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Purpose: To evaluate the safety and effectiveness of yttrium-90 ( 90 Y) radioembolization as first-line treatment for unresectable intrahepatic cholangiocarcinoma (ICC)., Materials and Methods: This prospective study enrolled patients who had never received chemotherapy, liver embolization, and radiation therapy. The tumors were solitary in 16 patients, multiple in 8 patients, unilobar in 14 patients, and bilobar in 10 patients. Patients underwent transarterial radioembolization with 90 Y-labeled glass microspheres. The primary end point was hepatic progression-free survival (HPFS). Secondary end points were overall survival (OS), tumor response, and toxicity., Results: Twenty-four patients (age, 72.3 years ± 9.3; 12 women) were included in the study. The median delivered radiation dose was 135.5 Gy (interquartile range, 77.6 Gy). The median HPFS was 5.5 months (95% CI, 3.9-7.0 months). Analysis failed to identify any prognostic factor associated with HPFS. Imaging response at 3 months showed 56% disease control, and the best radiographic response was 71% disease control. The median OS from the radioembolization treatment was 19.4 months (95% CI, 5.0-33.7). Patients with solitary ICC had significantly longer median OS than patients with multifocal ICC: 25.9 months (95% CI, 20.8-31.0 months) versus 10.7 months (95% CI, 8.0-13.4 months) (P = .02). Patients with progression on the 3-month imaging follow-up had significantly shorter median OS than patients who had stable disease at 3 months: 10.7 months (95% CI, 0.7-20.7 months) versus 37.3 months (95% CI, 16.5-58.1 months) (P = .003). Two (8%) Grade 3 toxicities were reported., Conclusions: First-line treatment of ICC with radioembolization showed promising OS and minimal toxicity, especially in patients with solitary tumor. Radioembolization may be considered as a first-line treatment option for unresectable ICC., (Copyright © 2023 SIR. Published by Elsevier Inc. All rights reserved.)

Introduction: The mainstay pharmacological approaches to patients with hepatocellular carcinoma (HCC) are tyrosine kinase inhibitors, antiangiogenic agents, and immune checkpoint inhibitors in combination therapy. Aberrant signaling of fibroblast growth factor 19 (FGF19) and its corresponding receptor, fibroblast growth factor receptor 4 (FGFR4), are a driver of HCC cell growth and survival. However, the clinical potential of agents targeting aberrant FGF19/FGFR4 signaling has not been adequately explored., Areas Covered: We evaluate the existing literature on aberrant signaling of FGF19/FGFR4 in HCC and address the recent preclinical and clinical advances of selective FGFR4 inhibitors in the treatment of advanced HCC. Our literature search was performed in September 2021 on clinical trials and ongoing studies published in journals or presented in conferences for cancer research., Expert Opinion: Preclinical studies show selective FGFR4 inhibitors to be highly potent. These inhibitors also show promise in clinical trials and demonstrate manageable on-target side effects. An emphasis should be placed on the development of predictive biomarkers and on enhancing the understanding of primary and acquired resistance mechanisms. This will inspire rationale combination therapy strategies for testing in future clinical trials.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide with no clinically confirmed oncogenic driver. Although preclinical studies implicate the FGF19 receptor FGFR4 in hepatocarcinogenesis, the dependence of human cancer on FGFR4 has not been demonstrated. Fisogatinib (BLU-554) is a potent and selective inhibitor of FGFR4 and demonstrates clinical benefit and tumor regression in patients with HCC with aberrant FGF19 expression. Mutations were identified in the gatekeeper and hinge-1 residues in the kinase domain of FGFR4 upon disease progression in 2 patients treated with fisogatinib, which were confirmed to mediate resistance in vitro and in vivo . A gatekeeper-agnostic, pan-FGFR inhibitor decreased HCC xenograft growth in the presence of these mutations, demonstrating continued FGF19-FGFR4 pathway dependence. These results validate FGFR4 as an oncogenic driver and warrant further therapeutic targeting of this kinase in the clinic. SIGNIFICANCE: Our study is the first to demonstrate on-target FGFR4 kinase domain mutations as a mechanism of acquired clinical resistance to targeted therapy. This further establishes FGF19-FGFR4 pathway activation as an oncogenic driver. These findings support further investigation of fisogatinib in HCC and inform the profile of potential next-generation inhibitors. See related commentary by Subbiah and Pal, p. 1646 . This article is highlighted in the In This Issue feature, p. 1631 ., (©2019 American Association for Cancer Research.)

Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients [median duration of response: 5.3 months (95% CI, 3.7-not reached)] and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC. SIGNIFICANCE: Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection. See related commentary by Subbiah and Pal, p. 1646 . This article is highlighted in the In This Issue feature, p. 1631 ., (©2019 American Association for Cancer Research.)

Background: The efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC)., Patients and Methods: Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS)., Results: The estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival., Conclusions: Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC., Trial Registration: ClinicalTrials.gov, NCT01210495., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Involvement of the IVC has traditionally been considered a relative contraindication to resection for advanced tumors of the liver. Combined resection of the liver and IVC for malignancy can be performed safely and results in long-term survival in select patients., Study Design: Sixty patients undergoing hepatic and IVC resection by the primary author from 1996 to 2012 were reviewed. Median age was 52 years. Resections were carried out for cholangiocarcinoma (n = 26), hepatocellular carcinoma (n = 16), colorectal metastases (n = 13), gastrointestinal stromal tumor (n = 2), hepatoblastoma (n = 2), and squamous cell carcinoma (n = 1). Resections performed included 27 right and 5 left trisegmentectomies and 25 right and 3 left lobectomies, including the caudate lobe. Ex vivo procedures were performed in 6 patients using veno-venous bypass and the other 54 procedures were performed using varying degrees of vascular isolation. In situ cold perfusion of the liver was used in 8 patients. The IVC was reconstructed using a tube graft (n = 38) primarily (n = 8) or with patches (n = 14)., Results: There were 5 perioperative deaths (8%). Three patients died of liver failure, 1 patient died of pulmonary hemorrhage, and 1 patient died of massive pulmonary embolism. Nine patients had evidence of postoperative liver failure that resolved with supportive management. Three patients required temporary dialysis. With a median follow-up of 31 months, 14 patients have died of recurrent malignancy between 22 and 44 months, and an additional 4 patients are alive with disease at 16 to 33 months. Actuarial 1- and 5-year survival rates were 89% and 35%, respectively., Conclusions: Inferior vena cava involvement by malignancy does not obviate liver resection. The procedure's increased risk is balanced by the possible benefits, given the lack of alternative curative approaches., (Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Hepatitis C (HCV) is the most common liver disease in patients transplanted with hepatocellular carcinoma (HCC) in the West. We examined predictors of HCC recurrence in liver transplant recipients with HCV., Methods: From 1997 to 2006, 53 patients with HCC and HCV underwent liver transplantation. Pre-and post-operative data (including liver biopsies 4 months post-transplant) were collected. Differences between HCC recurrence and non-recurrence groups were detected by Student's t test or chi-square test. Data were analyzed as predictors of HCC recurrence by logistic regression multivariate analysis. Cumulative survival was analyzed by Kaplan-Meier curves and compared by the log-rank test., Results: Eleven of 53 patients (20.8%) developed HCC recurrence at a median interval of 15 months (2 to 55 months). Median Histology Activity Index (HAI) of liver biopsies, AST, and ALT at 4 months were significantly greater in patients with HCC recurrence. Independent predictors of HCC recurrence were HAI ≥ 4 at 4 months, ALT ≥ 100 at 4 months, and vascular invasion. Patients with HCC recurrence had significantly decreased survival., Conclusions: In this preliminary study, Histology Activity Index and ALT at 4 months, as well as vascular invasion, predicted HCC recurrence in liver transplant recipients with HCV.

Current liver allocation policy in the United States grants liver transplant candidates with stage T2 hepatocellular carcinoma (HCC) a priority Model for End-Stage Liver Disease (MELD) score of 22, regardless of age. Because advanced age may portend an increase in all-cause mortality after transplantation for any diagnosis, the aim of this study was to examine overall posttransplant survival in elderly patients with HCC versus younger cohorts. Based on Organ Procurement and Transplantation Network data, Kaplan-Meier 5-year survival rates were compared. Recipients undergoing primary liver transplantation were stratified into cohorts based on age (<70 or ≥ 70 years) and the receipt of MELD exception points for HCC. Log-rank and Wilcoxon tests were used for statistical comparisons. In 2009, 143 transplants were performed for patients who were 70 years old or older. Forty-two percent of these patients received a MELD exception for HCC. Regardless of the diagnosis, the overall survival rate was significantly attenuated for the septuagenarians versus the younger cohort. After 5 years of follow-up, this disparity exceeded 10% to 15% depending on the populations being compared. The 1-, 2-, 3-, 4-, and 5-year actuarial survival rates were 88.4%, 83.2%, 79.6%, 76.1%, and 72.7%, respectively, for the patients who were younger than 70 years and 81.1%, 73.8%, 67.1%, 61.9%, and 55.2%, respectively, for the patients who were 70 years old or older. Five-year survival was negatively affected for patients with HCC who were younger than 70 years; this disparity was not observed for patients with HCC who were 70 years old or older. In conclusion, although patients who are 70 years old or older compose a small fraction of transplant recipients in the United States, patients in this group undergoing transplantation for HCC form an even smaller subset. Overall, transplantation in this age group yields outcomes inferior to those for younger cohorts. However, unlike patients who are less than 70 years old and receive MELD exception points, overall liver transplant survival is not affected by HCC at an advanced age., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background: Combined resection of both the liver and pancreas for malignancy remains a controversial procedure. To many, the need for such an extended procedure implies an extent of disease that is usually not amenable to surgical control, and the extent of the procedure exposes the patients to substantial operative risks. The purpose of this study was to assess our results with combined resection of the liver and pancreas., Study Design: Forty patients underwent combined liver and pancreas resection from 1996 to 2009. Patient ages ranged from 39 to 69 years (mean 53 years). Underlying diagnoses were neuroendocrine tumor (13), cholangiocarcinoma (13), gallbladder carcinoma (9), gastrointestinal stromal tumor (3), colorectal cancer (1), and metastatic ocular melanoma (1). Pancreatic resections included 26 pancreaticoduodenectomies (PD) and 14 distal pancreatic resections. Liver resections included 18 trisectionectomies (13 right, 5 left), 10 lobectomies (8 right, 2 left), and 12 segmental resections., Results: There was no perioperative mortality. One patient who underwent PD with right trisegmentectomy for gallbladder cancer developed postoperative liver failure that improved with supportive management. Two patients developed bile leaks that resolved with conservative management. One patient developed a pancreatic leak/hemorrhage and required a completion pancreatectomy. Mean hospital stay was 14 days (range 7 to 42 days). Median follow-up was 30 months (range 3 to 76 months). Patients undergoing resection for neuroendocrine tumors had a better 5-year survival than those with hepatobiliary malignancies (100% vs 37% p = 0.01)., Conclusions: Combined resection of the liver and pancreas can be performed safely. The need for combined partial hepatectomy and pancreatectomy to remove malignancy should not be considered a contraindication to resection in selected patients., (Copyright 2010 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

We present a case of a 10-month-old boy with BA who developed HCC and was treated with liver transplantation. A four-month-old boy was referred to our institution because of persistent jaundice, hepatomegaly, and coagulopathy. He had been treated for the diagnosis of neonatal hepatitis at an outside hospital. He was evaluated and was accepted as a liver transplant candidate, and was subsequently transplanted with a deceased donor liver allograft at the age of 10 months. His native liver showed established cirrhosis because of BA with one focus of moderately differentiated HCC, measuring 0.7 cm in a diameter with microscopic vascular invasion in pathological study. The postoperative course was uneventful, and he is well without recurrence four months after liver transplantation. The occurrence of HCC in a child under one yr old is extremely rare, and only three cases are reported so far including our case.

Purpose: 17-(demethoxy), 17-allylamino geldanamycin (17-AAG) suppresses growth in some cancers by inhibiting Heat shock protein 90 (Hsp90). We examined the effects of 17-AAG-mediated Hsp90 inhibition on human hepatocellular carcinoma (HCC) growth in vitro and in vivo., Methods: Human HCC cell lines, Hep3B and HuH7, were exposed to 17-AAG and cell viabilities and apoptosis were determined. Cell cycle profiles were analyzed and the G(2)/M cell cycle checkpoint proteins cdc2 and cyclin B1 were examined. Studies were performed to determine whether 17-AAG-mediated cdc2 decrease was due to altered gene expression, transcription, or protein degradation. The effects of 17-AAG on Hep3B and HuH7 xenograft growth in athymic nude mice were also examined., Results: Hep3B and HuH7 treated with 17-AAG versus untreated controls showed decreased cell viability and increased apoptosis. Cells treated with 17-AAG also showed an increased fraction in G(2)/M phase and an associated decrease in cdc2 through protein degradation rather than through other mechanisms. Hsp90 inhibition by 17-AAG also decreased HCC xenograft growth in association with decreased cdc2 expression., Conclusions: 17-AAG-mediated inhibition of Hsp90 abrogates human HCC cell growth in vitro and in vivo through cdc2 decrease, which in turn induces G(2)/M cell cycle arrest and apoptosis. Hsp90 is a mediator of HCC growth and survival and its inhibition may serve as a potential treatment.

Management of hepatocellular carcinoma in the early cirrhotic remains controversial. The exact role of liver transplantation versus resection remains to be determined. The following short review attempts to present the evidence for the respective roles of liver transplantation versus liver resection in early stage HCC.

Background: The definition of what is unresectable in liver surgery is controversial. Problems that many believe render patients unresectable can currently be resected using advanced techniques of liver surgery. This study assesses liver resection in patients who were unresectable with standard liver resection but were potentially resectable using an aggressive approach to liver surgery., Study Design: From 1997 to 2007, 830 adult patients undergoing hepatectomy were reviewed. Patients were categorized as having unresectable disease by standard resection if the disease could not be resected without resection of the IVC, hepatic vasculature, or because of tumor extent., Results: One hundred sixteen patients were initially believed to have unresectable disease but went on to laparotomy. Eighteen patients were unresectable at operation, although 98 patients were resected. Seventy-eight trisectionectomies; 18 lobectomies; 1 mesohepatectomy; and 1 segment 5, 6 resection, combined with pancreaticoduodenectomy, nephrectomy, and colectomy, were performed. Fourteen patients also had pancreatic resections. Vascular reconstructions were performed on the IVC (n = 35), hepatic veins (n = 21), portal vein (n = 34), and hepatic artery (n = 5). Hypothermic perfusion of the liver was used in 12 patients (4 ex vivo, 8 in situ cold perfusion). Patients undergoing resection had 6% mortality with a morbidity of 35%. Median survival was 37 months (95% CI, 34-42 months). Five-year actuarial survival was 32%., Conclusions: Patients with liver tumors considered "unresectable" by standard liver resection should be considered for resection with an aggressive approach to liver surgery. Five-year survival of approximately one-third of patients can be expected.

Background: Patients with hepatic and pulmonary metastases from colorectal cancer (CRC) may benefit from aggressive surgical therapy. We examined the longterm outcomes of patients who underwent both lung and liver resections for colorectal metastases over a 10-year period., Study Design: Four hundred twenty-three hepatectomies were performed for metastatic CRC between 1992 and 2002 at two university-affiliated hospitals. Patients who underwent both lung and liver resections for metastatic CRC were studied. Demographic, perioperative, and survival data were evaluated by retrospective chart review. Disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier analysis and survival curves were compared using the log-rank test., Results: Thirty-nine patients underwent both lung and liver resections for metastatic CRC. Eleven patients (28%) underwent staged liver and lung metastasectomy from synchronously identified metastases. Twenty-eight patients (72%) underwent sequential metastasectomy because of recurrent disease. The median disease-free and overall survivals after initial metastasectomy were 19.8 and 87 months, respectively. Serial metastasectomy was common in this patient population. The mean number of metastasectomies performed was 2.6 per patient (range 1 to 4). There was no difference in overall survival for patients with synchronous versus metachronous presentation of liver and lung metastases (p=0.45). The site of first recurrence after initial metastasectomy was, most commonly, the lung (n=19, 49%), followed by the liver (n=8, 21%). Nineteen patients (49%) underwent subsequent resections for recurrences. Seven patients (18%) underwent 2 or more liver resections for recurrent disease, and 12 (31%) underwent multiple lung resections., Conclusions: An aggressive multidisciplinary surgical approach should be undertaken for recurrent CRC metastases. In selected patients, serial metastasectomy for recurrent metastatic disease is safe and results in excellent longterm survival after CRC resection.

Background: Early recurrence (ER) (<1 year) after liver resection is one of the most important factors that impact the prognosis of patients with hepatocellular carcinoma (HCC). We sought to determine factors associated with ER of HCC and examine the outcomes thereafter., Study Design: From March 2001 to June 2003, 56 patients underwent hepatic resection for HCC at University of Toronto and were prospectively followed with median followup of 24 months. Patients with ER were compared with those who remained disease free for more than 1 year. Patient characteristics, tumor stage, and operative procedures were evaluated for their prognostic significance by univariate and multivariable analysis. Time to recurrence and time to death were analyzed using Kaplan-Meier survival curves and compared using log-rank analysis., Results: The initial procedure in all patients was surgical hepatectomy. ER occurred in 21 patients (38%), 31 (55%) remained disease free for more than 1 year, and 4 (7%) were omitted from evaluation because of early (<30 days) death. Median survival after initial hepatic resection for those with ER was 27 months, and 2-year survival was 54%. There were no deaths in the group that remained disease free for more than 1 year (100% 2-year survival, p < 0.05). By multivariate analysis, vascular invasion and positive microscopic margins were significant predictors when all 4 variables were considered in the model (p < 0.05). After ER, 11 of 21 patients (52%) underwent additional therapy with significant improvement in median survival (33 months) compared with those not eligible for conventional therapy (18 months, p = 0.05)., Conclusions: ER after liver resection for HCC is the leading cause of death during the first 2 years after potentially curative resection. ER will develop in approximately 75% of patients with either vascular invasion or positive margins. For patients with these predictive factors additional treatment might be advised.

Background: Surgical resection and liver transplantation remain the only treatments that offer cure for hepatoma, but are limited to those with early stage disease. Prelisting radiological staging is not always definitive. In this study, we sought to delineate the role of laparoscopy for clarification of staging in advanced cirrhotic patients when radiological assessment during evaluation for orthotopic liver transplants (OLTx) is equivocal., Methods: Over a 3-year period, 18 patients with advanced liver insufficiency being evaluated for OLTx listing underwent laparoscopic staging when the following criteria were met: (1) lesion(s) with indeterminate size/borders, (2) an indeterminate number of lesions, or (3) lesion(s) and alpha-fero protein (AFP) less than 100 ng/ml. Patients underwent exploratory laparoscopy and laparoscopic ultrasound with biopsy, with or without ablation of lesion(s)., Results: Laparoscopic staging was initiated in 18 patients; four of the first six patients were converted to open procedures. Twelve patients were restaged as a result of the procedure: six down-staged and six up-staged. Stage changes were based on laparoscopic visualization of advanced disease in two, ultrasonographic clarification of tumor size/number in seven, and biopsy in three. Twelve of the 14 laparoscopic procedures included laparoscopic radiofrequency ablation while one received ethanol ablation. One patient required 2 units of red blood cells. One patient died on postoperative day 7 because of gastrointestinal bleeding. Four of the six down-staged patients underwent liver transplant, and pathological staging of the explants agreed with laparoscopic staging in all cases., Conclusion: Laparoscopic staging for HCC in advanced cirrhosis can clearly characterize tumor burden when preoperative radiological assessment is equivocal.

Background: Following hypoosmotic stress-induced cell volume change, the actin cytoskeleton reorganizes itself. The role of this reorganization in the activation of the phosphatidylinositol 3-OH-kinase/protein kinase B/activator protein 1 (PI-3-K/PKB/AP-1) proliferative signaling cascade is unknown. Focal adhesion kinase (FAK) participates in the cytoskeleton-based activation of PI-3-K. We hypothesized that hypoosmotic stress-induced activation of PKB and AP-1 in HepG2 cells is dependent on an intact actin cytoskeleton and subsequent FAK phosphorylation., Methods: HepG2 cells were incubated for 1 h with or without 20 microM cytochalasin D, an actin disrupter, and were then exposed for up to 30 min to hypoosmotic medium (200 mOsm/L) to induce swelling. Tumor necrosis factor alpha (1.4 nM) and medium alone served as positive and negative controls, respectively. Western blots measured cytoplasmic phosphorylated or total FAK and PKB. EMSAs measured nuclear AP-1. All experiments were performed in triplicate., Results: Exposure to hypoosmotic stress resulted in activation of the following signaling messengers in a sequential fashion: (1) phosphorylation of FAK occurred by 2 min, (2) phosphorylation of PKB occurred by 10 min, (3) nuclear translocation of AP-1 occurred by 30 min. All three signaling events were abolished when these cells were pretreated with cytochalasin D., Conclusion: Actin reorganization following hypoosmotic stress is essential for the FAK-mediated activation of the PI-3-K/PKB/AP-1 proliferative cascade. These data delineate a possible mechanism by which the cell swelling-induced cytoskeletal changes can initiate proliferative signal transduction in human liver cancer., (Copyright 2001 Academic Press.)