Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development.

Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutrition led to the production of proinflammatory cytokines TNF and IL-1ß in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.

Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.

Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self-sufficiency. The egress of progenitor cells and tumor formation were associated with the autocrine production of cytokines previously provided by the niche. ELSs developed via cooperation between the innate immune system and adaptive immune system, an event facilitated by activation of the transcription factor NF-κB and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy.

Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma.

BACKGROUND & AIMS: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. METHODS: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. RESULTS: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. CONCLUSION: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.

Is Repeat Resection for Recurrent Intrahepatic Cholangiocarcinoma Warranted? Outcomes of an International Analysis.

BACKGROUND: Recurrence of intrahepatic cholangiocarcinoma (ICC) after liver resection (LR) remains high, and optimal therapy for recurrent ICC is challenging. Herein, we assess the outcomes of patients undergoing repeat resection for recurrent ICC in a large, international multicenter cohort. PATIENTS AND METHODS: Outcomes of adults from six large hepatobiliary centers in North America, Europe, and Asia with recurrent ICC following primary LR between 2001 and 2015 were analyzed. Cox models determined predictors of post-recurrence survival. RESULTS: Of patients undergoing LR for ICC, 499 developed recurrence. The median time to recurrence was 10 months, and 47% were intrahepatic. Overall 3-year post-recurrence survival rate was 28.6%. In total, 121 patients (25%) underwent repeat resection, including 74 (61%) repeat LRs. Surgically treated patients were more likely to have solitary intrahepatic recurrences and significantly prolonged survival compared with those receiving locoregional or systemic therapy alone with a 3-year post-recurrence survival rate of 47%. Independent predictors of post-recurrence death included time to recurrence < 1 year [HR 1.66 (1.32-2.10), p < 0.001], site of recurrence [HR 1.74 (1.28-2.38), p < 0.001], macrovascular invasion [HR 1.43 (1.05-1.95), p = 0.024], and size of recurrence > 3 cm [HR 1.68 (1.24-2.29), p = 0.001]. Repeat resection was independently associated with decreased post-recurrence death [HR 0.58 0.43-0.78), p < 0.001]. CONCLUSIONS: Repeat resection for recurrent ICC in select patients can result in extended survival. Thus, challenging the paradigm of offering these patients locoregional or chemo/palliative therapy alone as the mainstay of treatment.

Outcomes of liver transplantation for nonalcoholic steatohepatitis-associated hepatocellular carcinoma.

BACKGROUND: Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is the second-leading cause of liver transplantation (LT) performed for HCC. Despite this, little is known about the clinical characteristics and outcomes of NASH-HCC. METHODS: Patients undergoing LT for HCC from 2001 to 2017 at a single center were reviewed. Outcomes of NASH-HCC (n = 51) were compared to other etiologies of HCC including hepatitis C (HCV) hepatitis B (HBV), and alcoholic liver disease (ALD). Outcomes of NASH-HCC were also compared to HCV in the direct-acting antiviral (DAA) era (2014-2017). RESULTS: The frequency of NASH-HCC as the primary indication for LT in patients with HCC increased significantly during the study period from 4.4% (2001-2008) to 15.6% in 2017. NASH-HCC patients were significantly older (median age 65 vs. 60; P < 0.001) with significantly lower alpha-fetoprotein levels (7.5 vs. 26.5, P < 0.001) compared to other etiologies. The 1-, 3-, and 5-year overall survival of NASH-HCC was 92%, 86%, and 80%. Overall survival of NASH-HCC was not significantly different compared to HCV, HBV, or ALD. Compared to HCV-HCC in the DAA era (n = 99), NASH-HCC had comparable post-LT survival (3-year survival 87% vs. 86%, P = 0.870). CONCLUSION: In this large single-center experience of NASH-HCC, we demonstrate favorable outcomes of NASH-HCC following LT comparable to other common etiologies of HCC.

Outcomes of transplantation for HBV- vs. HCV-related HCC: impact of DAA HCV therapy in a national analysis of >20,000 patients.

BACKGROUND: The development of direct-acting antiviral (DAA) therapy has revolutionized HCV management. We present a large national study comparing post-LT outcomes for HBV-HCC vs. HCV-HCC according to DAA era. METHODS: Data were collected from OPTN/UNOS Registry. Groups included pre-DAA (January 2003-October 2013) and post-DAA (November2013-January2019) eras. Outcomes for patients with HBV(n = 2000) vs. HCV(n = 18,964) were compared in each era. RESULTS: In the pre-DAA era, there were significant differences between HBV-versus HCV, including the percentage of Caucasian race, pre-LT and maximum AFP levels <20 ng/mL, MELD-score, complete tumor necrosis, and vascular invasion. In the post-DAA-era, differences were noted in wait time>9 months, the percentage of Caucasian race, pre-LT and AFP(max) levels<20 ng/mL, and MELD-score. In the pre-DAA-era, the 5-and-10 year survival rates were 80.5% and 71% for HBV-HCC, and 69% and 54.4% for HCV-HCC (p < 0.001); in the post-DAA-era, 5-year survival was 83.4% for HBV-HCC and 78.5% for HCV-HCC(p = 0.08). Independent pre-LT predictors of lower survival included recipient and donor age>50yrs, wait-time>9months, higher MELD-score (p < 0.001), AFP level>20 ng/mL, and MC at diagnosis. HCV status did not predict outcome in the post-DAA-era after adjusting for tumor characteristics. CONCLUSION: After the introduction of effective DAA-HCV therapy, results of LT for HCV-HCC are significantly improved and are no longer statistically different from results in patients with HBV-HCC.

Morphology of tumor and nontumor tissue in liver resection specimens for hepatocellular carcinoma following nivolumab therapy.

Nivolumab is an immune checkpoint inhibitor (ICI) approved for treatment of many cancers, including hepatocellular carcinoma (HCC). Liver injury is a known complication in patients treated with nivolumab for nonliver tumors. To date, the morphologic changes to tumor and nontumor liver have not been well-characterized in HCC patients. We identified 20 patients who underwent partial hepatectomy or liver transplantation after receiving nivolumab for HCC. Demographics, laboratory values, and imaging results were obtained from medical records. All available slides from resection specimens were evaluated for tumor necrosis, tumor-infiltrating lymphocytes (TILs), and features of liver injury. Patients in the study included 16 males and 4 females with median age of 56 years. The underlying liver disease was HBV in 10, HCV in 6, and unknown/other in 4. Twelve patients were treated with nivolumab in the neoadjuvant setting, whereas eight were treated with nivolumab, usually along with other therapies, before undergoing liver transplantation. On review of resection specimens, three patients (all from the neoadjuvant group) demonstrated marked treatment response attributable to nivolumab. TILs were present in 17/20 cases. One case that showed treatment response in the neoadjuvant group demonstrated non-necrotizing granulomas and prominent bile duct intraepithelial lymphocytes (IELs) in the nontumor liver. One case from the transplant group showed bile duct damage and prominent ductular reaction after long-term nivolumab therapy (32 doses). Our findings indicate that nivolumab is effective in a subset of patients, including in the neoadjuvant setting. Granulomas and bile duct IELs are rare findings in cases treated with nivolumab but, when seen, may indicate potential response to therapy. Bile duct damage and ductular reaction may be manifestations of long-term nivolumab therapy. Future prospective and longitudinal studies with pretreatment tumor biopsies may help identify patients apt to respond to ICI therapy and further characterize patterns of ICI-related liver injury.

Resection of Mixed Hepatocellular-Cholangiocarcinoma, Hepatocellular Carcinoma, and Intrahepatic Cholangiocarcinoma.

Mixed hepatocellular-cholangiocarcinoma (HCC-CC) is a biphenotypic liver cancer thought to have unfavorable tumor biology and a poor prognosis. Surgical outcomes of HCC-CC remain unclear. We aimed to evaluate the clinical characteristics and surgical outcomes of HCC-CC. We analyzed a series of patients undergoing resection for HCC-CC (n = 47), hepatocellular carcinoma (HCC; n = 468), and intrahepatic cholangiocarcinoma (ICC; n = 108) at a single Western center between 2001 and 2015. Patients with HCC-CC were matched to patients with HCC and ICC on important clinical factors including tumor characteristics (size, vascular invasion, and differentiation) and underlying cirrhosis. Patients with HCC-CC had rates of viral hepatitis comparable to patients with HCC (78.7% versus 80.0%), and 42.5% had underlying cirrhosis. When matched on tumor size, HCC-CC was more poorly differentiated than HCC (68.3% versus 27.3%; P < 0.001) and ICC (68.3% versus 34.8%; P = 0.01) but had similar postresection survival (5-year survival: HCC-CC 49.7%, HCC 54.8%, ICC 68.7%; P = 0.61) and recurrence (3-year recurrence: HCC-CC 57.9%, HCC 61.5%, and ICC 56%; P = 0.58). Outcomes were similar between HCC-CC and HCC when matched on underlying cirrhosis and tumor size. Cancer type was not predictive of survival or tumor recurrence. Survival after resection of HCC-CC is similar to HCC when matched for tumor size, despite HCC-CC tumors being more poorly differentiated. Exclusion of HCC-CC from management strategies recommended for HCC, including consideration for liver transplantation, may not be warranted.

Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma.

BACKGROUND & AIMS: According to the clonal model of tumor evolution, trunk alterations arise at early stages and are ubiquitous. Through the characterization of early stages of hepatocarcinogenesis, we aimed to identify trunk alterations in hepatocellular carcinoma (HCC) and study their intra- and inter-tumor distribution in advanced lesions. METHODS: A total of 151 samples representing the multistep process of hepatocarcinogenesis were analyzed by targeted-sequencing and a single nucleotide polymorphism array. Genes altered in early lesions (31 dysplastic nodules [DNs] and 38 small HCCs [sHCC]) were defined as trunk. Their distribution was explored in: a) different regions of large tumors (43 regions, 21 tumors), and b) different nodules of the same patient (39 tumors, 17 patients). Multinodular lesions were classified as intrahepatic metastases (IMs) or synchronous tumors based on chromosomal aberrations. RESULTS: TERT promoter mutations (10.5%) and broad copy-number aberrations in chromosomes 1 and 8 (3-7%) were identified as trunk gatekeepers in DNs and were maintained in sHCCs. Trunk drivers identified in sHCCs included TP53 (23%) and CTNNB1 (11%) mutations, and focal amplifications or deletions in known drivers (6%). Overall, TERT, TP53 and CTNNB1 mutations were the most frequent trunk events and at least one was present in 51% of sHCCs. Around 90% of mutations in these genes were ubiquitous among different regions of large tumors. In multinodular HCCs, 35% of patients harbored IMs; 85% of mutations in TERT, TP53 and/or CTNNB1 were retained in primary and metastatic tumors. CONCLUSIONS: Trunk events in early stages (TERT, TP53, CTNNB1 mutations) were ubiquitous across different regions of the same tumor and between primary and metastatic nodules in >85% of cases. This concept supports the knowledge that single biopsies would suffice to capture trunk mutations in HCC. LAY SUMMARY: Trunk alterations arise at early stages of cancer and are shared among all malignant cells of the tumor. In order to identify trunk alterations in HCC, we characterized early stages of hepatocarcinogenesis represented by dysplastic nodules and small lesions. Mutations in TERT, TP53 and CTNNB1 genes were the most frequent. Analyses in more advanced lesions showed that mutations in these same genes were shared between different regions of the same tumor and between primary and metastatic tumors, suggesting their trunk role in this disease.

Mixed hepatocellular cholangiocarcinoma tumors: Cholangiolocellular carcinoma is a distinct molecular entity.

BACKGROUND & AIMS: Mixed hepatocellular cholangiocarcinoma (HCC-CCA) is a rare and poorly understood type of primary liver cancer. We aimed to perform a comprehensive molecular characterization of this malignancy. METHODS: Gene expression profiling, DNA copy number detection, and exome sequencing using formalin-fixed samples from 18 patients with mixed HCC-CCA were performed, encompassing the whole histological spectrum of the disease. Comparative genomic analysis was carried out, using independent datasets of HCC (n=164) and intrahepatic cholangiocarcinoma (iCCA) (n=149). RESULTS: Integrative genomic analysis of HCC-CCAs revealed that cholangiolocellular carcinoma (CLC) represents a distinct biliary-derived entity compared with the stem-cell and classical types. CLC tumors were neural cell adhesion molecule (NCAM) positive (6/6 vs. 1/12, p<0.001), chromosomally stable (mean chromosomal aberrations 5.7 vs. 14.1, p=0.008), showed significant upregulation of transforming growth factor (TGF)-ß signaling and enrichment of inflammation-related and immune response signatures (p<0.001). Stem-cell tumors were characterized by spalt-like transcription factor 4 (SALL4) positivity (6/8 vs. 0/10, p<0.001), enrichment of progenitor-like signatures, activation of specific oncogenic pathways (i.e., MYC and insulin-like growth factor [IGF]), and signatures related to poor clinical outcome. In the classical type, there was a significant correlation in the copy number variation of the iCCA and HCC components, suggesting a clonal origin. Exome sequencing revealed an average of 63 non-synonymous mutations per tumor (2 mean driver mutations per tumor). Among those, TP53 was the most frequently mutated gene (6/21, 29%) in HCC-CCAs. CONCLUSIONS: Mixed HCC-CCA represents a heterogeneous group of tumors, with the stem-cell type characterized by features of poor prognosis, and the classical type with common lineage for HCC and iCCA components. CLC stands alone as a distinct biliary-derived entity associated with chromosomal stability and active TGF-ß signaling. LAY SUMMARY: Molecular analysis of mixed hepatocellular cholangiocarcinoma (HCC-CCA) showed that cholangiolocellular carcinoma (CLC) is distinct and biliary in origin. It has none of the traits of hepatocellular carcinoma (HCC). However, within mixed HCC-CCA, stem-cell type tumors shared an aggressive nature and poor outcome, whereas the classic type showed a common cell lineage for both the HCC and the intrahepatic CCA component. The pathological classification of mixed HCC-CCA should be redefined because of the new molecular data provided.

Ischemia time impacts recurrence of hepatocellular carcinoma after liver transplantation.

UNLABELLED: Although experimental evidence has indicated that ischemia-reperfusion (I/R) injury of the liver stimulates growth of micrometastases and adhesion of tumor cells, the clinical impact of I/R injury on recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has not been fully investigated. To study this issue, we conducted a retrospective review of the medical records of 391 patients from two transplant centers who underwent LT for HCC. Ischemia times along with other tumor/recipient variables were analyzed as risk factors for recurrence of HCC. Subgroup analysis focused on patients with HCC who had pathologically proven vascular invasion (VI) because of the associated increased risk of micrometastasis. Recurrence occurred in 60 patients (15.3%) with median time to recurrence of 0.9 years (range, 40 days-4.6 years). Cumulative recurrence curves according to cold ischemia time (CIT) at 2-hour intervals and warm ischemia time (WIT) at 10-minute intervals showed that CIT>10 hours and WIT>50 minutes were associated with significantly increased recurrence (P=0.015 and 0.036, respectively). Multivariate Cox's regression analysis identified prolonged cold (>10 hours; P=0.03; hazard ratio [HR]=1.9) and warm (>50 minutes; P=0.003; HR=2.84) ischemia times as independent risk factors for HCC recurrence, along with tumor factors, including poor differentiation, micro- and macrovacular invasion, exceeding Milan criteria, and alpha-fetoprotein>200 ng/mL. Prolonged CIT (P=0.04; HR=2.24) and WIT (P=0.001; HR=5.1) were also significantly associated with early (within 1 year) recurrence. In the subgroup analysis, prolonged CIT (P=0.01; HR=2.6) and WIT (P=0.01; HR=3.23) were independent risk factors for recurrence in patients with VI, whereas there was no association between ischemia times and HCC recurrence in patients with no VI. CONCLUSION: Reducing ischemia time may be a useful strategy to decrease HCC recurrence after LT, especially in those with other risk factors.

Disentangling the effects of race and socioeconomic factors on liver transplantation rates for hepatocellular carcinoma.

INTRODUCTION: Liver transplantation is the most effective treatment for hepatocellular carcinoma (HCC) in eligible patients, but is not accessed equally by all. We explored the effects of race and socioeconomic factors on transplantation for HCC while controlling for stage, resection status, and transplant candidacy. PATIENTS AND METHODS: All HCC patients, 2003-2013, were retrospectively analyzed using multivariate analysis to explore differences in transplantation rates among cohorts. RESULTS: Of 3078 HCC patients, 754 (24%) were considered transplant eligible. Odds of transplantation were significantly higher for those with commercial insurance (OR = 1.99, 95% CI [1.42, 2.79]) and lower for black patients (OR = 0.55, 95% CI [0.33, 0.91]). Asians were more likely to be resected than white patients with similarly staged tumors and transplant criteria (p < 0.001). Patients not listed for transplantation for non-medical reasons were more likely to be government-insured (p = 0.02) and not white (p = 0.05). No step along the transplantation pathway was identified as the dominant hurdle. DISCUSSION: Patients who are black or government-insured are significantly less likely to undergo transplantation for HCC despite controlling for tumor stage, resection status, and transplant eligibility. Asian patients have higher rates of hepatic resection, but also appear to have lower transplantation rates beyond this effect.

Prognostic significance of lymph node metastases in small intestinal neuroendocrine tumors.

BACKGROUND/AIMS: Current staging guidelines for small intestinal neuroendocrine tumors (SI-NETs) differentiate between the presence (N1) and absence (N0) of lymph node (LN) metastases. However, the prognostic significance of the extent of LN involvement remains unknown. In this study, we used data from a population-based cancer registry to examine whether involvement of a higher number of LNs is associated with worse survival. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with histologically confirmed, surgically resected SI-NETS diagnosed between 1988 and 2010. Patients were classified into three groups by the LN ratio (number of positive LNs/number of total LNs examined, LNR): ≤0.2, >0.2-0.5, and >0.5. We used the Kaplan-Meier method and Cox models to assess NET cancer-specific survival differences (up to 10 years from diagnosis) according to LNR status. RESULTS: We identified 2,984 surgically resected patients with stage IIIb (N1, M0) SI-NETs with detailed LN data. More than half of the NETs were located in the ileum. A higher LNR was significantly associated with worse NET cancer-specific survival (p < 0.0001). Ten-year NET-specific survival was 85, 77, and 74% for patients in the ≤0.2, >0.2-0.5, and >0.5 LNR groups, respectively. In stratified analyses, higher LNR groups had worse survival only in early tumor (T1, T2) disease (p < 0.0001). CONCLUSIONS: The extent of LN involvement provides independent prognostic information on patients with LN-positive SI-NETs. This information may be used to identify patients at high risk of recurrence and inform decisions about the use of adjuvant therapy.

Liver transplantation for metastatic neuroendocrine tumors: Outcomes and prognostic variables.

BACKGROUND: Patient selection for liver transplantation for metastatic neuroendocrine tumors remains a topic of debate. There is no established MELD exception, making it difficult to obtain donor organs. METHODS: A multicenter database was created assessing outcomes for liver and multivisceral transplantation for metastatic neuroendocrine tumors and identifying prognostic factors for survival. Demographic, transplant, primary tumor site and management, pathology, recurrent disease and survival data were collected and analyzed. Survival probabilities were calculated using the Kaplan-Meier method. RESULTS: Analysis included 85 patients who underwent liver transplantation November 1988-January 2012 at 28 centers. One, three, and five-year patient survival rates were 83%, 60%, and 52%, respectively; 40 of 85 patients died, with 20 of 40 deaths due to recurrent disease. In univariate analyses, the following were predictors of poor prognosis: large vessel invasion (P < 0.001), extent of extrahepatic resection at liver transplant (P = 0.007), and tumor differentiation (P = 0.003). In multivariable analysis, predictors of poor overall survival included large vessel invasion (P = 0.001), and extent of extrahepatic resection at liver transplant (P = 0.015). CONCLUSION: In the absence of poor prognostic factors, metastatic neuroendocrine tumor is an acceptable indication for liver transplantation. Identification of favorable prognostic factors should allow assignment of a MELD exception similar to hepatocellular carcinoma.

Outcomes following resection of intrahepatic cholangiocarcinoma.

OBJECTIVES: The aim of this analysis was to examine prognostic features and outcomes in patients undergoing resection for intrahepatic cholangiocarcinoma (ICC). METHODS: A retrospective chart review was performed in all patients who underwent R0 or R1 resection for primary ICC between 1995 and 2011. Clinical data were abstracted and statistical analyses were conducted in the standard fashion. RESULTS: A total of 82 patients underwent curative hepatectomy for primary ICC; 51 patients in this cohort developed recurrence. The median follow-up of survivors was 27 months (range: 1-116 months). Recurrences were intrahepatic (65%), associated with multiple tumours (54%) and occurred during the first 2 years after hepatectomy (86%). The main factor associated with recurrence after resection was the presence of satellite lesions. Overall 5-year disease-free survival after primary resection was 16%. Factors associated with poor survival were transfusion and perineural invasion. Treatment of recurrence was undertaken in 89% of patients and repeat surgical resection was performed in 15 patients. The 3-year survival rate after recurrence was 25%. Prolonged survival after recurrence was associated with a solitary tumour recurrence. CONCLUSIONS: Despite curative resection of ICC, recurrence can be expected to occur in 79% of patients at 5 years. Predictors of survival and recurrence after resection vary in the literature. In patients with recurrence, selection of the optimal treatment remains challenging.

Differences in surgical outcomes between hepatitis B- and hepatitis C-related hepatocellular carcinoma: a retrospective analysis of a single North American center.

OBJECTIVE: Compare surgical outcomes for hepatitis B virus (HBV)-hepatocellular carcinoma (HCC) versus hepatitis C virus (HCV)-hepatocellular carcinoma (HCC). BACKGROUND: HCC is the second leading cause of death from cancer worldwide and is associated with hepatitis virus infection in 80% of cases. METHODS: Between 1997 and 2011, 1008 patients with hepatitis B (HBV, n = 431) or hepatitis C (HCV, n = 577) underwent resection (n = 567) or transplantation (n = 441). Resection was indicated for Child's A patients with single HCC; transplantation was indicated for patients within Milan criteria. Univariate and multivariate analyses were performed as well as survival and recurrence analysis using log-rank test. RESULTS: Based on uniform application of these criteria, resection: transplantation ratio was 3.6 for patients with HBV and 0.67 for patients with HCV. Resection: Patients with HBV had larger tumors and higher α-fetoprotein but less satellites and macrovascular invasion; 68% of HBV versus 89% of HCV were cirrhotic. Survival was better (P < 0.001) and recurrence was lower (P = 0.009) for HBV. Independent predictors of death included HCV (P = 0.024), transfusion (P = 0.013), and HCC of greater than 5 cm (P = 0.013). Limiting analysis to patients with cirrhosis, survival with HBV remained superior (P = 0.020) but recurrence did not. Transplantation: Tumors were similar in HBV and HCV. Survival was better (P = 0.002) for HBV; recurrence was similar. Independent predictors of death were HCV (P < 0.001), poor differentiation (P = 0.049), vascular invasion (P = 0.002), and outside Milan (P = 0.032). Limiting analysis to patients within Milan, HBV survival remained better for both resection (P = 0.030) and transplantation (P = 0.002). CONCLUSIONS: Survival after both resection and transplantation for HCC was better in HBV- than in HCV-related HCC whereas recurrence was also lower for HBV-HCC in the resection group, these differences are influenced by both liver and tumor factors.

Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes.

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.

Metzenbaum-assisted liver resection: a safe and effective liver resection technique.

AIM: We hereby present and evaluate a technique for hepatic parenchymal transection based on the application of Metzenbaum scissors and clips during liver ischemia. METHODS: Our technique was retrospectively evaluated in 32 noncirrhotic, noncholestatic patients with intrahepatic cholangiocarcinoma and 32 patients with hepatocellular carcinoma (23 of whom cirrhotic, 71.9%). Patient data were retrieved from our Hepatobiliary Surgery Database. Type and duration of vascular clamping, blood transfusion requirements, marginal status and immediate postoperative complications were analyzed. RESULTS: Twenty-seven extended (>4 liver segments; 42.2%) and 37 nonextended (≤4 liver segments; 57.8%) liver resections were analyzed. Warm liver ischemia duration was 14 (interquartile range: 11-17.8) min. Thirty-three patients (51.6%) were transfused with a median of 2 (1.5-3) units of packed red blood cells. Tumor-free margins were achieved in 90.6% of cases (n = 58). The overall morbidity rate was 18.8% with a 4.7% mortality rate. Our technique allowed for excellent identification and safe dissection and preservation, or ligation of major liver vessels. CONCLUSIONS: The proposed technique is simple, fast, safe and with low cost. It is associated with limited postoperative complications while from an oncologic standpoint it enables the surgeon to achieve a high percentage of tumor-free margins while protecting major vascular structures.

Actual 10-year survival following hepatectomy for hepatocellular carcinoma.

OBJECTIVES: This study was conducted to compare 10-year survivors with patients who survived <10 years in a large Western series of patients submitted to hepatectomy for hepatocellular carcinoma (HCC). METHODS: A retrospective review of a series of hepatic resections conducted in a referral centre for HCC between January 1987 and October 2002 was conducted. RESULTS: A total of 176 patients were analysed. Twenty-eight patients survived ≥ 10 years (Group A) and were compared with the 148 patients who did not (Group B). Group A had smaller tumours (5.7 cm versus 8.2 cm; P = 0.001) and a lower incidence of microvascular invasion (18.5% versus 37.1%; P = 0.004). Recurrence did not differ significantly (Group A 18/28, 64.3% versus Group B 94/148, 63.5%). Median time to recurrence was longer in Group A (70 months versus 15 months; P < 0.0001), and more patients in Group A were able to undergo curative treatment for recurrence (88.8% versus 40.4%; P < 0.0001). Multivariate analysis showed that lack of vascular invasion (P = 0.020), absence of perioperative transfusion (P = 0.014), and recurrence at >2 years after primary resection (P = 0.045) were significantly associated with 10-year survival. CONCLUSIONS: Ten-year survival after liver resection for HCC can be expected in approximately 15% of patients. Recurrence does not preclude longterm survival. Recurrence at >2 years after resection, absence of vascular invasion, and absence of perioperative transfusion are independently associated with 10-year survival.