HepatoScore-14: Measures of Biological Heterogeneity Significantly Improve Prediction of Hepatocellular Carcinoma Risk.

BACKGROUND AND AIMS: Therapeutic, clinical trial entry and stratification decisions for hepatocellular carcinoma (HCC) are made based on prognostic assessments, using clinical staging systems based on small numbers of empirically selected variables that insufficiently account for differences in biological characteristics of individual patients' disease. APPROACH AND RESULTS: We propose an approach for constructing risk scores from circulating biomarkers that produce a global biological characterization of individual patient's disease. Plasma samples were collected prospectively from 767 patients with HCC and 200 controls, and 317 proteins were quantified in a Clinical Laboratory Improvement Amendments-certified biomarker testing laboratory. We constructed a circulating biomarker aberration score for each patient, a score between 0 and 1 that measures the degree of aberration of his or her biomarker panel relative to normal, which we call HepatoScore. We used log-rank tests to assess its ability to substratify patients within existing staging systems/prognostic factors. To enhance clinical application, we constructed a single-sample score, HepatoScore-14, which requires only a subset of 14 representative proteins encompassing the global biological effects. Patients with HCC were split into three distinct groups (low, medium, and high HepatoScore) with vastly different prognoses (medial overall survival 38.2/18.3/7.1 months; P < 0.0001). Furthermore, HepatoScore accurately substratified patients within levels of existing prognostic factors and staging systems (P < 0.0001 for nearly all), providing substantial and sometimes dramatic refinement of expected patient outcomes with strong therapeutic implications. These results were recapitulated by HepatoScore-14, rigorously validated in repeated training/test splits, concordant across Myriad RBM (Austin, TX) and enzyme-linked immunosorbent assay kits, and established as an independent prognostic factor. CONCLUSIONS: HepatoScore-14 augments existing HCC staging systems, dramatically refining patient prognostic assessments and therapeutic decision making and enrollment in clinical trials. The underlying strategy provides a global biological characterization of disease, and can be applied broadly to other disease settings and biological media.

Impact of Integrating Insulin-Like Growth Factor 1 Levels into Model for End-Stage Liver Disease Score for Survival Prediction in Hepatocellular Carcinoma Patients.

BACKGROUND: Liver reserve affects survival in hepatocellular carcinoma (HCC). Model for End-Stage Liver Disease (MELD) score is used to predict overall survival (OS) and to prioritize HCC patients on the transplantation waiting list, but more accurate models are needed. We hypothesized that integrating insulin-like growth factor 1 (IGF-1) levels into MELD score (MELD-IGF-1) improves OS prediction as compared to MELD. METHODS: We measured plasma IGF-1 levels in training (n = 310) and validation (n = 155) HCC cohorts and created MELD-IGF-1 score. Cox models were used to determine the association of MELD and MELD-IGF-1 with OS. Harrell's c-index was used to compare the predictive capacity. RESULTS: IGF-1 was significantly associated with OS in both cohorts. Patients with an IGF-1 level of ≤26 ng/mL in the training cohort and in the validation cohorts had significantly higher hazard ratios than patients with the same MELD but IGF-1 >26 ng/mL. In both cohorts, MELD-IGF-1 scores had higher c-indices (0.60 and 0.66) than MELD scores (0.58 and 0.60) (p < 0.001 in both cohorts). Overall, 26% of training and 52.9% of validation cohort patients were reclassified into different risk groups by MELD-IGF-1 (p < 0.001). CONCLUSIONS: After independent validation, the MELD-IGF-1 could be used to risk-stratify patients in clinical trials and for priority assignment for patients on liver transplantation waiting list.

Automated Volumetric Assessment of Hepatocellular Carcinoma Response to Sorafenib: A Pilot Study.

PURPOSE: This pilot study evaluates the feasibility of automated volumetric quantification of hepatocellular carcinoma (HCC) as an imaging biomarker to assess treatment response for sorafenib. METHODS: In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study, a training database of manually labeled background liver, enhancing and nonenhancing tumor tissue was established using pretherapy and first posttherapy multiphasic computed tomography images from a registry of 13 HCC patients. For each patient, Hounsfield density and geometry-based feature images were generated from registered multiphasic computed tomography data sets and used as the input for a random forest-based classifier of enhancing and nonenhancing tumor tissue. Leave-one-out cross-validation of the dice similarity measure was applied to quantify the classifier accuracy. A Cox regression model was used to confirm volume changes as predictors of time to progression (TTP) of target lesions for both manual and automatic methods. RESULTS: When compared with manual labels, an overall classification accuracy of dice similarity coefficient of 0.71 for pretherapy and 0.66 posttherapy enhancing tumor labels and 0.45 for pretherapy and 0.59 for posttherapy nonenhancing tumor labels was observed. Automated methods for quantifying volumetric changes in the enhancing lesion agreed with manual methods and were observed as a significant predictor of TTP. CONCLUSIONS: Automated volumetric analysis was determined to be feasible for monitoring HCC response to treatment. The information extracted using automated volumetrics is likely to reproduce labor-intensive manual data and provide a good predictor for TTP. Further work will extend these studies to additional treatment modalities and larger patient populations.

Estrogen Replacement Reduces Risk and Increases Survival Times of Women With Hepatocellular Carcinoma.

BACKGROUND & AIMS: Environmental factors have been identified that affect risk of hepatocellular carcinoma (HCC), but little is known about the effects of sex hormones on liver cancer development or outcome. The authors investigated whether menopause hormone therapy (MHT) affects risk, age at onset, or outcome of HCC. METHODS: We performed a case-control study of 234 female patients treated for HCC at a tertiary medical center and with 282 healthy women (controls) from January 1, 2004 through May 31, 2015. We collected detailed information on environmental exposures, ages of menarche and menopause, hysterectomies, and uses of birth control and MHT. We performed multivariable logistic and Cox regression analyses to determine the independent effects of factors associated with women on risk and clinical outcome in HCC. The primary outcomes were effect of MHT on HCC risk, the relationship between MHT with hepatitis virus infection on HCC development, and effect of MHT on age at HCC onset or survival after diagnosis of HCC. RESULTS: The estimated adjusted odds ratio (AOR) for HCC in women who ever used estrogen was 0.53 (95% confidence interval [CI], 0.32-0.88). This association was supported by the older age of HCC onset among estrogen users (mean, 64.5 ± 0.9 years) vs nonusers (mean 59.2 ± 1.1 years; P = .001) and the reduced risk of HCC among long-term users (more than 5 years) (AOR, 0.36; 95% CI, 0.20-0.63). Users of estrogen also had a reduced risk for hepatitis-associated HCC: AOR for users, 4.37 (95% CI, 1.67-11.44) vs AOR for nonusers, 17.60 (95% CI, 3.88-79.83). Estrogen use reduced risk of death from HCC (hazard ratio, 0.55; 95% CI, 0.40-0.77; P = .01). Median overall survival times were 33.5 months for estrogen users (95% CI, 25.7-41.3 months) and 24.1 months for nonusers (95% CI, 19.02-29.30 months; P = .008). CONCLUSION: In a case-control study of women with HCC vs female control subjects at a single center, we associated use of estrogen MHT with reduced risk of HCC and increased overall survival times of patients with HCC. Further studies are needed to determine the benefits of estrogen therapy for women and patients with HCC, and effects of tumor expression of estrogen receptor.

Natural History of T1N0M0 Hepatocellular Carcinoma: Large-Scale Study in the United States.

BACKGROUND: Hepatocellular carcinoma (HCC) prognosis depends on clinicopathological features in addition to the treatment provided. We aimed to assess the natural history of TNM stage I HCC tumors which received different treatment over a period of 20 years. METHODS: Between 1992 and 2011, a total of 397 stage I HCC patients were included. Detailed information was retrieved from MD Anderson Cancer Center patients' medical records. The Kaplan-Meier method was used to calculate patients' overall survival (OS). Cox regression analysis was used to calculate the estimated hazard ratio and 95% confidence interval of different prognostic factors. RESULTS: Out of 397 patients, 67.5% were males, 42.8% had hepatitis-related HCC, and 59.7% had underlying cirrhosis. After adjustment for confounding factors, we found that all therapeutic modalities were associated with a significant mortality rate reduction with an OS of 63, 42.03, 34.3, and 22.1 months among patients treated with surgery, ablation, local, and systemic therapy, respectively. A restricted analysis of cirrhotic and noncirrhotic patients showed that ablative and local therapy were significantly associated with a longer OS compared to systemic therapy. CONCLUSION: TNM stage I HCC patients have a favorable prognosis regardless of the type of treatment. Notably, ablative and local therapy significantly improved OS compared to systemic therapy.

Refining prognosis in patients with hepatocellular carcinoma through incorporation of metabolic imaging biomarkers.

PURPOSE: 18F-fluorodeoxyglucose positron emission tomopraphy/computed tomography (FDGPET/CT) has been proven to be useful for imaging many types of cancer; however, its role is not well defined in hepatocellular carcinoma (HCC). We assessed the prognostic value of metabolic imaging biomarkers as established by baseline pretreatment FDG PET/CT in patients with HCC. METHODS: We retrospectively analyzed the records of patients with HCC who underwent FDG PET/CT before initial treatment from May 2013 through May 2014. Four PET/CT parameters were measured: maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and tumor-to-normal-liver SUV ratio (TNR). Optimal cut-off values for the PET/CT parameters to stratify patients in terms of overall survival (OS) were determined. Multivariate analysis was performed to determine whether the PET/CT parameters could add to the prognostic value of the Cancer of the Liver Italian Program (CLIP) scoring system and the Barcelona-Clinic Liver Cancer (BCLC) staging system. RESULTS: The analysis included 56 patients. Univariate analysis of the association between OS and continuous variables, including the PET/CT parameters SUVmax, TLG, tumor size, total bilirubin level, and alkaline phosphatase level were significant predictors of OS. SUVmax ≥ 11.7, TLG ≥ 1,341, MTV ≥ 230 mL, and TNR ≥ 4.8 were identified as cut-off values. Multivariate analysis revealed that SUVmax ≥ 11.7 and TNR ≥ 4.8 were independent factors predicting a poor prognosis in both the CLIP scoring system and the BCLC staging system, as was TLG in the BCLC staging system. CONCLUSION: Pretreatment FDG PET/CT in patients with HCC can add to the prognostic value of standard clinical measures. Incorporation of imaging biomarkers derived from FDG PET/CT into HCC staging systems should be considered.

Obesity Early in Adulthood Increases Risk but Does Not Affect Outcomes of Hepatocellular Carcinoma.

BACKGROUND & AIMS: Despite the significant association between obesity and several cancers, it has been difficult to establish an association between obesity and hepatocellular carcinoma (HCC). Patients with HCC often have ascites, making it a challenge to determine body mass index (BMI) accurately, and many factors contribute to the development of HCC. We performed a case-control study to investigate whether obesity early in adulthood affects risk, age of onset, or outcomes of patients with HCC. METHODS: We interviewed 622 patients newly diagnosed with HCC from January 2004 through December 2013, along with 660 healthy controls (frequency-matched by age and sex) to determine weights, heights, and body sizes (self-reported) at various ages before HCC development or enrollment as controls. Multivariable logistic and Cox regression analyses were performed to determine the independent effects of early obesity on risk for HCC and patient outcomes, respectively. BMI was calculated, and patients with a BMI of 30 kg/m(2) or greater were considered obese. RESULTS: Obesity in early adulthood (age, mid-20s to mid-40s) is a significant risk factor for HCC. The estimated odds ratios were 2.6 (95% confidence interval [CI], 1.4-4.4), 2.3 (95% CI, 1.2-4.4), and 3.6 (95% CI, 1.5-8.9) for the entire population, for men, and for women, respectively. Each unit increase in BMI at early adulthood was associated with a 3.89-month decrease in age at HCC diagnosis (P < .001). Moreover, there was a synergistic interaction between obesity and hepatitis virus infection. However, we found no effect of obesity on the overall survival of patients with HCC. CONCLUSIONS: Early adulthood obesity is associated with an increased risk of developing HCC at a young age in the absence of major HCC risk factors, with no effect on outcomes of patients with HCC.

Independent of Primary Sclerosing Cholangitis and Cirrhosis, Early Adulthood Obesity Is Associated with Cholangiocarcinoma.

BACKGROUND: It is estimated that 6% to 20% of all cholangiocarcinoma (CCA) diagnoses are explained by primary sclerosing cholangitis (PSC), but the underlying risk factors in the absence of PSC are unclear. We examined associations of different risk factors with intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) in the United States. METHODS: We conducted a case-control study of 121 patients with ECC and 308 patients with ICC treated at MD Anderson Cancer Center between May 2014 and March 2020, compared with 1,061 healthy controls. Multivariable logistic regression analysis was applied to estimate the adjusted OR (AOR) and 95% confidence interval (CI) for each risk factor. RESULTS: Being Asian, diabetes mellitus, family history of cancer, and gallbladder stones were associated with higher odds of developing ICC and ECC. Each 1-unit increase in body mass index in early adulthood (ages 20-40 years) was associated with a decrease in age at diagnosis of CCA (6.7 months, P < 0.001; 6.1 months for ICC, P = 0.001; 8.2 months for ECC, P = 0.007). A family history of cancer was significantly associated with the risk of ICC and ECC development; the AORs (95% CI) were 1.11 (1.06-1.48) and 1.32 (1.01-2.00) for ICC and ECC, respectively. CONCLUSIONS: In this study, early adulthood onset of obesity was significantly associated with CCA and may predict early diagnosis at younger age than normal weight individuals. IMPACT: The study highlights the association between obesity and CCA, independent of PSC. There is a need to consider the mechanistic pathways of obesity in the absence of fatty liver and cirrhosis.

Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer.

DNA repair gene aberrations (GAs) occur in several cancers, may be prognostic and are actionable. We investigated the frequency of DNA repair GAs in gallbladder cancer (GBC), association with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) expression. Comprehensive genomic profiling (CGP) of 760 GBC was performed. We investigated GAs in 19 DNA repair genes including direct DNA repair genes (ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, and RAD50) and caretaker genes (BAP1, CDK12, MLL3, TP53, and BLM) and classified patients into 3 groups based on TMB level: low (< 5.5 mutations/Mb), intermediate (5.5-19.5 mutations/Mb), and high (≥ 19.5 mutations/Mb). We assessed MSI status and PD-1 & PD-L1 expression. 658 (86.6%) had at least 1 actionable GA. Direct DNA repair gene GAs were identified in 109 patients (14.2%), while 476 (62.6%) had GAs in caretaker genes. Both direct and caretaker DNA repair GAs were significantly associated with high TMB (P = 0.0005 and 0.0001, respectively). Tumor PD-L1 expression was positive in 119 (15.6%), with 17 (2.2%) being moderate or high. DNA repair GAs are relatively frequent in GBC and associated with coexisting actionable mutations and a high TMB.

Intrahepatic Cholangiocarcinoma: Genomic Heterogeneity Between Eastern and Western Patients.

PURPOSE: Intrahepatic cholangiocarcinoma (IHCCA), a global health problem, is increasing in incidence and has differing etiologies worldwide. Next-generation sequencing (NGS) is rapidly being incorporated into the clinical management of biliary cancers. IHCCA is enriched with actionable mutations, and there are several promising targeted therapies under development. NGS data from Asia, where IHCCA is most prevalent, are limited. METHODS: Comprehensive genomic profiling of formalin-fixed paraffin-embedded tumor tissue from 164 Asian and 283 Western patients with IHCCA was performed using NGS. We measured the distribution of DNA repair genetic aberrations (GAs) in IHCCA, along with actionable mutations. Also, we evaluated the association between DNA repair GAs and tumor mutation burden (TMB). Based on the TMB status, patients were distinguished into 3 levels: low (< 6 mut/Mb), intermediate (6-10 mut/Mb), and high (TMB-H; ≥ 10 mut/Mb). RESULTS: Seventy-two percent of Asian patients had ≥ 1 actionable GA, with a significantly higher frequency in KMT2C , BRCA1/2, and DDR2 compared with Western patients (P = .02, .003, and .003, respectively); 60.9% of Western patients had ≥ 1 actionable GA and higher frequency of CDKN2A/B and IDH1/2 GAs (P = .0004 and < .001, respectively). GAs in nuclear factor kappa B pathway regulators and DNA repair genes occurred more frequently in Asian patients (P = .006 and .001, respectively). There was a higher frequency of TMB-H in Asian compared with the Western cohort (12.2% v 5.9%; P = .07). CONCLUSION: A higher burden of DNA repair mutations and frequency of patients with TMB-H in the Asian IHCCA cohort compared with the Western patients suggests a potential role for DNA repair and immune checkpoint inhibitors in the Asian population. Future clinical trials should account for this genetic heterogeneity.

Somatic genetic aberrations in gallbladder cancer: comparison between Chinese and US patients.

BACKGROUND: Gallbladder cancer (GBC) is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis. The five-year survival rate of this cancer when diagnosed at an advanced stage is below 5%, and the median survival time is less than a year with standard gemcitabine-based chemotherapy. Survival benefit with second-line treatment is unknown. Thus, there is an urgent need for novel treatment strategies and targeted therapy based on next generation sequencing (NGS) may be of value. METHODS: Comprehensive genomic profiling (CGP) was performed with NGS panel on paraffin-embedded tumors from a cohort of 108 Chinese and 107 US GBC patients. Clinical data were collected using an IRB approved protocol from a single-center in US and from China. RESULTS: In Chinese and US GBC cohorts, an average of 6.4 vs. 3.8 genomic alterations (GAs) were identified per patient. The most frequent alterations were TP53 (69.4%), CDKN2A/B (26%), ERBB2 (18.5%), PIK3CA (17%) and CCNE1 (13%) in Chinese cohort, TP53 (57.9%), CDKN2A/B (25%), SMAD4 (17%), ARID1A (14%), PIK3CA (14%) and ERBB2 (13.1%) in US patients. NFE2L2 mutations were present in 6.5% of Chinese patients and not observed in the US cohort. Interestingly, ERBB2 genetic aberrations were significantly associated with better pathological tumor differentiation and tended to co-occurrence with CDKN2A/B mutations in both the Chinese and US GBC cases. Out of the top 9 dysregulated genetic pathways in cancer, Chinese patients harbored more frequent mutations in ERBB genes (30.6% vs. 19.0%, P=0.04). High frequency of PI3K/mTOR pathway variations was observed in both Chinese (37%) and US cohort (33%) (P=0.5). Additionally, both Chinese and US GBC patients exhibited a relatively high tumor mutational burden (TMB) (17.6% and 17.0%, respectively). In the Chinese cohort, a significant association was seen between direct repair gene alterations and TMB ≥10 muts/Mb (P=0.004). CONCLUSIONS: In our study, over 83% Chinese and 68% US GBC patients had actionable alterations that could potentially guide and influence personalized treatment options. The identification of high TMB, ERBB2, CDKN2A/B, PI3K/mTOR pathway and DNA repair mutations indicated that both Chinese and US GBC patients may benefit from targeted or immune checkpoint inhibitors.

Molecular Profiling of Hepatocellular Carcinoma Using Circulating Cell-Free DNA.

PURPOSE: Molecular profiling has been used to select patients for targeted therapy and determine prognosis. Noninvasive strategies are critical to hepatocellular carcinoma (HCC) given the challenge of obtaining liver tissue biopsies. EXPERIMENTAL DESIGN: We analyzed blood samples from 206 patients with HCC using comprehensive genomic testing (Guardant Health) of circulating tumor DNA (ctDNA). RESULTS: A total of 153/206 (74.3%) were men; median age, 62 years (range, 18-91 years). A total of 181/206 patients had ≥1 alteration. The total number of alterations was 680 (nonunique); median number of alterations/patient was three (range, 1-13); median mutant allele frequency (% cfDNA), 0.49% (range, 0.06%-55.03%). TP53 was the common altered gene [>120 alterations (non-unique)] followed by EGFR, MET, ARID1A, MYC, NF1, BRAF, and ERBB2 [20-38 alterations (nonunique)/gene]. Of the patients with alterations, 56.9% (103/181) had ≥1 actionable alterations, most commonly in MYC, EGFR, ERBB2, BRAF, CCNE1, MET, PIK3CA, ARID1A, CDK6, and KRAS. In these genes, amplifications occurred more frequently than mutations. Hepatitis B (HBV)-positive patients were more likely to have ERBB2 alterations, 35.7% (5/14) versus 8.8% HBV-negative (P = 0.04). CONCLUSIONS: This study represents the first large-scale analysis of blood-derived ctDNA in HCC in United States. The genomic distinction based on HCC risk factors and the high percentage of potentially actionable genomic alterations suggests potential clinical utility for this technology.

Baseline Apparent Diffusion Coefficient as a Predictor of Response to Liver-Directed Therapies in Hepatocellular Carcinoma.

Predicting outcomes in patients with hepatocellular carcinoma (HCC) who undergo locoregional therapies remains a substantial clinical challenge. The purpose of this study was to investigate pre-procedure diffusion weighted magnetic resonance imaging (DW-MRI) as an imaging biomarker for tumoral response to therapy for patients with HCC undergoing drug eluting embolic (DEE) chemoembolization and radioembolization. A retrospective review of HCC patients who underwent DEE chemoembolization or radioembolization was performed. Of the 58 patients who comprised the study population, 32 underwent DEE chemoembolization and 26 underwent radioembolization. There was no significant difference in median apparent diffusion coefficient (ADC) values across the two treatment groups (1.01 × 10-3 mm²/s, P = 0.25). The immediate objective response (OR) rate was 71% (40/56). Tumors with high ADC values were found to have a higher probability of OR within 90 days (odds ratio 4.4, P = 0.03). Moreover, index lesion specific progression free survival (PFS) was greater for high ADC tumors, independent of conventional predictors of treatment response (hazard ratio 0.44, P = 0.01). Low ADC was associated with poorer PFS (P = 0.02). Pre-procedure ADC < 1.01 × 10-3 mm²/s is an independent predictor of poorer immediate OR and index lesion specific PFS in patients with HCC undergoing DEE chemoembolization or radioembolization.

Randomized, phase I/II study of gemcitabine plus IGF-1R antagonist (MK-0646) versus gemcitabine plus erlotinib with and without MK-0646 for advanced pancreatic adenocarcinoma.

BACKGROUND: Binding of insulin-like growth factor-I (IGF-1) to its receptor (IGF-1R) initiates downstream signals that activate PI3K/Akt/mTOR and MEK/Erk pathways, which stimulate cancer cell proliferation and induce drug resistance. Cross talk between IGF-1R and epidermal growth factor receptor (EGFR) mediates resistance to anti-EGFR agents. We studied safety, tolerability, and outcomes of MK-0646, IGF-1 monoclonal antibody, in combination with gemcitabine (G) ± erlotinib (E) in metastatic pancreatic cancer. METHODS: Our study included a phase I dose escalation and phase II randomization and expansion cohorts. A 3 + 3 dose escalation protocol was used to determine MK-0646 maximum tolerable dose (MTD) in combination with G ± E standard doses. For phase II, patients were randomized to arm A (G + MK), arm B (G + MK + E), or arm C (G + E). Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, toxicity, and correlation between OS and IGF-1 in patients treated with MK-0646. RESULTS: MK-0646 MTD was 10 mg/kg in combination with G and 5 mg/kg in combination with G + E. In randomization cohort, 15 patients were treated in each arm. Disease control rates were 50, 60, and 40% respectively. PFS was not different between the three arms. OS was significantly different between arm A (10.4 months) and C (5.7 months) (P = 0.02). However, addition of erlotinib in arm B yielded no OS benefit compared to arm A (P = 0.6). Plasma and tissue IGF-1 levels did not correlate with OS (P = 0.64, 0.87). Grade 3-4 toxicity during phase II cohorts were neutropenia (10/arm A, 14/arm B, 5/arm C), leukopenia (5/A, 5/B, 7/C), thrombocytopenia (8/A, 9/B, 2/C), hyponatremia (1/A, 3/B), and hyperglycemia (8/A, 1/B). CONCLUSIONS: MK-0646 was tolerable in combination with G and associated with improvement in OS but not PFS as compared with G + E. Tissue and serum IGF-1 did not correlate with clinical outcome. TRIAL REGISTRATION: This trial is registered in ClinicalTrial.gov under the Identifier NCT00769483 and registration date was October 9, 2008.

Clinical and prognostic significance of circulating levels of angiopoietin-1 and angiopoietin-2 in hepatocellular carcinoma.

Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) play critical roles in angiogenesis in hepatocellular carcinoma (HCC). In addition, recent data suggest that Ang-1/Ang-2 are involved in regulating the immune response. The aim of our study was to explore the clinical prognostic significance of plasma Ang-1 and Ang-2 in HCC. We prospectively enrolled and collected data and blood samples from 767 HCC patients treated at MD Anderson Cancer Center between 2001 and 2014. Controls consisted of cirrhotic patients (n = 75) and healthy volunteers (n = 200). The cutoff value was the median level of each angiogenic factor. Overall survival (OS) was estimated by Kaplan-Meier curves and compared by the log-rank test. Higher plasma Ang-2 was significantly associated with advanced clinicopathologic features of advanced HCC and lower OS. Median OS was 61.8 months (95% confidence interval [CI], 45.1-78.5 months) for low Ang-2 compared with 28.5 months (95% CI, 24.8-32.1 months) for high Ang-2 (p < 0.001). In contrast, higher Ang-1 was associated with longer OS. Median OS was 37.2 months (95% CI, 31.0-43.4 months) for high Ang-1 compared with 26.2 months (95% CI, 22.2-30.3 months) for those with low Ang-1 (p = 0.043). In conclusion, our findings indicate that plasma Ang-1 and Ang-2 levels are potential diagnostic and prognostic biomarkers in HCC.

Cholangiocarcinoma With FGFR Genetic Aberrations: A Unique Clinical Phenotype.

PURPOSE: FGFR genetic aberrations (GAs) occur in an estimated 10% to 16% of intrahepatic cholangiocarcinomas (CCAs). The natural history of CCA with FGFR GAs, the prognostic role of coexisting GAs, and the outcome with FGFR-targeted inhibitors are unknown. PATIENTS AND METHODS: Patients with CCA with FGFR GAs were identified using next-generation sequencing or fluorescence in situ hybridization from four tertiary cancer centers and compared with FGFR wild-type counterparts. Data reviewed included demographic, treatment, overall survival (OS), and GA data. Fisher's exact test, Kaplan-Meier plots, and log-rank tests were used for statistical analysis. RESULTS: Three hundred seventy-seven patients with CCA were identified, and 95 had FGFR GAs. FGFR2 GA was most common (n = 74, with 63 fusions) and seen in intrahepatic CCA. In patients with CCA, FGFR GAs occurred more frequently in younger patients (≤ 40 years; 20%) compared with older patients (> 40 years; 6.7%; P < .001), presented at an earlier stage (TNM stage I/II v III/IV: 35.8% v 22%, respectively; P = .001), and were associated with a longer OS compared with patients without FGFR GAs (37 v 20 months, respectively; P < .001). This difference remained significant after excluding 36 patients treated with FGFR inhibitors. There was no OS difference (P = .60) between CCA with FGFR2 fusions (n = 63) versus other FGFR GAs (n = 29). Patients with FGFR GAs had a better OS with FGFR-targeted therapy compared with standard treatment (P = .01). BAP1 mutation was the most common coexisting mutation without prognostic impact, whereas TP53 (P = .04) and CDKN2A/B (P = .04) were correlated with a shorter OS. CONCLUSION: CCA with FGFR GAs represents a unique subtype occurring in younger patients with an indolent disease course. FGFR-targeted therapy may have a positive impact on OS in this subgroup.

Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: a prospective case-series.

BACKGROUND: At present, intrahepatic cholangiocarcinoma is a contraindication for liver transplantation. However, previous studies in this field did not preselect patients on the basis of chemosensitivity or disease trajectory after neoadjuvant therapy. Experience with hilar cholangiocarcinoma has indicated that neoadjuvant therapy followed by liver transplantation in patients without disease progression results in a long-term survival benefit. We aimed to establish the potential efficacy of liver transplantation in patients with biologically responsive intrahepatic cholangiocarcinoma who have had sustained tumour stability or regression with neoadjuvant therapy. METHODS: In this prospective case-series, patients with locally advanced, unresectable intrahepatic cholangiocarcinoma, without extrahepatic disease or vascular involvement, were treated at a single liver transplant centre according to a non-randomised, centre-approved clinical management protocol with neoadjuvant chemotherapy followed by liver transplantation. Neoadjuvant therapy consisted of gemcitabine-based chemotherapy, such as gemcitabine-cisplatin or gemcitabine-capecitabine, with second-line or third-line therapies given per institutional standards. Patients with a minimum of 6 months of radiographic response or stability were listed for liver transplantation. The primary endpoints were overall survival and recurrence-free survival after liver transplantation, assessed with Kaplan-Meier analysis. This report includes interim data from the initial case-series treated under this ongoing clinical management protocol, censored on Dec 1, 2017. FINDINGS: Between Jan 1, 2010, and Dec 1, 2017, 21 patients were referred for evaluation and 12 patients were accepted, of whom six patients have undergone liver transplantation for intrahepatic cholangiocarcinoma. Three patients received livers from extended criteria deceased donors that would otherwise have been discarded, two from domino living donors, and one from a standard criteria liver donor. Median duration from diagnosis to transplantation was 26 months (IQR 17-33) and median follow-up from transplantation was 36 months (29-51). All patients received neoadjuvant chemotherapy while awaiting liver transplantation. Overall survival was 100% (95% CI 100-100) at 1 year, 83·3% (27·3-97·5) at 3 years, and 83·3% (27·3-97·5) at 5 years. Three patients developed recurrent disease at a median of 7·6 months (IQR 5·8-8·6) after transplantation, with 50% (95% CI 11·1-80·4) recurrence-free survival at 1, 3, and 5 years. Adverse events after liver transplantation included one patient with postoperative ileus (grade 3) and one patient with acute kidney injury requiring temporary dialysis (grade 4). INTERPRETATION: Selected patients with locally advanced intrahepatic cholangiocarcinoma who show pre-transplant disease stability on neoadjuvant therapy might benefit from liver transplantation. FUNDING: None.

Nonalcoholic steatohepatitis-related hepatocellular carcinoma: is there a role for the androgen receptor pathway?

The epidemic of insulin resistance, obesity, and metabolic syndrome has led to the emergence of nonalcoholic steatohepatitis (NASH) as the most common cause of liver disease in the US. Patients with NASH are at an increased risk for hepatic disease-related morbidity and death, and chronic inflammation in NASH patients can lead to hepatocellular carcinoma (HCC). The prevalence of HCC is higher in males than in females, and genetic studies have identified androgen and androgen receptors (ARs) as partially responsible for the gender disparity in the development of liver disease and HCC. Although many factors are known to play important roles in the progression of inflammation in NASH patients, the role of androgen and AR in the progression of NASH to HCC has been understudied. This review summarizes the evidence for a potential role of androgen and the AR pathway in the development of NASH-related HCC and in the treatment of HCC. It has been proposed that AR plays a role in the progression of HCC: inhibitory roles in early stages of hepatocarcinogenesis and tumor-promoting roles in advanced stages. AR can be activated by several pathways, even in the absence of androgen. While AR has been explored as a potential therapeutic target in HCC, several clinical trials have failed to demonstrate a clinical benefit of antiandrogen drugs in HCC. This review discusses the potential reason for these observations and discuss the potential future trials design in this important setting.

Evaluating clinical and prognostic implications of Glypican-3 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide. In patients with HCC, histopathogical differentiation is an important indicator of prognosis; however, because determination of HCC differentiation is difficult, the recently described immunohistochemical (IHC) marker glypican3 (GPC3) might assist in HCC prognostication.The goal of our study was to investigate GPC3's IHC staining pattern and define the relationship between its expression and patients' clinicopathologic features and overall survival. We retrieved clinical parameters from 101 pathologically diagnosed HCC patients' medical records and classified these patients into 4 clinical score categories (0-3) based on increasing GPC3 staining intensity and the percentage of stained tumor cells in their resection and biopsy specimens. Histopathological samples were well, moderately, and poorly differentiated in 33, 22, and 12 patients, respectively, and the GPC3 expression rate was 63%, 86%, and 92%,respectively. The median overall survival was 49.9 months (confidence interval (CI): 35.3-64.6 months) for clinical scores 0-1 and 30.7 months (CI: 19.4-41.9 months) for clinical scores 2-3. This difference was not statistically significant (P = .06) but showed a strong trend. In conclusion, a greater GPC3 expression is associated with a worse HCC prognosis and may be a promising prognostic marker.