Progressive Hepatocellular Carcinoma Research Articles

Long-term progression-free survival in a case of hepatocellular carcinoma with vertebral metastasis treated with a reduced dose of sorafenib: Case report and review of the literature

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver. Prognosis and treatment options are stage-dependent. Typically, prognosis of patients with unresectable HCC is poor, particularly for patients with distant metastasis. Sorafenib has demonstrated an overall survival benefit and has become the new standard of care for advanced HCC. However, in metastatic HCC, long-term progression-free survival for five years with reduced doses of sorafenib is extremely rare. In clinical practice, certain patients are discontinuing the use of this drug due to its side-effects. We highlight the importance of prolonged sorafenib administration, even at reduced doses. We describe an unusual case of a 74-year-old patient with HCC metastatic to the vertebrae that responded to a reduced dose of sorafenib and has subsequently demonstrated no signs of disease progression since starting treatment almost five years ago. This suggests that certain patients with highly progressive HCC involving bone metastasis may achieve long-term survival by reduced doses of sorafenib.

Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis

Epigenetic alterations and microRNA (miRNA) deregulation are common in hepatocellular carcinoma (HCC). The histone H3 lysine 27 (H3K27) tri-methylating enzyme, enhancer of zeste homolog 2 (EZH2) mediates epigenetic silencing of gene expression and is frequently up-regulated in human cancers. In this study we aimed to delineate the implications of EZH2 up-regulation in miRNA deregulation and HCC metastasis. Expressions of a total of 90 epigenetic regulators were first determined in 38 pairs of primary HCCs and their corresponding nontumorous livers. We identified EZH2 and its associated polycomb repressive complex 2 (PRC2) as one of the most significantly deregulated epigenetic regulators in primary HCC samples. Up-regulation of EZH2 was next confirmed in 69.5% (41/59) of primary HCCs. Clinicopathologically, EZH2 up-regulation was associated with HCC progression and multiple HCC metastatic features, including venous invasion (P = 0.043), direct liver invasion (P = 0.014), and absence of tumor encapsulation (P = 0.043). We further demonstrated that knockdown of EZH2 in HCC cell lines reduced the global levels of tri-methylated H3K27, and suppressed HCC motility in vitro and pulmonary metastasis in a nude mouse model. By interrogating the miRNA expression profile in EZH2-knockdown cell lines and primary HCC samples, we identified a subset of miRNA that was epigenetically suppressed by EZH2 in human HCC. These included well-characterized tumor-suppressor miRNAs, such as miR-139-5p, miR-125b, miR-101, let-7c, and miR-200b. Pathway enrichment analysis revealed a common regulatory role of these EZH2-silenced miRNAs in modulating cell motility and metastasis-related pathways. Our findings suggest that EZH2 exerts its prometastatic function by way of epigenetic silencing of multiple tumor suppressor miRNAs. Our study demonstrated that EZH2 epigenetically silenced multiple miRNAs that negatively regulate HCC metastasis.

Rapamycin in patients with advanced hepatocellular carcinoma progressing on prior antiangiogenic therapy.

356 Background: PI3K/Akt/mTOR is a critical survival pathway in hepatocellular carcinoma (HCC) often correlated with poor prognosis. Rapamycin (sirolimus) and its analogue everolimus, are specific mTOR inhibitors that showed promising antitumor activity in preclinical models and clinical cases of HCC Aims: To evaluate the safety and efficacy of rapamycin in patients (pts) with advanced HCC after failure or intolerance to prior antiangiogenic therapy Methods: In this retrospective cohort, we analyzed consecutive patients with progressive HCC after 1 to 3 lines of treatment including at least sorafenib. All pts received oral rapamycin at 20 to 30 mg once a week. Adverse events (AEs) were assessed using NCI-CTCAE v3.0, and tumor response was evaluated according to RECIST criteria. Results: Nine patients (F/M: 1/8) with compensated liver cirrhosis (Child A, n = 6; Child B7, n = 2) or no cirrhosis (n=1) and histologically proven HCC were included in this study. Overall, therapy with rapamycin was well tolerated. Most common toxicities were asthenia (grade 1-2: 5 pts) anaemia (all grade: 5 pts; grade 3: 2 pts ) and thrombocytopenia (grade 1-2: 2 pts). Liver function deterioration was observed in 2 pts with advanced cirrhosis (Child B7). Radiological evaluation was available in 6 pts. No objective tumor response was observed however stable disease ≥ 3 months was observed in 4 cases. Moreover, 2 pts showed stable disease at 6 months. Prolonged stabilization under rapamycin was observed in pts who were previously controlled at least for 6 months with sorafenib. Rapamycin was discontinued due to disease progression in 7/8 pts, toxicity in 1/8 pts. One pt shows ongoing long-lasting disease stabilization (8 + months). Conclusions: Rapamycin displayed an acceptable safety profile and may achieved disease stabilization in patients with heavily pretreated advanced HCC.

Risk Factors, Clinical Features, and Prognosis of the Hepatocellular Carcinoma with Peritoneal Metastasis

The clinical features and prognosis of hepatocellular carcinoma (HCC) with peritoneal metastasis have not been fully evaluated. This study aimed to investigate the risk factors, clinical features, and prognosis of HCC with peritoneal metastasis. Patients who were diagnosed as HCC with peritoneal metastasis and the same number of randomly selected, risk factor-matched HCC controls without peritoneal metastasis were included. The risk factors and overall survival were compared between peritoneal metastasis-positive and -negative groups after adjustment of other variables. HCC rupture was an independent risk factor for peritoneal metastasis in HCC patients (P = 0.008). When the risk factors (age, sex, Child-Pugh score, and intrahepatic tumor stage) were matched, peritoneal metastasis failed to independently affect overall survival (P = 0.511). In the peritoneal metastasis-positive group, advanced Child-Pugh class [hazard ratio (HR), 1.99; 95% confidence interval (CI), 1.07-3.72; P = 0.030] and progressive intrahepatic HCC status (HR, 19.04; 95% CI, 2.55-142.13; P = 0.004) were independent risk factors for early death. Complications such as ileus, bleeding, and hydronephrosis due to rectovesical mass were reported in 1.5-7.4% in the peritoneal metastasis-positive group. Peritoneal metastasis was not found to be an independent prognostic factor of HCC, and among HCC patients with peritoneal metastasis, those with advanced Child-Pugh class and with uncontrolled intrahepatic HCC showed poor survival. Therefore, the maintenance of favorable hepatic function and control of intrahepatic HCC should still be emphasized in HCC patients with peritoneal metastasis.

A high level of liver-specific expression of oncogenic KrasV12 drives robust liver tumorigenesis in transgenic zebrafish

SUMMARYHuman liver cancer is one of the deadliest cancers worldwide, with hepatocellular carcinoma (HCC) being the most common type. Aberrant Ras signaling has been implicated in the development and progression of human HCC, but a complete understanding of the molecular mechanisms of this protein in hepatocarcinogenesis remains elusive. In this study, a stable in vivo liver cancer model using transgenic zebrafish was generated to elucidate Ras-driven tumorigenesis in HCC. Using the liver-specific fabp10 (fatty acid binding protein 10) promoter, we overexpressed oncogenic krasV12 specifically in the transgenic zebrafish liver. Only a high level of krasV12 expression initiated liver tumorigenesis, which progressed from hyperplasia to benign and malignant tumors with activation of the Ras-Raf-MEK-ERK and Wnt–β-catenin pathways. Histological diagnosis of zebrafish tumors identified HCC as the main lesion. The tumors were invasive and transplantable, indicating malignancy of these HCC cells. Oncogenic krasV12 was also found to trigger p53-dependent senescence as a tumor suppressive barrier in the pre-neoplastic stage. Microarray analysis of zebrafish liver hyperplasia and HCC uncovered the deregulation of several stage-specific and common biological processes and signaling pathways responsible for krasV12-driven liver tumorigenesis that recapitulated the molecular hallmarks of human liver cancer. Cross-species comparisons of cancer transcriptomes further defined a HCC-specific gene signature as well as a liver cancer progression gene signature that are evolutionarily conserved between human and zebrafish. Collectively, our study presents a comprehensive portrait of molecular mechanisms during progressive Ras-induced HCC. These observations indicate the validity of our transgenic zebrafish to model human liver cancer, and this model might act as a useful platform for drug screening and identifying new therapeutic targets.

Spontaneous Liver Rupture After Treatment With Drug-Eluting Beads

Spontaneous rupture of hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE) is a rare and life-threatening complication. Pathophysiologic mechanisms are not yet fully known; it is suggested that rupture is preceded by reactive tissue edema and intratumerous bleeding, leading to a rapid expansion of tumour mass with risk of extrahepatic bleeding in the case of subcapsular localisation. This case report discusses a sudden, unexpected lethal complication in a 74year-old male patient treated with TACE using DC Bead loaded with doxorubicin (DEBDOX) in a progressive multifocal HCC.

MRI findings of rapidly progressive hepatocellular carcinoma

The purpose of this study is to determine the magnetic resonance imaging (MRI) and patient characteristics in subjects with hepatocellular carcinoma (HCC) that exhibit rapid progression. In this unblinded retrospective study, initial and follow up MR images were reviewed, before and after rapid progression of HCC, respectively. Rapid progression was defined as a lesion <3 cm which exhibited >3 cm increase in one year or 2 cm increase in 6 months. Patient characteristics and MRI findings were determined using clinical information from the institution clinical information system and records from the Radiology and Pathology Departments, Hepatology Division and Liver Transplant Service of the Department of Medicine. Seven individuals were identified with HCC that showed rapid progression. Five of the patients had underlying hepatitis C, one had alcoholic hepatitis, and one had immunosuppression due to liver transplantation. On initial MRI, six patients had early intense ring enhancing lesions, which rapidly progressed in size. Five patients died within 6 months, one within 1 year after progression despite treatment. Six of the seven patients also had multiple other liver nodules on initial MRI; those that showed ring enhancement rapidly progressed but those without, did not show rapid progression. Patients with rapidly progressive HCC had underlying hepatitis C and intense ring enhancement on initial MRI. This group of patients should be evaluated further to determine if they might benefit from early intervention.

Commentary: Sorafenib Use in Patients with Advanced Hepatocellular Carcinoma and Underlying Child-Pugh B Cirrhosis—Evidence and Controversy

Sorafenib (Nexavar ; Bayer HealthCare Pharmaceuticals, West Haven, CT, and Onyx Pharmaceuticals, Emeryville, CA) is a small molecule that inhibits tumor-cell proliferation and tumor angiogenesis by targeting the serine–threonine kinases Raf-1 and B-Raf and the receptor tyrosine kinases of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 and platelet-derived growth factor receptor [1, 2]. Encouraged by the strong rationale of its mechanism of action, promising preclinical data against hepatocellular carcinoma (HCC), and early evidence of antitumor activity from the phase II study [3], the international, phase III, placebo-controlled Sorafenib HCC Assessment Randomized Protocol (SHARP) trial was subsequently conducted [4]. That study demonstrated a longer overall survival (OS) time and time to tumor progression (TTP). The median OS time was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio for the sorafenib group, 0.69; p .001). The median TTP was 5.5 months in the sorafenib group and 2.8 months in the placebo group (p .001). In another randomized phase III study conducted in Asia, sorafenib also demonstrated a longer OS time in patients with advanced HCC [5]. The OS time was 6.5 months in the sorafenib group versus 4.2 months in the placebo group (hazard ratio for the sorafenib group, 0.68; p .014). These studies have led to the approval of sorafenib for the treatment of advanced HCC in the U.S. and many other countries around the world. Most patients with HCC have underlying cirrhosis of various etiologies, including hepatitis B virus, hepatitis C virus, alcohol, nonalcoholic fatty liver disease, and hemochromatosis. Therefore, patients with HCC have competing causes of death from progressive HCC versus worsening underlying cirrhosis. The most commonly used instrument to assess cirrhosis is the Child-Turcotte-Pugh (CTP) score. A systematic review of 118 studies of patients with cirrhosis but no known HCC reported that Child-Pugh class A (CPA) patients have 1-year and 2-year actuarial survival rates of 95% and 90%, versus 80% and 70% in Child-Pugh class B (CPB) patients and 45% and 38% in Child-Pugh class C (CPC) patients, respectively [6]. Recognizing that death from cirrhosis could potentially mask treatmentrelated antitumor efficacy, both of the above phase III studies have elected to target patients with underlying CPA

Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma

The authors conducted a phase 2 trial of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in combination with the gemcitabine plus oxaliplatin (GEMOX) regimen in patients with documented progressive hepatocellular carcinoma (HCC). Forty-five untreated patients with advanced-stage progressive HCC were prospectively enrolled. Treatment consisted of cetuximab at a dose of 400 mg/m2 initially then 250 mg/m2 weekly, plus gemcitabine at a dose of 1000 mg/m2 on Day 1 and oxaliplatin at a dose of 100 mg/m2 on Day 2, every 2 weeks. Treatment was continued until disease progression, unacceptable toxicity, or patient refusal. Overall, 306 cycles were administered. Grade 3 to 4 hematologic toxicity consisted of thrombocytopenia (24%), neutropenia (20%), and anemia (4%). Grade 3 oxaliplatin-induced neurotoxicity occurred in 5 patients (11%) and grade 3 cutaneous toxicity in 7 patients (16%). There were no treatment-related deaths. The confirmed response rate was 20% and disease stabilization was obtained in 40% of patients. The median progression-free and overall survival times were 4.7 months and 9.5 months, respectively. The 1-year survival rate was 40%. In poor-prognosis patients with progressive advanced-stage HCC, the GEMOX-cetuximab combination appears to be active and to have manageable toxicity. A comparative randomized trial is now being planned.

Gemcitabine, oxaliplatin (GEMOX) and cetuximab for treatment of hepatocellular carcinoma (HCC): Results of the phase II study ERGO

4594 Background: A promising efficacy of the GEMOX combination was previously reported in HCC. Moreover, the EGFR signalling pathway is involved in hepatic carcinogenesis and tumor progression. This phase II study of GEMOX plus cetuximab was therefore undertaken in patients with unresectable HCC. Methods: 44 patients were included in the study between November 2005 and October 2006. All patients received cetuximab (initial dose 400 mg/m2 BSA then 250 mg/m2 weekly) combined with GEMOX (gemcitabine 1000 mg/m2, Day 1 and oxaliplatin 100 mg/m2, Day 2), repeated every 14 days until disease progression or limiting toxicity. Inclusion criteria were: histologically proven HCC or morphologically typical hepatic tumor with alpha-feto protein (AFP) level &gt;250 ng/mL, ECOG performance status (PS) 0–2, age =18, measurable lesion, platelets &gt;100.109 G/L, PNN &gt;1.5.109 G/L, creatinine &lt;120 μmol/L, non decompensated Child A or B cirrhosis, documented tumor progression (RECIST), informed consent. Results: 43 patients, including 22 with baseline AFP &gt;400, were evaluable for safety and 35 for efficacy. Patients’ characteristics, toxicity and efficacy are summarized in the table below; 26% of patients received prior intra-arterial chemotherapy. Only one grade 4 toxicity was reported (thrombocytopenia). Grade 3 toxicities were: thrombocytopenia (21%) neutropenia (19%), acneiform rash (19%), asthenia (7%). Grade 2 and 3 neurotoxicity (specific scale) occurred in 16% and 5% of patients, respectively. No toxic death or other severe toxicity was reported. Conclusion: GEMOX plus cetuximab was well tolerated and induced a satisfactory control of disease in progressive HCC. Final results will be presented at the meeting. [Table: see text] No significant financial relationships to disclose.

Metastatic Hepatocellular Carcinoma on the Mandibular Gingival-Case Report

Hepatocellular carcinoma (HCC) is a common tumor in Taiwan. HCC usually causes transvascular metastasis to the lungs, peritoneum, bone, intracelial organs, and adrenal glands, but rarely to the oral tissues. This article reports a case of HCC in a 62-year-old male patient with metastasis to the left posterior mandibular gingiva. The metastatic HCC was totally excised. No evidence of invasion of the mandibular bone was found. Histopathologically, the tumor cells were positive for hepatocyte-specific antigen (HSA) and low-molecular-weight cytokeratin and focally positive for high- molecular-weight cytokeratin, but were negative for α-fetoprotein. The anti-CD31 and anti-CD34 immunostaining highlighted the intervening sinusoidal spaces between the tumor cell nests and trabeculae, and strongly supported the diagnosis of HCC. The patient died of progressive HCC 2.5 months after excision of the oral metastatic tumor, and no recurrence of oral lesion was found. We suggest that the diagnosis of a metastatic HCC requires immunohistochemical studies with a panel of liver-specific antibodies. Hepatocyte-specific antigen is a highly specific marker of HCC. Although tumor cells of HCC are negative for CD 31 and CD34, anti-CD31 and anti-CD34 immunostaining can highlight the growth pattern of HCC and provide support for the diagnosis of HCC.

HBx M130K and V131I (T-A) mutations in HBV genotype F during a follow-up study in chronic carriers

BackgroundAround 400 million people worldwide are chronically infected with Hepatitis B virus (HBV). An estimated 10% of these chronic patients develop progressive liver damage including cirrhosis and Hepatocellular Carcinoma (HCC). The HBx gene encodes a protein of 154 amino acids which is a transactivator and has been associated with HBV pathogenesis. A change in the amino acid sequences at positions 130 and 131 in the HBV-X protein (M130K and V131I) produced by T-A point mutations at the nucleic acids level has been associated with severe liver damage and HCC in patients from China and Africa. Further, such changes have been proposed as a prognostic marker for progressive liver damage and HCC. The purpose of this study was to determine if T-A mutations are present in HBV chronic carriers with genotype F (the major genotype in Costa Rica) and further, if these mutations are associated with HBV disease progression in Costa Rica HBV patients from 1972 to 1985.ResultsSerum samples from 50 HBV positive individuals were amplified and directly sequenced, 48 belonged to genotype F, 1 from genotype D and another was classified as D or E.T-;A mutations were absent in 17 acute patients who recovered, but was present in 12 of 29 chronic carrier samples (42.8%), in one sample the T-A mutations were detected as early as 29 days after clinical onset of disease. In 17 carriers with available liver biopsies, T-;A mutations were found in 8 sera of 13 (61.5%) classified as moderate or severe, and none in 4 biopsies with mild liver damage. However, it was not possible to demonstrate a statistical association between the presence of T-A mutations and moderate/severe liver damage, using a Fischer exact test, 1 tail, p = 0.05.In 4 patients HCC was diagnosed, and 2 of them presented the T-A mutations in their sera.ConclusionT-A mutations were found in HBV genotype F in chronic carriers but not in patients who recovered from acute infection. These mutations could be developing early during infection although the possibility of infection with the mutant virus could not be excluded.More studies are necessary to establish if the T-A mutation can be used as a prognostic marker for severity of liver disease in patients infected with HBV.

Multimodal therapy before liver transplantation for hepatocellular carcinoma

: The use of orthotopic liver transplantation (OLT) for the treatment of patients with hepatocellular carcinoma (HCC) remains controversial because of the risk of both exclusion from the waiting list due to tumor progression and post OLT HCC recurrence. The aim of the present study was to evaluate the effect of an aggressive HCC treatment during the waiting list time on overall and recurrence-free survival of HCC transplanted patients in a single institutional study. : Since 1991, 40 HCC patients joined the OLT-waiting list. Poorly differentiated HCC cases were excluded, while size and number of nodules were not considered as absolute selection criteria. In all, 90% of the study group had HCC treatment while on the waiting list (transarterial chemoembolization, percutaneous therapies, chemotherapy). : Only one patient (2.5%) was removed from the waiting list after developing neoplastic portal thrombosis 3 months after listing, while 33 (82.5%) underwent to OLT after a median waiting list time of 11 months (range 3-16 months). On histological examination, 42% of the group did not meet the "Milan criteria" and 42% were pTNM stages III and IV. The median follow-up was 42 months. The 5-year actuarial survival rate was 64% and recurrence-free survival was 91%. HCC recurred in only two patients (6%). : The use of routine pre-OLT tumor grading and of an aggressive HCC treatment during the waiting list, in our experience, resulted in a very low risk of pre OLT tumor progression leading to exclusion and of post OLT HCC recurrence.

Hepatocellular carcinoma: Clinicopathological aspects

The histopathology and clinical picture of hepatocellular carcinoma (HCC) varies between individual patients and regions. These variations are perhaps due to differences in the genetic alterations that precede hepatocarcinogenesis. In this study, the clinicopathological features of HCC were compared between southern African blacks and Japanese, indicating large differences in the frequency of underlying cirrhosis, grade of cancer cell differentiation and clinical course. Intra-abdominal bleeding and febrile, rapidly progressive HCC are more common among blacks. Such a difference is accounted for, in part, by frequent encapsulation of the tumour which is well differentiated, and grows slowly in an expanding fashion in Japan. Encapsulated HCC was not seen among the black patients studied. Other distinct clinicopathological types discussed in this paper include diffuse-type HCC which is usually caused by multiple portal spread occurring almost simultaneously; the clinical course is fulminant. Sclerosing carcinoma is frequently associated with hypercalcaemia in the United States, but not in Japan. Fibrolamellar carcinoma is nearly non-existent in Asia, whereas it is common among young adults in the West. Its prognosis is generally better than ordinary HCC. Hepatocellular carcinoma has a strong propensity to invade vessel and duct systems. Portal invasion does not produce distinct clinical signs although it may aggravate portal hypertension. Patients with tumour occlusion in the major portal vein may give rise to ischaemic hepatitis when blood pressure drops suddenly in the preterminal stage. Liver parenchyma develops submassive necrosis and clinically there is an acute rise in alanine aminotransferase (ALT). Invasion into a major hepatic vein and the inferior vena cava also occurs, but less frequently compared with portal invasion. The patient can live even with a tumour thrombus in the atrium crossing the tricuspid valves. Intraductal invasion causes acute jaundice as well as an occasional haemobilia with pain. We recently found that a distinct pathological type called 'extrahepatic growth' or 'pedunculated HCC' develops as a result of fusion of right-sided adrenal metastasis of HCC and the liver, perhaps through the 'adreno-hepatic fusion' which is rather common in cirrhotic livers.