Citations

4033 Background: HCC is a major health problem across the world. The global HCC BRIDGE study is the first global, large-scale, observational study to document the real-world experience of HCC patients from diagnosis to death. Methods: This longitudinal cohort study (started March 2009) includes HCC patients newly diagnosed between January 2005 and June 2011 and treated at major medical centers, with data collected retrospectively and prospectively as recorded in patient charts. Full patient enrollment is expected at the end of January 2012. Results: At the time of the first interim analysis (July 2011), 12,442 treated HCC patients were enrolled at 42 sites in Asia (n=8909, 72% [China: n=6295, 71%; Japan: n=295, 3%]), Europe (n=2040, 16%) and North America 1493 (n=1493, 12%). Mean age was 57 years; 82% were male. The predominant risk factor was HBV in Asia (76%) and HCV in Europe (48%), North America (45%) and Japan (69%). Most patients were diagnosed without surveillance (Asia, 82%; Europe, 73%; North America, 69%; Japan, 64%). In Asia, Europe and North America, the predominant BCLC stage at diagnosis was C (48%, 46%, 46%) followed by A (34%, 28%, 26%). First recorded treatments in Asia, Europe and North America were resection (31%, 15%, 21%), transplantation (1%, 3%, 1%), TACE (49%, 30%, 36%), other locoregional therapy (12%, 35%, 23%) and systemic therapy (3%, 10%, 8%). Treatments ever used (2005–2011) in Asia, Europe and North America were resection (33%, 17%, 24%), transplantation (2%, 6%, 12%), TACE (57%, 35%, 48%), other locoregional therapy (20%, 42%, 37%) and systemic therapy (9%, 20%, 21%). These results will be updated with data from the full study population (approx. 19,000 patients), and preliminary survival data will be presented. Conclusions: As the largest study of its type, in 19,000 patients worldwide, the HCC BRIDGE study provides valuable insights into global HCC disease characteristics and patient management. Based on prior analyses, differences in risk factors among regions confirm well-known trends, while other observed differences (e.g., treatment variations) may be related to country- and site-specific practices and patient characteristics.

3587 Background: The Insulin like Growth Factor I receptor (IGF-IR), a tyrosine kinase, is widely expressed in human tissues. IGF- IR and its ligands (IGF-I and IGF-II) are expressed by many human cancers (e.g., breast, prostate, colorectal and non-small cell lung). Binding of the ligands to the IGF-IR activates key cellular signaling pathways important for stimulating cellular proliferation and inhibiting apoptosis. IGF- I and IGF-II are present in the circulation, but also locally expressed in neoplastic tissue. Bioavailability of these ligands is regulated by a family of IGF binding proteins (IGFBPs1–6). CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of IGF-IR activation. In vitro experiments show that binding of CP 751,871 to IGF-IR induces receptor internalization and degradation. This antibody has been shown to have antineoplastic activity using both in vivo and in vitro pre-clinical models. Methods: Blood samples were collected for characterization of the pharmacokinetic and pharmacodynamic properties of CP-751,871 in phase 1 trials of this agent given to cancer patients either alone or in combination with chemotherapy. The endpoints assessed included among others: CP-751,871 plasma concentrations, total and free IGF-I, IGFBP-3, soluble IGF-IR and IGF-IR expression on granulocytes and tumor cells. Results: CP 751,871 exposure increased with dose over the 800-fold dose range investigated. Pharmacokinetic profiles were consistent with target-mediated disposition. A dose-dependent downregulation of soluble IGF-IR serum concentration and IGF-IR expression was observed, with sustained inhibition for the entire dosing period (3–4 week cycles) observed at doses ≥ 1.5 mg/kg. As predicted for an agent that interferes with IGF-I action, IGF-I and IGFBP-3 serum levels were up-regulated in a similar dose-dependent manner. Conclusions: The pharmacodynamic endpoints of clinical trials provide evidence that CP-751,871 targets IGF-IR in granulocytes, tumor cells and tissues involved in regulation of the growth hormone -IGF-I axis. These data provide proof of principle for the use of CP-751,871 as a first-in-class therapeutic approach to inhibit the IGF-IR pathway in cancer patients. No significant financial relationships to disclose.

3507 Purpose: To detect IGF-1R on circulating tumor cells (CTCs) as a biomarker in the clinical development of a monoclonal human antibody, CP-751,871, targeting IGF-1R. Experimental Design: An automated sample preparation and analysis system for enumerating CTCs (Celltracks) was adapted for detecting IGF-1R positive CTCs with a diagnostic antibody targeting a different IGF-1R epitope to CP-751,871. This assay was utilized in three phase I trials of CP-751,871 as a single agent or with chemotherapy and was validated using cell lines and blood samples from healthy volunteers and patients with metastatic carcinoma. Results: There was no interference between the analytical and therapeutic antibodies. CP-751,871 was well tolerated as a single agent, and in combination with docetaxel or carboplatin and paclitaxel, at doses ranging from 0.05 mg/kg to 20 mg/kg. Eighty patients were enrolled on phase 1 studies of CP-751,871, with 47 (59%) patients having CTCs detected during the study. Prior to treatment 26 patients (33%) had CTCs, with 23 having detectable IGF-1R positive CTCs. CP-751,871 alone, and CP-751,871 with cytotoxic chemotherapy, decreased CTCs and IGF-1R positive CTCs; these increased towards the end of the 21-day cycle in some patients, falling again with retreatment. CTCs were commonest in advanced hormone refractory prostate cancer (11/20). Detectable IGF-1R expression on CTCs before treatment with CP-751,871 and docetaxel was associated with a higher frequency of PSA decline by more than 50% (6/10 vs 2/8 patients). A relationship was observed between sustained falls in CTCs counts and PSA declines by more than 50%. Conclusions: IGF-1R expression is detectable by immunofluorescence on CTCs. These data support the further evaluation of CTCs in pharmacodynamic studies and patient selection, particularly in advanced prostate cancer. No significant financial relationships to disclose.

Background and Aims Statins have been proven to be cytotoxic to human cholangiocarcinoma cells by inhibiting cell division and inducing apoptosis. We aimed to determine the effect of statin use on the risk of cancer development and survival in patients with extrahepatic cholangiocarcinoma (ECC), including perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). Approach and Results A total of 394 patients with ECC and hyperlipidemia who received care at Mayo Clinic Rochester between 2005 and 2015 were matched by age, sex, race, ethnicity, and residency to 788 controls with hyperlipidemia. Clinical and outcome data were abstracted. The odds ratios (ORs) for risk and hazard ratios for outcomes were calculated. The mean age and standard deviation (SD) for cases and controls was 65.6 years (13.8). The number of statin users in cases and controls was 73 (19%) and 403 (51%), respectively. Hepatitis C virus infection (OR, 15.84; 95% confidence interval [CI], 4.06‐61.87; P < 0.001) was the most significant risk factor for pCCA followed by inflammatory bowel disease and cirrhosis, whereas other liver disease, including biliary stone disease (OR, 4.06; CI, 2.24‐7.36; P < 0.001), was the only significant risk factor for dCCA. Statin use was associated with significantly reduced risk for all ECC (OR, 0.22; CI, 0.16‐0.29) as well as for the subtypes pCCA (OR, 0.3; CI, 0.21‐0.41) and dCCA (OR, 0.06; CI, 0.03‐0.14), all P < 0.0001. Moderate‐intensity dosage was found to decrease the risk of ECC (OR, 0.48; CI, 0.34‐0.67; P < 0.001). Comparing statin ever users to nonusers, patients with dCCA who used statins had significantly overall better survival (hazard ratio = 0.53; CI, 0.29‐0.97; P = 0.04). Conclusions This case‐control study suggests that statins decrease the risk of ECC and may improve survival in patients with dCCA. Additional validation studies are warranted.

Abstract Objectives A cluster of specialized KIR genes of specialized KIR genes has been shown to be associated with susceptibility or resistance to viral infections in humans. Therefore, this pilot study, this pilot investigation sought to determine the frequencies of KIR genes human immunodeficiency virus type 1( HIV-1) patients and establish their potential clinical involvement in disease progression and staging. Methods HIV-1 infected and healthy individuals were selected for this study. Hepatitis B surface antigen (HBsAg), anti-HCV antibodies and anti-HIV-1/2 antibody/ antigen were screened using a 4 th generation ELISA assay (Cobas e 411 Analyzer, Roche Diagnostics GmbH Mannheim, Germany). SSP-PCR was used to evaluate the frequencies of KIR genes. CD4 + T counts and HIV-1 viral load were measured in patients using respectively BD FACSCount and Abbott m2000rt instruments. Results We found a significant association between the frequencies of KIR2DL2 (OR=4.41; p < 0.001), KIR2DS2 (OR=4.76; p < 0.001), KIR2DS3 (OR=2.27; p=0.004), KIR2DS4 (OR=1.76; p=0.026), KIR3DS1 (OR=2.43; p=0.016) and HIV-1 infection; whilst the KIR3DL1 gene (OR= 0.39; p < 0.001) was associated with protection against HIV-1 infection. HIV-1 replication was found to be associated with the presence of KIR2DS2 (OR=6.08, p = 0.024). In contrary the pseudogene KIR2DP1 (OR=0.39; p=0.026) were linked to a protective status with the highest number of lymphocyte T CD4 counts. Conclusion Our data showed that KIR2DL2, KIR2DS2, KIR2DS3, KIR2DS4 , and KIR3DS1 were significantly associated with HIV-1 infection whereas KIR3DL1 was associated with protection against HIV-1 infection. Further investigations are needed to fully comprehend the clinical significance of KIR genes in HIV disease progression.

Background and Aims Presence of malignant regional lymph nodes (MRLNs) precludes curative oncological resection or liver transplantation for cholangiocarcinoma (CCA). Limited data support the utility of endoscopic ultrasound (EUS)/fine needle aspiration (FNA) for detection of MRLNs in extrahepatic CCA, but there are no data for its role in intrahepatic CCA (iCCA). The aim of this study is to evaluate the staging impact of EUS for CCA, including analysis by subtype. Approach and Results We identified consecutive patients with CCA who underwent EUS staging at a single tertiary care center from October 2014 to April 2018. Among this cohort, we abstracted clinical demographic, radiographical, procedural, cytopathological, and surgical data. STATA 15 software was used for comparative analysis calculations (StataCorp LP, College Station, TX). The study cohort included 157 patients; 24 (15%), 124 (79%), and 9 (6%) with intrahepatic, perihilar, and distal CCA, respectively. EUS was able to identify regional lymph nodes (RLNs) in a higher percentage of patients compared to cross‐sectional imaging (86% vs. 47%; P < 0.001). FNA was performed in 133 (98.5%) patients with RLNs, with a median of three passes per node. EUS‐FNA identified MRLN in 27 of 31 (87.1%) patients ultimately found to have MRLNs. For iCCA, EUS detected a higher percentage of RLN compared to cross‐sectional imaging (83% vs. 50%; P = 0.048), with MRLNs identified in 4 (17%) patients. Among the entire cohort, identification of at least one MRLN by EUS was associated with lower median survival (353 vs. 1,050 days; P < 0.001) and increased risk of death (hazard ratio = 4.1; P < 0.001). Conclusions EUS‐FNA is effective for identifying MRLN in patients with CCA, and should be routinely incorporated into staging of all CCA subtypes given the impact of MRLN on prognosis and management decisions.

Abstract Hepatocellular carcinoma (HCC) is a disease of global public health significance with mortality on the rise, despite the preventable nature of its risk factors especially in Africa. It is now the sixth most common cancer worldwide, fifth in males, and ninth in females. HCC incidence and mortality are predicted to increase in African countries constrained by limited resources to combat endemic levels of viral infection and synergistic environmental risk factors. The changing nature of HCC etiology is particularly illustrated here with the traditional risk factors like viral hepatitis coexisting alongside high human immunodeficiency virus (HIV) prevalence and rapidly increasing urbanization that have promoted a sharp increase in additional risk factors like coinfection, type 2 diabetes mellitus, and obesity. Although there are some differences in etiology between North Africa and sub-Saharan Africa, risk factors like chronic viral hepatitis B and C, aflatoxin exposure, and iron overload predominate. Aggressive hepatitis B genotypes, combined with hepatitis B virus/hepatitis C virus/HIV coinfections and aflatoxin exposure, promote a more aggressive molecular phenotype. In parallel to a better understanding of the molecular etiology of HCC, policy and planning initiatives to address the burden of HCC must be anchored within the reality of the limited resources available. Establishment and coordination of cancer registries across Africa is needed to improve the quality of data necessary to galvanize action. Preventive measures including hepatitis B vaccination programs, measures to prevent maternal-to-child and child-to-child transmission, delivery of universally accessible antiretroviral and antiviral treatments, and reduction of dietary aflatoxin exposure can contribute markedly to reduce HCC incidence. Finally, the development of biomarkers and new therapeutic interventions will need a better understanding of the unique genetic and epigenetic characteristics of HCC on the continent. We present a narrative review of HCC in Africa, discussing present and future trends.

INTRODUCTION: The discontinuous BALAD and continuous BALAD-2 scores derived from bilirubin, albumin, alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxyprothrombin (DCP) are effective in predicting HCC patient mortality, but have not been validated in North America. We validated the BALAD and BALAD-2 scores in North America. METHODS: Data from 148 HCC patients seen from 2000–2015 with results for all five biomarkers at diagnosis were abstracted. Hazard ratios (HR) and C-statistics were calculated. RESULTS: 75 of the 148 patients died during a median follow-up of 33 months (0.3-145 months),. The 1-year and 3-year survival rates were 70.8% and 47.6%, respectively. 114 (77%) patients had cirrhosis with a median MELD of 9.5 (range 6.4-29.5). HCC etiologies were HCV (34%), NASH (34%), alcohol (14%), and HBV (10%). Primary treatments were liver transplant, 21 (14%), surgical resection, 32 (22%), local ablation, 10 (7%), transarterial chemoembolization or radioembolization, 47 (32%), chemotherapy, 11 (7%), best supportive care, 9 (6%), and unknown treatment, 18 (12%). MELD, tumor size (cm), ≥2 tumors, tumor number, and neutrophil-lymphocyte ratio >4 significantly increased mortality with HR (95%CI) of 1.12 (1.06–1.18) per unit increase in MELD, 1.06 (1.0004–1.12) per cm increase in size, 1.21 (1.03–1.43) per number of tumor, and 1.93 (1.16–3.24). For the BALAD score analysis, 12, 49, 40, 31, 16 and 0 patients had BALAD scores of 0–5 respectively. The HR (95%CI) for death were 1.24 (0.42–3.67), 1.79 (0.61–5.26), 2.83 (0.95–8.38), and 7.19 (2.26–22.91) for BALAD scores 1, 2, 3, and 4 vs. BALAD 0. For the BALAD-2 analysis, 58, 35, 33, and 22 patients were BALAD-2 classes 1, 2, 3, and 4. The HR (95%CI) for death were 1.25 (0.65–2.40), 1.75 (0.94–3.23), and 6.20 (3.29–11.68) for BALAD-2 classes 2, 3, and 4 vs. BALAD-2 class 1. A multivariate model incorporating maximal tumor diameter, tumor number, neutrophil-lymphocyte ratio and BALAD had HR of 1.43 (1.14–1.81) per increase of 1 BALAD score. A similar multivariate model with BALAD-2 had HR of 1.50 (1.18–1.90) per increase of 1 BALAD-2 class. BALAD, BALAD-2 and BCLC had similar C-statistics of 0.69, 0.68, and 0.67. CONCLUSION: The BALAD score and BALAD-2 class at HCC diagnosis can predict survival of HCC patients in North America. AFP, AFP-L3, and DCP in the BALAD models incorporate HCC tumor biology and make the BALAD model distinguish from other previous predictive models.