[Show abstract][Hide abstract] ABSTRACT: Background Intrahepatic cholangiocarcinoma (ICC) often is a diagnosis determined by exclusion. Distinguishing ICC from other metastatic adenocarcinomas based on histopathologic or immunohistochemical analysis often is difficult and requires an extensive workup. This study aimed to determine whether albumin, whose expression is restricted to the liver, has potential as a biomarker for ICC using a novel and highly sensitive RNA in situ hybridization (ISH) platform. Methods Modified branched DNA probes were developed for albumin RNA ISH. The study evaluated 467 patient samples of primary and metastatic lesions. Results Of the 467 samples evaluated, 83 were ICCs, 42 were hepatocellular carcinomas (HCCs), and 332 were nonhepatic carcinomas including tumors arising from the perihilar region and bile duct, pancreas, stomach, esophagus, colon, breast, ovary, endometrium, kidney, and urinary bladder. Albumin RNA ISH was highly sensitive for cancers of liver origin, staining positive in 82 (99 %) of 83 ICCs and in 42 HCCs (100 %). Perihilar and distal bile duct carcinomas as well as carcinomas arising at other sites tested negative for albumin. Notably, 6 (22 %) of 27 intrahepatic tumors previously diagnosed as carcinomas of undetermined origin tested positive for albumin. Conclusions Albumin RNA ISH is a sensitive and highly specific diagnostic tool for distinguishing ICC from metastatic adenocarcinoma to the liver or carcinoma of unknown origin. Albumin RNA ISH could replace the extensive diagnostic workup, leading to timely confirmation of the ICC diagnosis. Additionally, the assay could serve as a guide to distinguish ICC from perihilar adenocarcinoma.
Annals of Surgical Oncology 12/2014; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Personalized care in oncology is expected to significantly improve morbidity and mortality, facilitated by our increasing understanding of the molecular mechanisms driving tumors and the ability to target those drivers. Hepatocellular carcinoma has a very high mortality to incidence ratio despite localized disease being curable, emphasizing the importance of early diagnosis. Radiomics, the use of imaging technology to extrapolate molecular tumor data, and the detection of circulating tumor cells (CTCs) are two new technologies that could be incorporated into the clinical setting with relative ease. Here we discuss the molecular mechanisms leading to the development of hepatocellular carcinoma focusing on the latest developments in liver magnetic resonance imaging, CTC, and radiomic technology and their potential to improve diagnosis, staging, and therapy.
[Show abstract][Hide abstract] ABSTRACT: Predicting which patients will benefit from radioembolization remains a challenge, as reliable prognostic indicators are not defined. Abnormal tumor vascular anatomy could not only impact the ability of cancer therapies to penetrate tumors, but may also contribute to a lesion's metastatic potential. Specifically, intratumoral vascular shunts could allow circulating tumor cells to initiate metastases by allowing them to gain access to distant sites in the body, bypassing capillary beds. Here, we describe how tumoral angiogenesis occurs and how intratumoral vascular shunts may form.
[Show abstract][Hide abstract] ABSTRACT: Background Ganetespib (STA-9090) is an Hsp90 inhibitor that downregulates VEGFR, c-MET, HER2, IGF-IR, EGFR, and other Hsp90 client proteins involved in hepatocarcinogenesis, thereby making it an attractive therapy for HCC. This Phase I study was performed to establish the safety, tolerability, recommended Phase 2 dose (RP2D), and preliminary clinical activity of ganetespib in previously treated patients with advanced HCC. Methods Patients with advanced HCC, Child-Pugh A cirrhosis, progression on or intolerance to sorafenib, and ECOG PS ≤ 1 were enrolled in a standard 3x3 dose escalation study at doses of 100 mg/m(2), 150 mg/m(2), and 200 mg/m(2) IV given on days 1, 8, and 15 of each 28-day cycle. Objective response by RECIST version 1.1 criteria was evaluated by CT/MRI every 8 weeks. Results Fourteen patients were enrolled in this trial and received at least one dose of the study drug. Of the 14 patients: median age, 57 years old; male 71 %; Asian 36 %; HCC etiology (HBV 36 %, HCV 43 %, Hemachromatosis 7 %, unknown 21 %); Child Pugh Class (A 93 %, B 7 %); median number of prior treatments 2; median baseline AFP 70.1 ng/mL. The RP2D was determined to be 200 mg/m(2). The most commonly seen AEs were diarrhea (93 %), fatigue (71 %), AST elevation (64 %), and hyperglycemia (64 %). The most common Gr 3/4 AEs were hyperglycemia (21 %) and lipasemia (21 %). One (7 %) patient had a fatal AE, septic shock, within 30 days of receiving the study drug. One dose-limiting toxicity, grade 3 lipasemia, was observed at the 100 mg/m(2) dose. Pharmacokinetics studies showed a t1/2, CL, Tmax, and Vss of 6.45 h, 48.28 L/h (25.56 L/h/m(2)), 0.76 h, and 191 L (100.4 L/m(2)), respectively. No objective responses were seen; one patient (7 %) had stable disease at 16 weeks. Median time to progression was 1.8 months, and median overall survival was 7.2 months. Conclusion Ganetespib had a manageable safety profile in patients with advanced HCC who had progressed on at least one line of systemic therapy. The pharmacokinetic profile showed that ganetespib exposure in patients with mild hepatic dysfunction is similar to that seen in patients with normal liver function. Ganetespib showed limited clinical benefit in patients with advanced HCC in this phase I trial.
Investigational New Drugs 09/2014; · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The 'omics revolution is facilitating a personalized approach to improving outcome by refining diagnosis, staging, treatment, and monitoring of hepatocellular carcinoma. Furthermore, the promise of being able to target a range of specific tumor drivers at a molecular level offers exciting new therapy prospects for a disease that is notoriously difficult to treat. We provide a unique perspective combining our understanding of the molecular mechanisms of hepatocellular carcinoma development with the potential of circulating tumor cells and radiogenomics to change the drivers of decision-making used in current practice.
[Show abstract][Hide abstract] ABSTRACT: Hepatobiliary cancers include a spectrum of invasive carcinomas arising in the liver (hepatocellular carcinoma), gall bladder, and bile ducts (cholangiocarcinomas). Gallbladder cancer and cholangiocarcinomas are collectively known as biliary tract cancers. Gallbladder cancer is the most common and aggressive type of all the biliary tract cancers. Cholangiocarcinomas are diagnosed throughout the biliary tree and are typically classified as either intrahepatic or extrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinomas are more common than intrahepatic cholangiocarcinomas. This manuscript focuses on the clinical management of patients with gallbladder cancer and cholangiocarcinomas (intrahepatic and extrahepatic).
Journal of the National Comprehensive Cancer Network: JNCCN 08/2014; 12(8):1152-82. · 5.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite the historically limited role of radiotherapy in the management of primary hepatic malignancies, modern advances in treatment design and delivery have renewed enthusiasm for radiation as a potentially curative treatment modality. Surgical resection and/or liver transplantation are traditionally regarded as the most effective forms of therapy, although the majority of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma present with locally advanced or unresectable disease on the basis of local vascular invasion or inadequate baseline hepatobiliary function. In this context, many efforts have focused on nonoperative treatment approaches including novel systemic therapies, transarterial chemoembolization, ethanol ablation, radiofrequency ablation, and stereotactic body radiation therapy (SBRT). This review aims to summarize modern advances in radiotherapy, particularly SBRT, in the treatment of primary hepatic malignancies.
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. OBJECTIVE To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. DESIGN, SETTING, AND PARTICIPANTS EVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent). INTERVENTIONS Everolimus, 7.5 mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2:1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group.
JAMA The Journal of the American Medical Association 07/2014; 312(1):57-67. · 29.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4α silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.
[Show abstract][Hide abstract] ABSTRACT: Background:Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer.Methods:Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0-2 were treated with panitumumab 6 mg kg(-1), GEM 1000 mg m(-2) (10 mg m(-2) min(-1)) and OX 85 mg m(-2) on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival.Results:Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5-24 months) and median overall survival 20.3 months (95% CI 9-25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%.Conclusions:The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.British Journal of Cancer advance online publication 24 June 2014; doi:10.1038/bjc.2014.343 www.bjcancer.com.
[Show abstract][Hide abstract] ABSTRACT: Immune checkpoint blockade has recently emerged as a promising therapeutic approach for various malignancies including hepatocellular carcinoma (HCC). Preclinical and clinical studies have shown the potential benefit of modulating immunogenicity of HCC. In addition, recent advances in tumor immunology have broadened our understanding of the complex mechanism of immune evasion. In this review, we summarize the current knowledge on HCC immunology, and discuss the potential of immune checkpoint blockade as a novel HCC therapy from the basic, translational, and clinical perspectives. (Hepatology 2014;).
[Show abstract][Hide abstract] ABSTRACT: The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection.
Annals of Surgical Oncology 06/2014; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients.
International journal of radiation oncology, biology, physics 05/2014; · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tumor vascular heterogeneity is a recognized biomarker for cancer progression. Our purpose was to assess the tumor perfusion heterogeneity during antiangiogenic therapy in hepatocellular carcinoma (HCC) by means of fractal analysis on computed tomography perfusion (CTP) images.
Twenty-two patients (15 men and 7 women; mean age: 61.5 years) with advanced HCC underwent CTP at baseline and 2 weeks after administration of bevacizumab. Perfusion maps of blood flow (BF) were generated by the adiabatic approximation to the tissue homogeneity model with a motion registration, and fractal analyses were applied to gray-scale perfusion maps using a plugin tool on ImageJ software (NIH, Bethesda, MD). A differential box-counting method was applied, and the fractal dimension (FD) was calculated as a heterogeneity parameter.
Patients were grouped into favorable progression-free survival (PFS) group (PFS>6 months, 11 patients) and unfavorable PFS group (PFS≤6, 11 patients). After 2 weeks of antiangiogenic therapy, the BF decreased significantly (P < .0001), whereas the FD showed no significant change (P = .69). The percent change of the FD in tumor BF was significantly different between patients with favorable PFS and those without (-2.52% vs. 3.72%, P = .01), whereas the change of tumor BF showed no significant difference between them (-28.93% vs. -25.47%, P = .64). In Kaplan-Meier analysis, patients with greater reduction in the percent change of FD and lower baseline FD in tumor BF showed significantly longer overall survival (P = .009, P = .005).
Fractal analysis of tumor BF can be a biomarker for antiangiogenic therapy.
[Show abstract][Hide abstract] ABSTRACT: Radiation therapy is emerging as a potentially effective treatment of locally advanced, unresectable hepatocellular carcinoma (HCC). Outcomes from early prospective studies seem promising, with improved survival compared with historical controls. Cure of early stage and unresectable HCC may be possible with high-quality radiation therapy. Many questions remain, including determination of the ideal radiation dose and fractionation schema, optimal patient selection criteria based on tumor size, tumor location, extent of vascular invasion, and baseline liver function, and the role of radiation therapy compared with other localized standard treatments including radiofrequency ablation or transarterial chemoembolization.
Surgical Oncology Clinics of North America 04/2014; 23(2):353-368. · 1.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE Intrahepatic cholangiocarcinoma (ICC) is a primary cancer of the liver that is increasing in incidence, and the prognostic factors associated with outcome after surgery remain poorly defined. OBJECTIVE To combine clinicopathologic variables associated with overall survival after resection of ICC into a prediction nomogram. DESIGN, SETTING, AND PARTICIPANTS We performed an international multicenter study of 514 patients who underwent resection for ICC at 13 major hepatobiliary centers in the United States, Europe, and Asia from May 1, 1990, through December 31, 2011. Multivariate Cox proportional hazards regression modeling with backward selection using the Akaike information criteria was used to select variables for construction of the nomogram. Discrimination and calibration were performed using Kaplan-Meier curves and calibration plots. INTERVENTIONS Surgical resection of ICC at a participating hospital. MAIN OUTCOMES AND MEASURES Long-term survival, effect of potential prognostic factors, and performance of proposed nomogram. RESULTS Median patient age was 59.2 years, and 53.1% of the patients were male. Most patients (74.7%) had a solitary tumor, and median tumor size was 6.0 cm. Patients were treated with an extended hepatectomy (202 [39.3%]), a hemihepatectomy (180 [35.0%]), or a minor liver resection (<3 segments) (132 [25.7%]). Most patients underwent R0 resection (87.9%), and 35.7% of patients had N1 disease. Using the backward selection of clinically relevant variables, we found that age at diagnosis (hazard ratio [HR], 1.31; P < .001), tumor size (HR, 1.50; P < .001), multiple tumors (HR, 1.58; P < .001), cirrhosis (HR, 1.51; P = .08), lymph node metastasis (HR, 1.78; P = .01), and macrovascular invasion (HR, 2.10; P < .001) were selected as factors predictive of survival. On the basis of these factors, a nomogram was created to predict survival of ICC after resection. Discrimination using Kaplan-Meier curves, calibration curves, and bootstrap cross-validation revealed good predictive abilities (C index, 0.692). CONCLUSIONS AND RELEVANCE On the basis of an Eastern and Western experience, a nomogram was developed to predict overall survival after resection for ICC. Validation revealed good discrimination and calibration, suggesting clinical utility to improve individualized predictions of survival for patients undergoing resection of ICC.
[Show abstract][Hide abstract] ABSTRACT: Intratumoral heterogeneity is a well-recognized feature of malignancy.
To assess the heterogeneity of tumor using fractal analysis of contrast-enhanced computed tomography (CE-CT) images for predicting survival of hepatocellular carcinoma (HCC) patients treated with sunitinib.
The patient cohort comprised 23 patients (19 men, 4 women; mean age 61.5 years) with HCC who underwent CE-CT at baseline and after one cycle of sunitinib. Arterial-phase (AP) and portal-phase (PP) CE-CT images were analyzed using a plugin software for ImageJ (NIH, Bethesda, MD). A differential box-counting method was employed to calculate the fractal dimension (FD) of the tumor. Tumor FD, density, and size were compared with survival.
Median progression-free survival (PFS) was 4.43 months. Patients were grouped into a favorable PFS (PFS >4.43 months; 9 patients) and an unfavorable PFS group (PFS ≤4.43; 13 patients). The baseline FD on both the AP and PP images was lower in the favorable PFS group than in the unfavorable PFS group (both P = 0.03). There was a significant difference in the change of the FD on the AP image between the favorable and unfavorable PFS groups (P = 0.02). Tumor density and size showed no significant correlations with PFS. In the Kaplan-Meier analysis, patients with tumors showing lower FD on the AP image at baseline showed longer PFS (P = 0.002). Patients with tumors showing a greater reduction in the FD on the PP image after one cycle of the therapy showed longer overall survival (P = 0.002).
The FD of the tumor on CE-CT images may be a useful biomarker for HCC patients treated with sunitinib.
Digestive Diseases and Sciences 02/2014; · 2.26 Impact Factor