Genomic Variations Between Fibrolamellar and Conventional Hepatocellular Carcinomas.

Aim The aim of this study is to define genomic variations between fibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) Methods This study used the American Association for Cancer Research (AACR) Project GENIE data as a foundational element. Specifically, information about both fibrolamellar and conventional hepatocellular carcinoma was retrieved from this database. Results A total of 719 patients diagnosed with HCC and 52 individuals presenting with FL-HCC underwent thorough analysis. Notably, distinct variances in gene alterations were observed between the two cohorts. Predominantly, the HCC group exhibited frequent occurrences of mutations within the TP53 and CTNNB1 genes. Conversely, DNAJB1 fusion was uniquely identified in FL-HCC cases. Conclusion This study significantly broadens our understanding of the genetic makeup associated with FL-HCC and HCC. It is particularly notable because it reveals clear disparities in gene modifications between FL-HCC and HCC. Further investigation is essential to unravel the functional consequences of these genetic variances. This exploration will aid in the development of targeted therapeutic approaches to enhance the prognosis of patients diagnosed with diverse subtypes of HCC.

Atualização das recomendações da Sociedade Brasileira de Hepatologia para o diagnóstico e tratamento do carcinoma hepatocellular / Brazilian society of hepatology updated recommendations for diagnosis and treatment of hepatocellular carcinoma

ABSTRACT Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2015 its first recommendations about the management of HCC. Since then, new data have emerged in the literature, prompting the governing board of SBH to sponsor a single-topic meeting in August 2018 in São Paulo. All the invited experts were asked to make a systematic review of the literature reviewing the management of HCC in subjects with cirrhosis. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of updated recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present manuscript is the final version of the reviewed manuscript containing the recommendations of SBH.

RESUMO O carcinoma hepatocelular (CHC) é uma das principais causas de mortalidade relacionada a câncer no Brasil e no mundo. A Sociedade Brasileira de Hepatologia (SBH) publicou em 2015 suas primeiras recomendações sobre a abordagem do CHC. Desde então, novas evidências sobre o diagnóstico e tratamento do CHC foram relatadas na literatura médica, levando a diretoria da SBH a promover uma reunião monotemática sobre câncer primário de fígado em agosto de 2018 com o intuito de atualizar as recomendações sobre o manejo da neoplasia. Um grupo de experts foi convidado para realizar uma revisão sistemática da literatura e apresentar uma atualização baseada em evidências científicas visando que pudesse nortear a prática clínica multidisciplinar do CHC. O texto resultante foi submetido a avaliação e aprovação de todos membros da SBH através de sua homepage. O documento atual é a versão final que contêm as recomendações atualizadas e revisadas da SBH.

Anaphylaxis preceded by erythema multiforme with sorafenib: First case report.

A 63-year-old female patient with recent diagnosis of hepatitis C and cirrhosis and no other comorbidities, on no medications, was found to have Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma and began systemic therapy with sorafenib 400mg twice daily. Five days after starting treatment, the patient went to an emergency department with pruritic, target-shaped, erythematous papules compatible with erythema multiforme, painful oral aphthous ulcers, and fever. Sorafenib was suspended and the patient underwent oral corticosteroid treatment for 5 days, showing significant improvement of the lesions. One month after discharge, the patient was reassessed at an outpatient clinic. As she was asymptomatic and had no skin lesions, sorafenib was resumed at a lower dose (200mg daily). Three hours after ingesting a single dose of sorafenib, the patient experienced chills, fever, rash, angioedema and stridor. She immediately sought the emergency department and was diagnosed with anaphylaxis. The patient received intravenous corticosteroid therapy, which improved her respiratory and cutaneous symptoms in 72h. Sorafenib was permanently suspended, and regorafenib could not be prescribed as second-line therapy. This is the first description of anaphylaxis to sorafenib.

Controversies in the management of hepatocellular carcinoma.

The management of hepatocellular carcinoma (HCC) has evolved considerably over the last decade. Surveillance of cirrhotic patients and refinements to imaging techniques have enabled a relevant proportion of patients to be diagnosed at an early stage, when effective therapies are feasible. Resection, transplantation and ablation are all options in patients with early stage HCC. Thus, there is some controversy regarding which is the best treatment approach in challenging scenarios. There have also been major developments in locoregional therapies, particularly in intra-arterial approaches. Finally, the systemic treatment for HCC has changed dramatically following the demonstration of a survival benefit with sorafenib; there are currently several first-line (sorafenib and lenvatinib) and second-line (regorafenib, cabozantinib and ramucirumab) treatments that have shown a survival benefit. Expectations for immune checkpoint inhibitors are high, with the results of the ongoing phase III trials eagerly awaited. In this review we discuss some of the controversies in the management of HCC, focussing in particular on systemic therapy.

Is Higher BMI Associated with Worse Overall Mortality in Hepatocellular Carcinoma Patients? An Evidence Based Case Report.

BACKGROUND: liver cancer is currently the second deadliest cancer in the world with hepatocelullar carcinoma (HCC) being the commonest form-accounting 90% of all its cases. With the current global alarming increase of obesity, there is hence an increase of fatty liver disease cases, which is one of the major non-viral etiology of cirrhosis in the world. The objective of this study is to evaluate whether obese HCC patients have worse survival outcome. METHODS: PubMed, Cochrane, Scopus, ProQuest, and EBSCOhost were comprehensively searched for systematic review and cohort prognostic researches studying overall survival of HCC patients who are underweight and obesity according to their BMI. Three studies were selected and critically appraised. Data were then summarized descriptively. RESULTS: the three studies included consist of one meta-analysis and two cohort studies. Meta-analysis study stated no association between overweight and obesity status with higher mortality rate in Asian race HCC patients (aHR, 1.10; 95% CI, 0.63-1.92). A cohort study from Japan reported while there was a significant difference of mortality rate in obese HCC patients in bivariate analysis, adjustment with other important prognostic factors with multivariate analysis found no significant correlation between obesity and HCC-related mortality rate (aHR, 1.00; 95% CI, 0.83-1.22). Another cohort study from China reported that HCC-related mortality rate in patients with higher BMI was lower than in patients with lower BMI (aHR, 0.347; 95% CI, 0.239-0.302). CONCLUSION: there is no association between higher BMI with HCC-related mortality in Asian race patients.

Current allocation policy is favorable for patients with hepatocellular carcinoma waiting for liver transplantation.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) are a growing population of the transplantation waiting list (WL) for orthotopic liver transplantation (OLT). There is no consensus to prioritize these patients while on the WL. AIMS: To assess whether patients with HCC were more prioritized than non-HCC patients based on their WL survival as primary outcome. METHODS: Restrospective cohort study including patients listed for elective OLT from January 2013 to January 2016. RESULTS: 165 patients with cirrhosis were listed for OLT: 64 in the HCC group (38.78%) and 101 in the non-HCC group (61.22%). Outcomes (HCC vs. non-HCC) were: OLT in 75.51% vs. 64.37%; death or dropout due to worsening in 20.41% vs. 27.59%, and delisting because of improvement in 4.08% vs. 8.05%. HCC patients had a significantly higher WL survival rate (HR = 0.45; 95% CI: 0.21-0.96); lower MELD score at transplantation (21 [20-24] vs. 24 [20-30]; p = 0.021); higher delta-MELD - the difference between MELD at transplantation and MELD at listing time - (3 [2-6] vs. 0 [0-5]; p = 0.024) and longer waiting time until OLT (143 [70-233] vs. 67 [21-164] days; p = 0.008). CONCLUSION: Despite having to wait longer, patients with HCC showed higher WL survival than non-HCC patients.

Caracterização do efeito anti-neoplásico do butirato em duas linhagens celulares de rato derivadas de tumores hepáticos com diferente ní­vel de diferenciação / Characterization of the anti-neoplastic effect of butyrate in two mouse cell lines derived from hepatic tumors with different levels of differentiation

O carcinoma hepatocelular (HCC) é uma neoplasia primária com mau prognóstico e alta taxa de recorrência. Estudos recentes demostram que o HCC pode ser classificado em três subtipos segundo o perfil molecular. Destes subtipos, o HCC pouco diferenciado apresenta pior prognostico. Neste sentido, torna-se de particular interesse o estudo de compostos com efeitos diferenciadores e citotóxicos nas células destas neoplasias pouco diferenciadas. O butirato, um ácido graxo de cadeia curta produzido pela fermentação microbiana da fibra alimentar no intestino, tem demonstrado atividade anti-neoplásica e capacidade moduladora da diferenciação celular em diversos tipos celulares, incluindo linhagens de HCC humano e células progenitoras hepáticas. Assim, objetivou-se neste estudo, caracterizar o efeito do butirato de sódio (NaBu) em duas linhagens de células neoplásicas de rato: uma pouco diferenciada (GP7TB) e a outra, uma linhagem derivada de um HCC diferenciado (JM-1). A linhagem GP7TB mostrou maior resistência ao NaBu (ED50= 7,7 mM) do que as células JM-1 (ED50= 5,2 mM). A redução na viabilidade celular após 72 h de tratamento com NaBu esteve relacionada com a diminuição na proliferação celular e no caso das células GP7TB, de um aumento na apoptose. O tratamento com NaBu induziu alterações morfológicas nas duas linhagens celulares, porém apenas nas células do tipo GP7TB, essas alterações sugerem um processo de diferenciação/transdiferenciação celular. O aumento na expressão de genes envolvidos no controle da pluripotência de células tronco, assim como de alguns marcadores de células tronco, sugere que o NaBu induziu uma reprogramação profunda das células GP7TB. Por outro lado, a redução na expressão de genes relacionados com migração e plasticidade celular assim como de proliferação celular apontam que estas células diminuíram seu potencial invasivo e a capacidade de autorenovação. Embora sejam necessárias análises adicionais para confirmar o efeito observado nos perfis de expressão gênica, os resultados deste estudo sugerem que o NaBu apresenta efeito antineoplásico por meio da redução da proliferação, aumento da apoptose e modulação da expressão de genes associados com a transição epitéliomesenquimal em células com características tronco tumorais

Hepatocellular carcinoma (HCC) is a primary neoplasia with poor prognosis and high recurrence rate. Recent evidence suggests that HCC can be classified in three different subtypes based on their molecular profile. Among these subtypes, the poorlydifferentiated HCC has the worst prognosis. Therefore, the study of compounds with pro-differentiating and cytotoxic effects on poorly-differentiated neoplastic cells represents a matter of primary concern. Butyrate which is a short-chain fatty acid produced by microbial fermentation in the intestine, has demonstrated anti-neoplastic activity and pro-differentiating potential in several cell types, including, human HCC cell lines and liver progenitor cells. In this study, we aimed to characterize the effect of sodium butyrate (NaBu) on two neoplastic cell lines derived from rats: a poorlydifferentiated cell line (GP7TB) and, a cell line derived from a well-differentiated HCC. GP7TB showed increased resistance to NaBu treatment (ED50= 7.7 mM) compared to JM-1 (ED50= 5.2 mM). The reduction in cell viability observed after 72 h of treatment was explained by a reduction in cell proliferation and, in the case of GP7TB, by increased levels of apoptosis. The NaBu treatment induced morphological alterations in both cell lines. However, only in the case of GP7TB cells, the alterations suggested a differentiation/transdifferentiation process. The up-regulation of genes involved in pluripotency and genes expressing stem cell markers indicated that NaBu triggered a deep reprogramming of GP7TB cells. Besides, a down-regulation in the expression of genes related with cell migration and plasticity suggested that these cells reduced their invasive potential and their self-renewal capacity. Additional analyses are necessary to confirm the observed effect on gene expression profiles. However, the results of this study suggest that NaBu exert anti-neoplastic effects through apoptosis, reduction of cell proliferation and downregulation of genes associated with epithelial-mesenchymal transition of cancer stem-like cells

Systemic treatment for advanced hepatocellular carcinoma: the search of new agents to join sorafenib in the effective therapeutic armamentarium.

INTRODUCTION: Hepatocelullar carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Despite the implementation of screening programs for high-risk individuals, a significant proportion of patients present with advanced disease at the moment of diagnosis. AREAS COVERED: In this review we will focus in the current treatment of advanced HCC, the research that has been done in the past few years, the achievements and failures in this setting and future perspectives. EXPERT OPINION: Sorafenib was the first drug that has shown to increase survival in patients with advanced hepatocelullar carcinoma with an adequate safety profile. Recently, regorafenib was reported to improve survival in a second line randomised placebo controlled phase 3 clinical trial, which represents a major breakthrough in this field after many disappointing results coming from several clinical trials. However, still there is an unmet need for an effective and tolerable treatment for patients who progressed and/or have intolerance to sorafenib. The ultimate goal of the research is to provide drugs that improve survival with acceptable adverse events. Understanding of mechanisms of hepatocarcinogesis, individualizing therapy according to the profile of the population and finding reliable surrogate end-points for survival for early phase trials with new agents should improve the likelihood of achieving these objectives.

Transplante de fígado em paciente com hepatocarcinoma fibrolamelar - relato de caso / Liver transplantation in patient with fibromellar hepatocarcinoma - case report

O hepatocarcinoma fibrolamelar (HCC-FL), variante do hepatocarcinoma (HCC), é uma neoplasia rara, responsável por 0,6-8,6% das neoplasias de origem no hepatócito. O diagnóstico é feito através de exames de imagem e confirmado pelo exame anatomopatológico. O transplante de fígado (TF) apresenta-se como tratamento curativo do HCC-FL. Neste relato, documentou-se um caso de hepatocarcinoma fibrolamelar irressecável tratado, de maneira curativa, com o transplante de fígado.

Fibrolamellar hepatocelullar carcinoma (FHCC), a variant of conventional hepatocelullar neoplasms originated in the carcinoma, is a rare neoplasm, responsible for 0.8-8.6% of all hepatocarcinomas. Diagnose is performed through image scans and confirmed through the anatomopatological examination. Liver ressection and liver transplantation are shown as a curative treatment for the FHCC. In this report, we documented a case of unresectable fibrolamellar hepatocellular carcinoma curatively treated with liver transplantation.

Hepatectomía derecha extendida con reconstrucción vascular y biliar como tratamiento del hepatocarcinoma fibrolamelar con trombosis portal tumoral e infiltración biliar. Reporte de un caso / Right extended hepatectomy with vascular and biliary reconstruction for fibrolamelar hcc with portal vein thrombosis and biliary infiltration. Case report

El hepatocarcinoma fibrolamelar, es un tumor de ocurrencia esporádica, que se desarrolla sobre la base de un hígado sano, en ausencia de hepatitis viral, alteraciones metabólicas o algún tipode condición inflamatoria en el hígado. Alcanza una supervivencia de hasta un 70% en 5 años en sujetos sometidos a cirugía con márgenes libres de enfermedad y en aquellos en estadios iniciales.Caso clínico: Paciente masculino de 14 años de edad, con clínica de ictericia y aumento de volumen en hipocondrio derecho, estudios de imagen demuestran lesión tumoral de 16 cm que ocupa los segmentos 1,5,6,7, con trombosis tumoral en porta derecha y tronco principal, marcada dilatación de vías biliares. Se practica hepatectomía derecha extendida al lóbulo caudado, con reconstrucción vascular de la vena porta (resección y anastomosis termino-terminal entre el tronco principal y la porta izquierda), resección en bloque de la vía biliar con reconstrucción biliar tipo colangioyeyuno anastomosis al hepático izquierdo. Tiempo quirúrgico 390 minutos, pérdidas sanguíneas estimadas en 1800 ml, estancia en terapia intensiva de 7 días, complicación grado III-A deClavien por colección subdiafragmática y derrame pleural derecho,estancia hospitalaria de 21 días. Resultado histopatológico: hepatocarcinoma fibrolamelar, márgenes de resección libres, trombosis tumoral en vena porta, infiltración tumoral simulando trombosis tumoral en la vía biliar principal y hepático derecho, márgenes de vía biliar libres de enfermedad neoplásica, ausencia de metástasis ganglionar. Recibió adyuvancia con gemcitabina y oxaloplatino (6 ciclos), actualmente 16 meses de seguimiento libre de enfermedad con vida sana(AU)

The fibrolamellar hepatocellular carcinoma it is a rare liver tumor,who growth in normal liver parenquima, in absent of viral hepatitis,metabolic liver disorders or any inflammatory condition, the long term survival can reach up to 70% in 5 years.Clinic case: A 14 years old male, with ictericia, abdominal growth circumference, the US and Abdominal CT revealed: 16cm liver tumor in segments 1,5,6,7, with tumoral thrombus in right portalve in and main trunk, and intrahepatic biliary dilatation. Surgical treatment: Extended right hepatectomy to segment 1, with vascular and biliary reconstruction (resection and anastomosis of portal vein). Operative time: 390 minutes, blood looses 1800 ml, ICU 7 days, total hospital stay 21 days, Clavien III-A complications(abdominal abscess and pleural effusion). Pathological results: Fibrolamellar hepatocellular carcinoma, free margin. Adjuvant therapy based on gemcitabine and oxaloplatin (6 cylcles), actually he is 16 months of follow up, disease free and with a normal life(AU)

Comparison of international guidelines for noninvasive diagnosis of hepatocellular carcinoma.

The aim of this review is to present the similarities and differences between the latest guidelines for noninvasive diagnosis of hepatocelullar carcinoma (HCC) of American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), Asian Pacific Association for the Study of the Liver (APASL), and Japanese Society of Hepatology. All the four guidelines defined a typical HCC vascular pattern as the homogeneous hyperenhancement (wash-in) in the arterial phase followed by wash-out in the venous or late phase. The AASLD and EASL guidelines accept only four-phase computed tomography and dynamic contrast magnetic resonance imaging (MRI) for HCC diagnosis, whereas the APASL and Japanese guidelines also accept contrast-enhanced ultrasound (CEUS). Regarding CEUS, the APASL guidelines accept the use of Levovist or Sonazoid as contrast agents, whereas the Japanese guidelines accept only the use of Sonazoid. The AASLD and EASL guidelines recommend using only extracellular contrast agents such as gadolinium for MRI, whereas the APASL guidelines also included the use of super paramagnetic iron oxid-MRI, and the Japanese guidelines recommended the use of gadolinium-ethoxybenzyl-diethylentriamine pentaacetic acid-MRI. The AASLD and EASL guidelines propos a diagnostic algorithm starting from the tumor size, whereas the APASL and Japanese guidelines recommend an algorithm starting from arterial tumor vascularity (hyper- or hypovascular in the arterial phase). In conclusion, important differences exist among the Western and Eastern guidelines for noninvasive HCC diagnosis.

Intention to treat survival following liver transplantation for hepatocellular carcinoma within a donor service area.

BACKGROUND: This study aimed to assess the impact of wait times on patient survival following liver transplantation for hepatocellular carcinoma (HCC) in a single donor service area. PATIENTS AND METHODS: Patients listed in the New England Organ Bank (NEOB) from 1996 to 2005 for liver transplantation with a diagnosis of HCC were identified from the United Network for Organ Sharing database. The following data were extracted: date of listing, date removed from the wait list, indication for wait list removal, patient death and date of last known follow-up. Kaplan-Meier survival estimates were calculated from the time of listing for transplant (intention to treat liver transplant survival, ITT OLT) and compared to those calculated from the date of transplant (liver transplant, OLT). RESULTS: There were 63 new registrations to the transplant list during the study period. Sixty-one patients were removed from the waiting list: transplanted 41 (65%), death seven (11%), candidate condition deteriorated/too sick to transplant eight (13%), medically unsuitable one (2%), other one (2%), transferred to another center two (3%), and transplanted at another center one (2%). Three-year survival following liver transplantation for primary liver cancer was 85%. When the results were analyzed using an intention to treat analysis there was a 10-20% decrease in survival rate at every time point due to wait list drop-out. CONCLUSION: Wait list drop-out adversely affects liver transplant survival in transplant centers served by the NEOB. These data should be considered when recommending transplant versus resection as first line therapy for stage I or II HCC in our region.

The Clinical Report of 1,078 Cases of Hepatocellular Carcinomas: National Cancer Center Experience / 대한간학회지

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer and the 5 year survival rate is 9.6% in Korea. To develop a strategy for surveillance and treatments, we studied the recent clinical characteristics of HCC diagnosed at single institution in Korea, where is in an endemic area of chronic hepatitis B. METHODS: One thousand and seventy eight patients with HCC who visited the National Cancer Center between June 2001 and December 2003 were retrospectively studied. RESULTS: The male/female ratio was 4.5:1. The mean age of the patients was 56.3 years. 74.2% of patient had hepatitis B virus (HBV) infections, 8.6% had hepatitis C virus (HCV) infections, 6.9% of the patients abused alcohol and 10.3% of the patients had non-B non-C considered as the etiologic factors of their HCC. Only 10.0% of patients had a tumor sized 2 cm or less and 53.3% of patients had a large tumor over 5 cm in diameter. 33.2% of patients had a single tumor. At the time of diagnosis, the modified UICC staging was as follows: 6.5%, 20.1%, 30.9%, 25.2% and 17.3% in stages I, II, III, IVa and IVb, respectively. The initial treatment performed was transcatheter arterial chemoembolization (48.2%), radiofrequency ablation (1.5%), hepatic resection (11.2%), systemic chemotherapy (7.5%), radiotherapy (2.1%), and conservative medical treatments (29.5%). The mean number of treatments was 1.65. The response rates to the initial treatments were 27.9% (complete response), 23.6% (partial response), 7.5% (minimal response), 14.2% (stable disease), and 30.4% (progressive disease). CONCLUSIONS: HBV infection is a major etiologic factor for Korean HCC patients. Most cases are still in advanced stages and these cases responded poorly to any treatments. The national surveillance program and its guideline for HCC are expected to improve the survival of HCC patients.