed in T1 or T3 tumors. Multivariate analysis confirmed the independent association of hepatic-side location with survival in T2 tumors (hazard ratio, 2.7; 95% CI, 1.7 to 4.2; P<0.001). This subclassification of T2 tumors predicted recurrence in the liver (23% vs. 3%, P=0.003) and distant lymph nodes (16% vs. 3%, P=0.019) even after radical resection. Conclusions After curative resection of T2 gallbladder cancer, tumor location predicts the pattern of recurrence and survival.

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