A randomized, double-blind, placebo-controlled, phase 3 study of tivantinib in Japanese patients with MET-high hepatocellular carcinoma.

A previous randomized phase 2 study of hepatocellular carcinoma revealed that the c-Met inhibitor tivantinib as second-line treatment significantly prolonged progression-free survival in a subpopulation whose tumor samples highly expressed c-Met (MET-high). Accordingly, this phase 3 study was conducted to evaluate the efficacy of tivantinib as a second-line treatment for Japanese patients with MET-high hepatocellular carcinoma. This randomized, double-blind, placebo-controlled study was conducted at 60 centers in Japan. Hepatocellular carcinoma patients with one prior sorafenib treatment and those with MET-high tumor samples were eligible for inclusion. Registered patients were randomly assigned to either the tivantinib or placebo group at a 2:1 ratio and were treated with twice-a-day oral tivantinib (120 mg bid) or placebo until the discontinuation criteria were met. The primary endpoint was progression-free survival while the secondary endpoints included overall survival and safety. Between January 2014 and June 2016, 386 patients provided consent, and 195 patients were randomized to the tivantinib (n = 134) or placebo (n = 61) group. Median progression-free survival was 2.8 (95% confidence interval: 2.7-2.9) and 2.3 (1.5-2.8) mo in the tivantinib and placebo groups, respectively (hazard ratio = 0.74, 95% confidence interval: 0.52-1.04, P = .082). Median overall survival was 10.3 (95% confidence interval: 8.1-11.6) and 8.5 (6.2-11.4) mo in the tivantinib and placebo group, respectively (hazard ratio = 0.82, 95% confidence interval: 0.58-1.15). The most common tivantinib-related grade ≥3 adverse events were neutropenia (31.6%), leukocytopenia (24.8%), and anemia (12.0%). This study did not confirm the significant efficacy of tivantinib as a second-line treatment for Japanese patients with MET-high hepatocellular carcinoma. (NCT02029157).

Establishment of practical recellularized liver graft for blood perfusion using primary rat hepatocytes and liver sinusoidal endothelial cells.

Tissue decellularization produces a three-dimensional scaffold that can be used to fabricate functional liver grafts following recellularization. Inappropriate cell distribution and clotting during blood perfusion hinder the practical use of recellularized livers. Here we aimed to establish a seeding method for the optimal distribution of parenchymal and endothelial cells, and to evaluate the effect of liver sinusoidal endothelial cells (LSECs) in the decellularized liver. Primary rat hepatocytes and LSECs were seeded into decellularized whole-liver scaffolds via the biliary duct and portal vein, respectively. Biliary duct seeding provided appropriate hepatocyte distribution into the parenchymal space, and portal vein-seeded LSECs simultaneously lined the portal lumen, thereby maintaining function and morphology. Hepatocytes co-seeded with LSECs retained their function compared with those seeded alone. Platelet deposition was significantly decreased and hepatocyte viability was maintained in the co-seeded group after extracorporeal blood perfusion. In conclusion, our seeding method provided optimal cell distribution into the parenchyma and vasculature according to the three-dimensional structure of the decellularized liver. LSECs maintained hepatic function, and supported hepatocyte viability under blood perfusion in the engineered liver graft owing to their antithrombogenicity. This recellularization procedure could help produce practical liver grafts with blood perfusion.

CD90 expression in human intrahepatic cholangiocarcinoma is associated with lymph node metastasis and poor prognosis.

BACKGROUND AND OBJECTIVES: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer. However, its prognosis remains poor. Expression of cluster of differentiation 90 (CD90) has been identified as an indicator of poor prognosis in many cancers. Here, we examined the importance of CD90 expression in ICC. METHODS: We performed immunohistological assays for CD90 in human ICC surgical specimens and assessed its relationship with clinicopathological findings and prognosis. Moreover, we analyzed the characteristics of CD90+/- cells, mainly with respect to metastatic potential, using human ICC cell lines. RESULTS: CD90 expression was significantly associated with lymph node metastasis and was revealed to be an independent prognostic factor. The CD90+ cells present in ICC specimens did not appear to be cancer-associated fibroblasts, as they did not express α-smooth muscle actin. In vitro, CD90 + cells exhibited greater migratory ability and higher expression of epithelial-mesenchymal transition (EMT)-related genes, including CXCR4 and MMP7, than CD90- cells. Wnt/ß-catenin signaling pathway activation was also heightened in CD90+ cells. In such cells, EMT appeared to be induced by CXCR4 and MMP7 expression through activation of Wnt/ß-catenin signaling. CONCLUSION: CD90+ cells demonstrate high metastatic potential owing to Wnt/ß-catenin signaling activation and are associated with poor prognosis in ICC.

Long-Term Survival of Recurrent Intrahepatic Cholangiocarcinoma: The Impact and Selection of Repeat Surgery.

BACKGROUND: Definitive guidelines for recurrent intrahepatic cholangiocarcinoma (ICC) do not exist. This study has focused on the repeat surgery when analyzing the survival outcomes of recurrent ICC. We evaluated the relationship between clinicopathological features of the primary tumor and implementation of the repeat surgery to identify its potential selection criteria. METHODS: A total of 108 patients with recurrent ICC between 1993 and 2015 were analyzed. Of these, 15 patients underwent repeat surgery and 93 did not. RESULTS: Seven out of 29 patients with intrahepatic recurrence and eight out of 44 patients with extrahepatic recurrence were amenable to the repeat surgery. Thirty-five patients with simultaneous or consequent intrahepatic recurrence and extrahepatic recurrence were not amenable to the repeat surgery. Patients who underwent repeat surgery had a lower proportion of lymph node metastases (n = 0 [0%] vs. n = 47 [50.5%], p < 0.001), multiple tumors in the primary tumor (n = 1 [6.7%] vs. n = 31 [33.3%], p = 0.037), or early recurrence (≤ 1 year; n = 4 [26.7%] vs. n = 62 [66.7%], p = 0.003). Survival after recurrence (SAR) was better in patients who underwent repeat surgery than in those who did not (median SAR time: 91.6 vs. 10.4 months, and 3-year survival: 86.7 vs. 8.7%, respectively, p < 0.001). CONCLUSIONS: Repeat surgery for recurrent ICC with an appropriate selection can be associated with prolonged survival. Regarding the feasibility, nodal status, number of tumors on the primary tumor, and time to recurrence may be considered as selection criteria.

Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs.

Citrullinemia type 1 (CTLN1) is a urea cycle disorder (UCD) caused by mutations of the ASS1 gene, which is responsible for production of the enzyme argininosuccinate synthetase (ASS), and classically presented as life-threatening hyperammonemia in newborns. Therapeutic options are limited, and neurological sequelae may persist. To understand the pathophysiology and find novel treatments, induced pluripotent stem cells (iPSCs) were generated from a CTLN1 patient and differentiated into hepatocyte-like cells (HLCs). CTLN1-HLCs have lower ureagenesis, recapitulating part of the patient's phenotype. l-arginine, an amino acid clinically used for UCD treatment, improved this phenotype in vitro. Metabolome analysis revealed an increase in tricarboxylic acid (TCA) cycle metabolites in CTLN1, suggesting a connection between CTLN1 and the TCA cycle. This CTLN1-iPSC model improves the understanding of CTLN1 pathophysiology and can be used to pursue new therapeutic approaches.

A Novel Biomarker-Based Preoperative Prognostic Grading System for Predicting Survival After Surgery for Intrahepatic Cholangiocarcinoma.

BACKGROUND: Although treatment strategies for intrahepatic cholangiocarcinoma (ICC) are shifting towards multidisciplinary approaches, preoperative radiographic methods for identifying patients requiring further therapy are unclear. This study was designed to establish a prognostic grading system using preoperatively available objective biomarkers. METHODS: A novel preoperative prognostic grading system for predicting survival after surgery for ICC was developed from multivariate analysis of 134 ICC patients who underwent surgery between 1996 and 2015 using preoperatively available biomarkers. RESULTS: The median overall survival time and 3- and 5 year survival rates were 33.3 months, 48, and 38%, respectively. Of the preoperative biomarkers, the neutrophil-to-lymphocyte ratio (≥5), and C-reactive protein (≥5 mg/L) and carbohydrate antigen 19-9 (≥500 IU/mL) levels were independently associated with poor overall survival. Based on the presence of these factors, the preoperative prognostic grades were defined as follows: grade 1, no factor; grade 2, one factor; and grade 3, two or three factors. The median overall survival time and 3- and 5 year survival rates of patients with grade 1 (70.3 months, 66, and 53%, respectively) were higher than those of patients with grade 2 (23.4 months, 37, and 30%, respectively; P = 0.004) and grade 3 (8.8 months, 5% both; 2 vs. 3, P < 0.001). Multivariable analysis revealed that the preoperative prognostic grading system independently predicted survival after adjusting for known prognostic factors. CONCLUSIONS: A novel biomarker-based preoperative prognostic grading system for ICC significantly stratifies survival after surgery and may identify patients requiring further treatment.

Portal vein reconstruction using vein grafts in pediatric living donor liver transplantation: Current status.

PV reconstruction is an important aspect of LDLT, with post-transplant outcomes depending on PV reconstruction methods. However, it is unclear whether the preferential selection of these techniques is dependent on preoperative recipient characteristics. This retrospective study assessed whether preoperative recipient factors differed in pediatric patients who did and did not receive VGs for PV reconstruction. Of 113 pediatric patients who underwent LDLT from January 2010 to July 2015, 31 (27%) underwent PV reconstruction with VGs and the other 82 (73%) without VGs. The presence of collateral vessels (P<.0001) and ascites (P=.02); PV size (P<.001), thrombosis (P=.01) and the direction of flow (P=.01), Child-Pugh class A vs B/C liver function (P=.01), Alb concentration (P=.02), primary diagnosis: BA vs non-BA (P=.03), and previous abdominal surgery (P<.005) differed significantly in patients who did and did not receive VGs for PV reconstruction. PV complications, patient survival, and graft survival did not differ significantly in patients with and without VGs at 1-year follow-up. VGs should be harvested for recipients with pretransplant hypoplastic PV, intense collaterals, hepatofugal flow, poor liver status, or previous abdominal surgery.

Multi-institutional phase II study on the feasibility of liver resection following preoperative mFOLFOX6 therapy for resectable liver metastases from colorectal cancers.

BACKGROUND: Although liver resection combined with preoperative chemotherapy is expected to improve outcomes of patients with resectable colorectal liver metastasis (CRLM), there is as yet insufficient clinical evidence supporting the efficacy of preoperative systemic chemotherapy. The aim of this phase II study was to assess the feasibility and efficacy of preoperative FOLFOX systemic chemotherapy for patients with initially resectable CRLM. METHODS: A prospective multi-institutional phase II study was conducted to evaluate the feasibility and efficacy of preoperative chemotherapy for resectable CRLM (ClinicalTrials.gov identifier number NCT00594529). Patients were scheduled to receive 6 cycles of mFOLFOX6 therapy before liver surgery. The primary endpoint was the macroscopic curative resection rate. RESULTS: A total of 30 patients were included in this study. Two patients who were diagnosed with hepatocellular and intrahepatic cholangiocellular carcinoma based on pathology were excluded from the analysis. More than half of the patients (57 %) had solitary liver metastasis. The completion rate of preoperative chemotherapy was 64.3 % and the response rate was 53.6 %. Two patients were unable to proceed to liver resections due to disease progression and severe postoperative complications following primary tumor resection. Macroscopic curative resection was obtained in 89.3 % of eligible patients. Postoperative mortality and severe complication (≥Gr. 3) rates were 0 and 11 %, respectively. The 3-year overall and progression-free survival rates were 81.9 and 47.4 %, respectively. CONCLUSION: Our phase II study demonstrated the feasibility of liver resection combined with preoperative mFOLFOX6 therapy in patients with initially resectable CRLM. Further study is warranted to address the oncological effects of preoperative chemotherapy.

Is routine abdominal drainage necessary after liver resection?

PURPOSE: Prophylactic abdominal drainage is performed routinely after liver resection in many centers. The aim of this study was to examine the safety and validity of liver resection without abdominal drainage and to clarify whether routine abdominal drainage after liver resection is necessary. METHODS: Patients who underwent elective liver resection without bilio-enteric anastomosis between July, 2006 and June, 2012 were divided into two groups, based on whether surgery was performed before or after, we adopted the no-drain strategy. The "former group" comprised 256 patients operated on between July, 2006 and June, 2009 and the "latter group" comprised 218 patients operated between July, 2009 and June, 2012. We compared the postoperative complications, percutaneous drainage, and postoperative hospital stay between the groups, retrospectively. RESULTS: There were no significant differences in the rates of postoperative bleeding, intraabdominal infection, or bile leakage between the groups. Drain insertion after liver resection did not reduce the rate of percutaneous drainage. Postoperative hospital stay was significantly shorter in the latter group. CONCLUSION: Routine abdominal drainage is unnecessary after liver resection without bilio-enteric anastomosis.

Phase I clinical trial of olprinone in liver surgery.

PURPOSE: Post-hepatectomy liver failure is one of the most serious complications liver surgeons must overcome. We previously examined olprinone, a selective phosphodiesterase III inhibitor, and demonstrated its hepatoprotective effects in rats and pigs. We herein report the results of a phase I clinical trial of olprinone in liver surgery (UMIN000004975). METHODS: Twenty-three patients who underwent hepatectomy between 2011 and 2015 were prospectively registered. In the first 6 cases, olprinone (0.1 µg/kg/min) was administered for 24 h from the start of surgery. In the remaining 17 cases, olprinone (0.05 µg/kg/min) was administered from the start of surgery until just before the transection of the liver parenchyma. The primary endpoint was safety, and the secondary endpoint was efficacy. For the evaluation of efficacy, the incidence of post-hepatectomy liver failure in 20 hepatocellular carcinoma patients was externally compared with 20 propensity score-matched patients. RESULTS: No intraoperative side effects were observed, and the morbidity rates in the analyzed cohorts were acceptable. The rate of post-hepatectomy liver failure frequency tended to be lower in the olprinone group. CONCLUSIONS: The safety of olprinone in liver surgery was confirmed. The efficacy of olprinone will be re-evaluated in clinical trials.

Significant Improvement in Outcomes of Patients with Intrahepatic Cholangiocarcinoma after Surgery.

BACKGROUND: The prognosis of intrahepatic cholangiocarcinoma (ICC) remains poor despite improvements in treatment and post-operative clinical management. We review our experiences and evaluate our current surgical approaches by comparing patients from two consecutive treatment periods. METHODS: One hundred forty-four patients who underwent hepatectomy for ICC between 1993 and 2014 were divided into groups that received treatment before (n = 65, first period) and after 2006 (n = 79, second period), when new treatment options such as adjuvant chemotherapy and multimodal therapy for recurrence were introduced. Clinicopathological characteristics and survival outcomes were compared between the groups. RESULTS: First-period patients exhibited more advanced tumor characteristics, including larger tumors, higher serum carbohydrate antigen 19-9 levels, and vascular invasion. Median overall survival (OS) durations of the first- and second-period groups were 21.4 and 57.7 months, respectively (p < 0.001); corresponding median disease-free survival (DFS) durations were 12.2 and 16.6 months, respectively (p = 0.027). Multivariate analysis found an independent association of the treatment time period with OS and DFS. Notably, second-period patients with N1 disease achieved a longer OS and DFS (median OS time: 12.4 and 26.0 months, p = 0.0018, and median DFS: 4.7 and 10.7 months p = 0.019, respectively). Among recurrent patients (first, n = 50 and second, n = 44), second-period patients had a significantly longer survival after recurrence (8.0 vs. 22.3 months, p < 0.001). CONCLUSION: ICC patients, particularly those with N1 disease, achieved significant survival improvements that were partly attributable to patient selection, adjuvant chemotherapy, and multimodal treatment after recurrence.

A non-smooth tumor margin on preoperative imaging predicts microvascular invasion of hepatocellular carcinoma.

PURPOSES: Microvascular invasion (mVI) is known to be a risk factor of hepatocellular carcinoma (HCC) recurrence. Several factors such as the tumor grade, tumor size, tumor margin status on imaging studies, fluorine-18 fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) results, and tumor markers have been proposed to predict mVI of HCC. However, the values of these factors have not yet been validated. METHODS: Among the patients evaluated using enhanced CT/MRI, (18)F-FDG-PET, and tumor markers prior to hepatectomy from 2007 to 2012, 79 HCC patients without apparent macrovascular invasion in preoperative imaging were enrolled in this study. The image tumor margin status (smooth/non-smooth), (18)F-FDG-PET, and tumor markers, which were previously described as predictors for mVI, were evaluated. RESULTS: Fifteen patients had mVI (mVI+ group) and 64 patients had no evidence of mVI (mVI- group) on pathological examinations. A univariate analysis showed that the mVI+ group had a higher SUV and TNR (5.2 vs 3.8, p = 0.02 and 1.8 vs 1.3, p = 0.02, respectively) and a higher portion of non-smooth tumor margin (87 vs 27 %, p = 0.0001). There was no significant difference in the tumor markers. A multivariate analysis showed that non-smooth tumor margin alone could independently predict mVI (odds ratio 18.3, 95 % CI 3.27-102.6, p = 0.0009). CONCLUSION: A non-smooth tumor margin on preoperative imaging predicts microvascular invasion of HCC.

Feasibility of the liver-first approach for patients with initially unresectable and not optimally resectable synchronous colorectal liver metastases.

PURPOSE: To investigate the outcomes of patients with colorectal cancer and initially unresectable or not optimally resectable liver metastases, who were treated using the liver-first approach in the era of modern chemotherapy in Japan. METHODS: We analyzed and compared data retrospectively on patients with asymptomatic resectable colorectal cancer and initially unresectable or not optimally resectable liver metastases, who were treated either using the liver-first approach (n = 12, LF group) or the primary-first approach (n = 13, PF group). RESULTS: Both groups of patients completed their therapeutic plan and there was no mortality. Postoperative morbidity rates after primary resection and hepatectomy, and post-hepatectomy liver failure rate were comparable between the groups (p = 1.00, p = 0.91, and p = 0.55, respectively). Recurrence rates, median recurrence-free survival since the last operation, and 3-year overall survival rates from diagnosis were also comparable between the LF and PF groups (58.3 vs. 61.5 %, p = 0.87; 10.5 vs. 18.6 months, p = 0.57; and 87.5 vs. 82.5 %, p = 0.46, respectively). CONCLUSIONS: The liver-first approach may be an appropriate treatment sequence without adversely affecting perioperative or survival outcomes for selected patients.

Impact of Hepatic Steatosis on Disease-Free Survival in Patients with Non-B Non-C Hepatocellular Carcinoma Undergoing Hepatic Resection.

BACKGROUND: Although the prevalence of non-B non-C hepatocellular carcinoma (NBNC HCC) has increased, its clinicopathologic characteristics remain unclear. METHODS: We retrospectively analyzed 518 HCC patients who underwent hepatic resection. Hepatitis B surface antigen- and hepatitis C antibody-negative patients were categorized into the NBNC HCC group (n = 145); others were categorized into the hepatitis B or C HCC (BC HCC) group (n = 373). We subdivided the etiologies of NBNC HCC according to alcohol intake and presence of steatosis. RESULTS: NBNC HCC was associated with nonalcoholic fatty liver disease (NAFLD) (13.1 %), fatty liver disease with moderate alcohol intake (9.0 %), alcoholic liver disease (ALD) (29.7 %), cryptogenic disease (44.1 %), and other known etiologies (4.1 %). The prevalence of obesity, diabetes mellitus, and hypertension was higher and hepatic function was better in the NBNC HCC group, which had significantly larger tumors than the BC HCC group. The entire NBNC HCC group displayed similar overall and disease-free survival as the BC HCC group. Among the subdivisions, NAFLD-associated HCC patients had significantly better disease-free survival than ALD-associated HCC and BC HCC patients. Microvascular invasion (hazard ratio [HR] 2.30; 95 % confidence interval [CI] 1.33-3.96) and steatosis area <5 % of noncancerous region (HR 2.13; 95 % CI 1.21-3.93) were associated with disease-free survival in NBNC HCC patients. CONCLUSIONS: The prognosis of NBNC HCC was similar to that of BC HCC. Among NBNC HCC patients, NAFLD-associated HCC patients had a relatively low recurrence risk. Absence of steatosis in hepatic parenchyma had a significant impact on disease-free survival in NBNC HCC patients.

Hepatocellular carcinoma with bile duct tumor thrombus: surgical outcomes and the prognostic impact of concomitant major vascular invasion.

BACKGROUND: The aim of this study was to clarify the long-term surgical outcomes of hepatocellular carcinoma (HCC) with bile duct tumor thrombus (BDTT) and to identify a therapeutic strategy for this condition. METHODS: Forty-four patients who underwent hepatectomy for HCC with BDTT or direct invasion involving the first branches of the bile duct or common hepatic duct were enrolled in this study. The overall survival time and time to recurrence were analyzed. RESULTS: The median survival time and the 5-year survival rate were 23.7 months and 31.0%, respectively. Child-Pugh classification B [hazard ratio (HR) 4.92; 95% confidence interval (CI) 1.97-11.65], major vascular invasion (MVI; HR 2.79; 95% CI 1.14-6.87), and serosal invasion (HR 2.71; 95% CI 1.19-6.02) were independent prognostic factors for overall survival. The median survival times were 12.3 and 72.3 months for the patients with and without MVI, respectively. Among the 41 patients who underwent macroscopic curative resection, the median time to recurrence and the 5-year recurrence rate were 8.6 months and 85.6%, respectively. MVI was the only independent prognostic factor for recurrence (HR 3.31; 95% CI 1.55-7.05). The median times to recurrence were 3.7 and 11.6 months for the patients with and without MVI, respectively. CONCLUSIONS: Concomitant MVI was a strong prognostic factor in the setting of HCC with BDTT. Extended hepatectomy provided a good prognosis for the patients with BDTT alone without MVI.

Hepatic Resection for Hepatocellular Carcinoma with Tumor Thrombus in the Major Portal Vein.

BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) with tumor thrombus in the major portal vein has been extremely poor. We investigated the outcome of hepatic resection in HCC with major portal vein tumor thrombus (PVTT). METHODS: We retrospectively evaluated 52 consecutive patients who underwent hepatic resection for HCC with tumor thrombi in the first branch or trunk of the portal vein. Factors related to disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: The median DFS and OS times were 8.9 and 27.6 months for the whole cohort, respectively. Multiple tumors (hazard ratio 2.12; 95% CI 1.11-4.33; p = 0.023), positive surgical margins (hazard ratio 2.45; 95% CI 1.19-4.81; p = 0.016), and non-adjuvant hepatic arterial infusion chemotherapy (HAIC; hazard ratio 2.07; 95% CI 1.11-3.90; p = 0.023) were independent risk factors for DFS. Non-adjuvant HAIC (hazard ratio 1.84; 95% CI 1.01-3.37; p = 0.047) was an independent risk factor for OS. CONCLUSIONS: Macroscopically curative resection seems to be of benefit to HCC patients with PVTT, even with tumor thrombi in the first branch or trunk of the portal vein. Adjuvant postoperative HAIC might improve DFS and OS in such patients.

High risk of lung metastasis after resection of hepatocellular carcinoma more than 7 cm in diameter.

PURPOSE: The relationship between the tumor size and organs of recurrence was analyzed to identify a high-risk group for the extrahepatic recurrence of hepatocellular carcinoma (HCC) after resection. METHODS: A total of 544 patients with HCC underwent primary surgical resection for HCC between 2001 and 2010. Of these, 293 patients had a solitary tumor but no macroscopic vascular invasion. The prognostic factors for the overall survival and relapse-free survival were analyzed among these 293 patients. The recurrent organs and frequency of recurrence were also examined. RESULTS: The analysis of the 293 patients showed that both the overall and relapse-free survival rates of the patients with a large tumor (>7 cm in diameter) were significantly worse than those of the patients with a tumor <7 cm. The incidence of lung metastasis was remarkably high in the group of patients with tumors more than 7 cm (24.0 %), in comparison to those with tumors <7 cm. A multivariate analysis revealed that the tumor size was the only independent risk factor for lung metastasis. CONCLUSIONS: The patients with large HCC tumors more than 7 cm in diameter were at high-risk for a poor prognosis due to a high percentage of lung metastasis, even if there was no macroscopic vascular invasion.

Preoperative FDG-PET predicts recurrence patterns in hepatocellular carcinoma.

PURPOSE: We investigated the usefulness of preoperative fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) as a tool for predicting recurrence patterns to select patients for liver resection as an initial surgical strategy for hepatocellular carcinoma. METHODS: Sixty-three consecutive hepatocellular carcinoma patients undergoing FDG-PET were enrolled. They were classified according to the initial recurrence patterns (beyond the Milan criteria [MC], within the MC, and no recurrence) and the time intervals before initial postoperative recurrence (within 1 year, after 1 year or later, and no recurrence). The tumor-to-nontumor ratio (TNR) obtained by FDG-PET and survival rates were compared among the groups. RESULTS: TNR in the recurrence within the MC group (1.9 ± 1.6) and no recurrence group (1.3 ± 1.5) was significantly lower than that in the beyond the MC group (2.9 ± 2.6). TNR was an independent predictive factor of recurrence patterns in multivariate analysis. TNR in the groups with recurrence after 1 year or later (1.6 ± 0.8) and no recurrence (1.3 ± 0.5) were significantly lower than that in the within 1-year group (3.1 ± 2.7). TNR was an independent predictive factor of the interval before initial recurrence by multivariate analysis. CONCLUSIONS: Preoperative FDG-PET predicts hepatocellular carcinoma recurrences within the MC or no recurrence and recurrences after 1 year or later. FDG-PET may be useful for selecting appropriate patients for liver resection as an initial surgical strategy.

Impact of anatomical liver resection on patient survival in KRAS-wild-type colorectal liver metastasis: A multicenter retrospective study.

BACKGROUND: Liver resection is a standard therapy for colorectal liver metastasis. However, the impact of anatomical resection and nonanatomical resection on the survival in patients with Kirsten rat sarcoma-wild-type and Kirsten rat sarcoma-mutated colorectal liver metastasis remain unclear. We investigated whether anatomical resection versus nonanatomical resection improves survival in colorectal liver metastasis stratified by Kirsten rat sarcoma mutational status. METHODS: Among 639 consecutive patients with colorectal liver metastasis who underwent primary liver resection between January 2008 and December 2017, 349 patients were excluded due to their unknown Kirsten rat sarcoma mutational status, or due to receiving anatomical resection with concomitant non-anatomical resection, radiofrequency, or R2 resection. Accordingly, 290 patients with colorectal liver metastasis were retrospectively assessed. The relationships between resection types and survival were investigated in Kirsten rat sarcoma-wild-type and -mutated groups. RESULTS: Anatomical resection was performed in 77/186 (41%) and 44/104 (42%) patients with Kirsten rat sarcoma-wild-type and Kirsten rat sarcoma-mutated genetic statuses, respectively. For both, the clinical-pathologic factors were comparable, except a larger maximum tumor size and surgical margin were observed in anatomical resection cases. Anatomical resection patients had significantly longer recurrence-free survival and overall survival than nonanatomical resection cases in the Kirsten rat sarcoma-wild-type group (recurrence-free survival, P < .001; overall survival, P = .005). No significant recurrence-free survival or overall survival differences were observed between Kirsten rat sarcoma-mutated anatomical resection and non-anatomical resection (recurrence-free survival, P = .132; overall survival, P = .563). Although, intrahepatic recurrence in Kirsten rat sarcoma-wild-type and -mutated colorectal liver metastasis was comparable (P = .973), extrahepatic recurrence was increased in Kirsten rat sarcoma-mutated versus -wild-type colorectal liver metastasis (P < .001). CONCLUSION: In contrast to Kirsten rat sarcoma-mutated colorectal liver metastasis with higher extrahepatic recurrence after liver resection, local liver control via anatomical resection improved the postoperative survival in patients with Kirsten rat sarcoma-wild-type colorectal liver metastasis.