Role of metformin in the diagnosis, prevention, and treatment of hepatocellular carcinoma / 中南大学学报(医学版)

Hepatocellular carcinoma is one of the most common malignant tumors in the world. Although there are many options for the treatment of hepatocellular carcinoma, such as surgical resection, interventional therapy, radiotherapy, chemotherapy, targeted therapy and liver transplantation, the poor therapeutic effect seriously reduces the quality of life for patients and also increases the social and economic burden. Metformin is originally used as the first-line drug for type 2 diabetes, but it has been found to play a certain effect in the prevention and treatment of malignant tumor. The potential roles of metformin against hepatocellular carcinoma, such as regulation of the microenvironment, proliferation signal pathway, metabolism, invasion and metastasis, apoptosis, autophagy, and epigenetics of hepatoma cells. It provides a new choice for the prevention and treatment of hepatocellular carcinoma.

Consensus on secondary prevention of primary liver cancer (2021 version) / 中华肝脏病杂志

In order to standardize the effective prevention, early screening and diagnosis of the population at risk of primary liver cancer, the Chinese Society of Hepatology and Chinese Medical Association organized the relevant domestic experts to formulate the "Consensus on Secondary Prevention of Primary Liver Cancer (2021 version)," based on the basic, clinical and preventive research progress, combined with the actual situation at home and abroad, so as to provide an important basis for the prevention, screening and early diagnosis of primary liver cancer in the population of chronic liver disease.

Atividade anticarcinogênica da tributirina associada ou não ao sorafenibe em ratos Fischer-344 implantados com células GP7TB / Evaluation of anticarcinogenic activity associated or not with sorafenib in Fischer-344 rats implanted with GP7TB cells

O câncer primário de fígado (CPF) apresenta mau prognóstico, o que torna importante sua quimioprevenção. Nesse sentido, a tributirina (TB), um pró-fármaco do ácido butírico (AB), presente em laticínios e no mel, mostrou-se um agente quimiopreventivo promissor da hepatocarcinogênese experimental. Os efeitos inibitórios da TB têm sido relacionados à inibição do desenvolvimento de lesões pré-neoplásicas, bem como indução de apoptose e hiperacetilação de histonas. A quimioterapia é uma das abordagens mais comuns para o tratamento de diversos tipos de câncer, inclusive o CPF. Neste caso, o tratamento com sorafenibe (SO) é capaz de prolongar a sobrevida média dos pacientes com a doença em fases avançadas em aproximadamente apenas três meses. Em vista disso, são necessários estudos da associação do sorafenibe com outros compostos que possam aumentar a eficácia do tratamento quimioterápico. Desta forma, a associação de fármacos anti-neoplásicos com compostos bioativos dos alimentos pode consistir em uma estratégia potencial para aumentar a eficácia contra o câncer. No presente estudo, foi avaliada a atividade anticarcinogênica da TB e do SO, isoladamente ou em associação, na etapa de progressão da hepatocarcinogênese. Para tanto, foram realizados implantes singênicos no flanco de ratos Fischer-344 a partir de células da linhagem tumoral GP7TB. Quando as neoplasias atingiram 1 cm3, os animais foram aleatorizados em grupos experimentais: Grupo controle (CO), constituído por 10 ratos Fischer 344 que receberam Maltodextrina (300mg/ 100 g. p. c.), controle isocolarico e solução de etanol à 12,5% e Cremofor à 12,5% em agua estéril; Grupo Tributirina (TB), constituído por 9 ratos Fischer 344 que receberam TB (200mg/ 100 g. p. c.) e solução de etanol à 12,5% e Cremofor à 12,5% em água estéril; Grupo sorafenibe (SO) constituído por 9 ratos Fischer 344 que receberam Maltodextrina (300 mg/ 100 g. p. c.), controle isocalorico e tosilato de sorafenibe (3mg / 100 g. p. c. ) em água estéril; Grupo associação da tributirina com o sorafenibe (AS) constituído por 9 ratos Fischer 344 que receberam TB (20 mg/ 100 g. p. c.) e tosiliato de sorafenibe (3mg/ 100 g. p. c.); tratados por administração intragástrica (i.g) diariamente por 5 semanas consecutivas. As concentrações de AB e SO foram analisadas por cromatografia gasosa associada à espectrometria de massa e as neoplasias foram caracterizadas por imunoistoquímica. Em relação à evolução do tamanho das neoplasias o grupo AS apresentou menor (p=0,009) tamanho das mesmas em relação ao grupo CO. No entanto, estas diferenças não atingiram diferenças significativas (p>0,05) entre os grupos TB e CO, bem como entre os grupos SO e CO. Contudo, quando ajustados os valores do tamanho da neoplasia pela latência, observou-se alterações significativas (p<0,05) nos diversos grupos quando comparados ao grupo CO. O grupo SO aumentou a área necrótica das neoplasias, embora esta diferença não tenha atingido diferença significativa (p>0,05), enquanto que o grupo TB reduziu essa área necrótica em relação ao grupo CO (p=0,005). O grupo TB e AS apresentaram significativamente maiores (p<0,05) concentrações hepáticas e neoplásicas de AB em relação ao grupo CO. O grupo SO e AS apresentaram significativamente maiores (p<0,05) concentrações neoplásicas de SO em relação ao grupo CO. Os grupos SO e AS reduziram a expressão de PTEN, quando comparados ao grupo CO, embora esta diferença não tenha atingido diferença significativa (p>0,05). O grupo TB por sua vez expressou maiores niveis de PTEN, embora esta diferença não tenha atigindo significância estatística (p>0,05). Todos os grupos expressaram maiores niveis de caspase 3 clivada quando comparada ao grupo CO (p>0,05). OS grupos TB e SO reduziram a expressão de pERK ½ quando comparados ao grupo CO. embora estas diferenças não tenham atingidos diferença estatística (p>0,05). O grupo AS apresentou maior expressão de pERK ½ quando comparada ao grupo CO, embora esta diferença não tenha atingido diferença significativa (p>0,05). A caracterização das neoplasias do grupo CO foi padronizada por imunoistoquímica, apresentando-se positivas para CK 7, CK8, CK19 e Arginase e negativas para HepPar1 e CK18. Assim, os resultados sugerem que as neoplasias obtidas por implantes com células da linhagem GP7TB apresentam características de CPF oriundo de células tronco neoplásicas. Além disso, os grupos experimentais TB e AS apresentaram atividade anticarcinogênica promissora no modelo de implantes singênicos com células GP7TB, que eventualmente envolvem mecanismos de ação distintos da atividade quimioterápica apresentada pelo SO

Primary liver cancer (PLC) presents poor prognosis, which makes its chemoprevention important. In this sense, tributyrin (TB), a prodrug of butyric acid (AB), present in dairy products and honey, has been shown to be a promising chemopreventive agent for experimental hepatocarcinogenesis. The inhibitory effects of TB have been related to inhibition of the development of pre-neoplastic lesions, as well as induction of apoptosis and hyperacetylation of histones. Chemotherapy is one of the most common approaches for treating various types of cancer, including PLC. In this case, treatment with sorafenib (SO) is able to prolong the average survival of patients with the disease in advanced stages in approximately three months. In view of this, studies of the association of sorafenib with other compounds that may increase the efficacy of chemotherapeutic treatment are necessary. Thus, the association of anti-neoplastic drugs with bioactive compounds in food may be a potential strategy to increase efficacy against cancer. In the present study, the anticarcinogenic activity of TB and SO was evaluated, alone or in combination, in the progression stage of hepatocarcinogenesis. For this purpose, syngenic implants were performed on the flank of Fischer-344 mice from GP7TB tumor cells. When the neoplasms reached 1 cm3, the animals were randomized into experimental groups: Control group (CO), consisting of 10 Fischer 344 rats receiving Maltodextrin (300mg / 100 g.p.c), isocaloric control and 12.5% ethanol solution, and Cremofor to 12.5% in sterile water; Tributyrin group (TB), consisting of 9 Fischer 344 rats that received TB (200mg / 100 g.p.c.) and 12.5% ethanol solution and Cremofor 12.5% in sterile water; Sorafenib group (SO) consisting of 9 Fischer 344 rats receiving maltodextrin (300 mg / 100 g, w / w), isocaloric control and sorafenib tosylate (3 mg / 100 g, w / w) in sterile water; The association group of tributyrin and sorafenib (AS) consisted of 9 Fischer 344 rats receiving TB (20 mg / 100 g p.o.) and sorafenib tosylate (3 mg / 100 g p.o.); treated intragastric (i.g) daily for 5 consecutive weeks. The concentrations of AB and SO were analyzed by gas chromatography associated with mass spectrometry and the neoplasms were characterized by immunohistochemistry. In relation to the evolution of the size of the neoplasias, the AS group presented smaller (p = 0.009) size of the same ones in relation to the CO group. However, these differences did not reach significant differences (p> 0.05) between the TB and CO groups, as well as between the SO and CO groups. However, when adjusted for size of the neoplasm by latency, significant changes (p <0.05) were observed in the different groups when compared to the CO group. The SO group increased the necrotic area of the neoplasias, although this difference did not reach a significant difference (p> 0.05), while the TB group reduced this necrotic area in relation to the CO group (p = 0.005). The TB and AS groups presented significantly higher (p <0.05) hepatic and neoplastic AB concentrations than the CO group. The SO and AS groups presented significantly higher (p <0.05) neoplastic concentrations of SO in relation to the CO group. The SO and AS groups reduced the PTEN expression when compared to the CO group, although this difference did not reach a significant difference (p> 0.05). The TB group in turn expressed higher levels of PTEN, although this difference did not increase statistical significance (p> 0.05). All groups expressed higher levels of caspase 3 cleaved when compared to the CO group (p> 0.05). The TB and SO groups reduced the expression of pERK ½ when compared to the CO group. although these differences did not reach statistical difference (p> 0.05). The AS group presented higher pERK ½ expression when compared to the CO group, although this difference did not reach a significant difference (p> 0.05). Characterization of the neoplasias of the CO group was standardized by immunohistochemistry, presenting positive for CK 7, CK8, CK19 and Arginase and negative for HepPar1 and CK18. Thus, the results suggest that the neoplasias obtained by implants with GP7TB cells present CPF characteristics originating from neoplastic stem cells. In addition, the experimental groups TB and AS presented promising anticarcinogenic activity in the model of syngeneic implants with GP7TB cells, which eventually involve mechanisms of action distinct from the chemotherapy activity presented by SO

Tratamiento de la hepatitis C en cirrosis: beneficios y riesgos / Treatment of hepatitis C in cirrhosis: risks and benefits

Hepatitis C virus infection is one of the main causes of liver disease affecting more than 180 million of people worldwide. In Chile it affects approximately 50,000 individuals. Chronic infection usually occurs with a long time of symptomless inflammation which defines a high risk of cirrhosis, hepatocellular carcinoma and liver transplantation. Effective antiviral therapy, defined as sustained virologic response (SVR) improves the prognosis of the infected subject. Current treatment regimens with direct acting antivirals have achieved high rates of therapeutic efficacy (SVR > 90 percent in different groups) with an appropriate safety profile. The addition of ribavirin increases the antiviral effect and reduces the duration of therapy. Cirrhotic patients are at greatest risk for developing complications, particularly liver cancer, and they have priority for treatment indication. Classically, cirrhotic show lower rates of effectiveness and high risk of adverse effects, but with the new antivirals, these patients can achieve high recovery rates. Therapy improves liver function and further decreases the viral reinfection after liver transplantation, so cirrhotic patients in the waiting list should be treated unless they have contraindications or high risk of side effects. Effective therapy is also associated with lower risk of developing hepatocellular carcinoma, but cirrhotic patients should keep vigilance programs despite effective treatment.

La infección crónica por virus de la hepatitis C es una de las principales causas de enfermedad hepática a nivel mundial, afectando a más de 180 millones de personas. En Chile, se estima que existen unos 50.000 infectados. La infección habitualmente cursa con largos períodos de inflamación asintomática que determinan un alto riesgo de desarrollo de cirrosis, carcinoma hepatocelular y trasplante hepático. La terapia antiviral efectiva, definida como respuesta viral sostenida (RVS) mejora el pronóstico global de los infectados. Los esquemas terapéuticos actuales, con antivirales de acción directa, han logrado altas tasas de eficacia terapéutica (RVS > 90 por ciento en la mayoría de los grupos) con un adecuado perfil de seguridad. El uso de ribavirina ha logrado potenciar el efecto antiviral y reducir la duración de la terapia. Los pacientes cirróticos son un grupo de mayor riesgo para el desarrollo de complicaciones, particularmente hepatocarcinoma, por lo que tienen prioridad para la indicación de tratamiento. Clásicamente, los cirróticos han tenido menores tasas de efectividad y alto riesgo de efectos adversos, pero con los nuevos antivirales, estos pacientes pueden lograr altas tasas de curación. La terapia mejora la función hepática y adicionalmente disminuye la reinfección viral post trasplante hepático, por lo que todos los cirróticos deberían tratarse pre trasplante, a menos que tengan contraindicaciones o alto riesgo de efectos adversos. La terapia efectiva también se asocia a menor riesgo de desarrollo de hepatocarcinoma, pero los pacientes cirróticos deben mantenerse en programas de seguimiento a pesar de un tratamiento efectivo.

Meta-tyrosine: A powerful anti-metastatic factor with undetectable toxic-side effects

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. While former studies have indicated that T-cell dependent processes mediate CR in hosts bearing immunogenic small tumors, the most universal manifestation of CR induced by immunogenic and non-immunogenic large tumors had been associated with an antitumor serum factor that remained an enigma for many years. In a recent paper, we identified that elusive factor(s) as an equi-molar mixture of meta-tyrosine and ortho-tyrosine, two isomers of tyrosine that are not present in normal proteins and that proved to be responsible for 90% and 10%, respectively, of the total serum anti-tumor activity. In this work, we have extended our previous findings demonstrating that a periodic intravenous administration of meta-tyrosine induced a dramatic reduction of lung and hepatic metastases generated in mice bearing two different metastatic murine tumors and decreased the rate of death from 100% up to 25% in tumor-excised mice that already exhibited established metastases at the time of surgery. These anti-metastatic effects were achieved even at very low concentrations and without displaying any detectable toxic-side effects, suggesting that the use of meta-tyrosine may help to develop new and less harmful means of managing malignant diseases, especially those aimed to control the growth of metastases that is the most serious problem in cancer pathology.

La resistencia concomitante antitumoral (RC) es el fenómeno según el cual un individuo portador de tumor inhibe el crecimiento de implantes tumorales secundarios y metástasis. Si bien desde hace tiempo se sabe que la RC inducida por tumores inmunogénicos de pequeño tamaño es generada por mecanismos inmunológicos dependientes de células T, por otro lado, la manifestación más universal de la RC, generada tanto por tumores inmunogénicos como no-inmunogénicos de gran tamaño, había sido asociada con un (unos) factor sérico antitumoral cuya naturaleza permaneció elusiva por años. En un trabajo reciente, nuestro grupo de trabajo identificó este factor como la mezcla equi-molar de meta-tirosina y orto-tirosina, dos isómeros de tirosina que no están presentes en proteínas normales y que demostraron ser responsables del 90% y 10%, respectivamente, de la actividad antitumoral total del suero. En este trabajo, continuamos nuestras investigaciones demostrando que la administración periódica de meta-tirosina reducía drásticamente el número de metástasis pulmonares y hepáticas en ratones portadores de dos tumores murinos altamente metastásicos y disminuía dramáticamente la mortandad (de 100% a 25%) de ratones con metástasis ya establecidas al momento de la extirpación quirúrgica del tumor. Estos efectos anti-metastásicos se lograron aun con muy bajas concentraciones de meta-tirosina y sin efectos tóxicos perceptibles, lo que sugiere que su uso puede ayudar a diseñar nuevas y menos nocivas estrategias para el tratamiento del cáncer, especialmente aquellas destinadas a controlar el crecimiento metastásico, que es el problema más grave en la enfermedad oncológica.

Imnunosupresión tras el trasplante hepático: más nefrones, menos hepatocarcinoma / Immunosupression after liver transplant: more nephrons, less hepatocellular carcinoma

Following liver transplantation, immunosuppressive drugs are responsible for a significant proportion of the morbidity and mortality. Thus, renal failure and hepatocellular carcinoma recurrence are critically related to the use of immunosuppressive drugs. In this article, the immunosuppressive strategies that allow preservation of the renal function and minimization of the recurrence rate of hepatocellular carcinoma are detailed.

Tras el trasplante hepático, la inmunosupresión es responsable de buena parte de la morbi-mortalidad asociada. El deterioro de la función renal y la recurrencia del hepatocarcinoma son ámbitos donde la inmunosupresión tiene un impacto significativo. En el presente artículo se abordan las estrategias inmunosupresoras que permiten preservar la función renal y minimizar la recurrencia del hepatocarcinoma tras el trasplante hepático.

Evolución clínica de pacientes chilenos con tirosinemia tipo I tratados con 2-(2-nitro-4-trifluorometilbenzoil)-1,3-ciclohexanediona (NTBC) / Clinical follow up of Chilean patients with tyrosinemia type 1 treated with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-ciclohexanedione (NTBC)

Background: Tyrosinemia type I is an inborn error of metabolism due to deficiency of fumarilacetoacetase. Acute presentation is with liver failure, hypophosphatemic rickets and peripheral neuropathy. Chronic presentation is with visceromegaly and subclinical rickets. The most severe complications are hepatic cancer and acute neurological crises. Without treatment, tyrosinemia type 1 is fatal. In 1992 treatment for tyrosinemia type 1 with 2-(2-nitro-4-trifluoromethybenzoyl)-1,3-ciclohexanedione (NTBC) was proposed. A clinical response was reported in 90% of patients. In cases that did not respond, a successful liver transplantation was performed, reducing mortality to 5%. Aim: To report the follow up of 12 patients treated with NTBC. Patients and Methods: Review of clinical records of 12 Chilean cases treated with NTBC at the Instituto de Nutrición y Tecnología de los Alimentos (INTA) from January 2004 until June 2010. Results: In all patients, a rapid metabolic control was achieved. Two patients developed hepatocarcinoma. One of these patients died and one was successfully treated with liver transplantation. One patient died after receiving a liver transplantation. Nine patients have at present good liver function, but 2 had peripheral neuropathy due to late diagnosis and discontinuing NTBC treatment. Conclusions: Treatment with NTBC allows metabolic normalization in tyrosinemia type 1, prevents liver cirrhosis and hepatic cancer, improving survival rates and quality of life in the patients. Neonatal screening is essential for the early diagnosis of this treatable disease, that otherwise may be lethal.

Intravenous KITENIN shRNA Injection Suppresses Hepatic Metastasis and Recurrence of Colon Cancer in an Orthotopic Mouse Model

KITENIN (KAI1 C-terminal interacting tetraspanin) promotes invasion and metastasis in mouse colon cancer models. In the present study, we evaluated the effects of KITENIN knockdown by intravenous administration of short hairpin RNAs (shRNAs) in an orthotopic mouse colon cancer model, simulating a primary or adjuvant treatment setting. We established orthotopic models for colon cancer using BALB/c mice and firefly luciferase-expressing CT-26 (CT26/Fluc) cells. Tumor progression and response to therapy were monitored by bioluminescence imaging (BLI). In the primary therapy model, treatment with KITENIN shRNA substantially delayed tumor growth (P = 0.028) and reduced the incidence of hepatic metastasis (P = 0.046). In the adjuvant therapy model, KITENIN shRNA significantly reduced the extent of tumor recurrence (P = 0.044). Mice treated with KITENIN shRNA showed a better survival tendency than the control mice (P = 0.074). Our results suggest that shRNA targeting KITENIN has the potential to be an effective tool for the treatment of colon cancer in both adjuvant and metastatic setting.

Effect of sustained virologic response on the incidence of hepatocellular carcinoma in patients with HCV cirrhosis

BACKGROUND AND OBJECTIVES: Evidence suggests that sustained virologic response to interferon treatment decreases incidence of hepatocellular carcinoma in patients with hepatitis C virus cirrhosis. This study was designed to compare the incidence of hepatocellular carcinoma among cirrhotic patients exposed to interferon based treatment with or without achieving a sustained virological response, in order to evaluate the role of interferon itself in the prevention hepatocellular carcinoma. METHODS: A cohort of 85 patients with compensated hepatitis C cirrhosis was followed after treatment with interferon and ribavirin. Sustained virological response was defined as negative polymerase chain reaction assay 24 weeks after the end of treatment. Patients were followed every 6 months with ultrasound and alpha-fetoprotein. Hepatocellular carcinoma was diagnosed by the finding of a focal liver lesion greater than 2 cm with arterial hypervascularization on two imaging techniques and/or by liver biopsy. RESULTS: The mean follow-up time was 32.1 ± 20 months for patients who achieved a sustained virological response and 28.2 ± 18 months among 47 patients (55 percent) without SVR. Hepatocellular carcinoma was diagnosed in 1 (3 percent) vs. 8 (17 percent) responders and non responders respectively (p = 0.02). CONCLUSION: Patients with cirrhosis due to hepatitis C virus who achieved sustained virological response had significantly lower incidence of hepatocellular carcinoma when compared to those without treatment response. Interferon treatment without achieving sustained virological response does not seem to protect against hepatocellular carcinoma.

Effects of acetylsalicylic acid and acetic acid solutions on VX2 liver carcinoma in rabbits: in vivo analysis / Efeitos das soluções de aspirina e de ácido acético em fígado de coelhos portadores de tumor hepático VX2. Análise in vivo

PURPOSE: To analyze, in vitro, the effects of acetylsalicylic acid (aspirin) and acetic acid solutions on VX2 carcinoma cells in the liver of rabbits with VX2 hepatic tumors; to determine the histolytic and anatomopathological characteristics of the solutions; and to evaluate the eventual biochemical and hepatic changes. METHODS: A total of 48 rabbits were evaluated. The animals were randomized into two groups, protocol 3 (study group) and protocol 4 (controls), and each group was then subdivided into 3 subgroups. Four days after implantation of the tumor in the liver, median laparotomy was performed with a 0.4-ml injection of a solution of either aspirin (5.0 percent), acetic acid (5.0 percent) or saline. The animals were sacrificed after 24 hours (protocol 3) or after 11 days (protocol 4). Body weight, clinical evolution and biochemical levels, as well as the abdominal and thoracic cavities, were evaluated, and liver microscopy was performed. RESULTS: No changes in clinical evolution, body weight or biochemical levels were reported. However, an increase in alkaline phosphatase was observed in protocol 4 (controls). The tumor was eliminated in both protocols. CONCLUSION: Acetylsalicylic acid and acetic acid solutions cause the destruction of experimental hepatic tumors.

OBJETIVO: Analisar os efeitos das soluções de aspirina e de ácido acético, in vivo, em fígado de coelhos portadores de tumor hepático VX2, verificando o efeito histolítico e anatomo-patológico das soluções e eventuais alterações bioquímicas hepáticas. MÉTODOS: Utilizou-se 48 coelhos, divididos em 2 protocolos experimentais(3 e 4), subdivididos em 3 grupos cada. Após 4 dias da implantação do tumor no fígado, procedeu-se a laparotomia mediana, com injeção de 0,4 ml da solução de aspirina (5,0 por cento), de ácido acético (5,0 por cento) e solução salina; o sacrifício ocorreu apos 24 horas (protocolo 3) e 11 dias (protocolo 4); avaliou-se o peso, evolução clinica, dosagens bioquímicas, cavidade abdominal e torácica e microscopia do fígado. RESULTADOS: Não foram observadas alterações na evolução clinica, peso e nas dosagens bioquímicas, apenas elevação da fosfatase alcalina no grupo controle do protocolo 4. Observamos desaparecimento do tumor em ambos os protocolos. CONCLUSÃO: As soluções de ácido acético e ácido acetilsalicílico acarretam destruição do tumor hepático experimental.

Prevention of Hepatocelluar Carcinoma / 대한소화기학회지

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and has the third highest mortality rate among malignancies in South Korea. Despite the continuing efforts for the early detection of HCC, the mortality rate and prognosis have not been improved yet. Its clinical behavior is quite different from other cancers. High recurrence rate after curative treatment might be the reason for poor prognosis. Several methods including chemoprevention, blocking the development of HCC, have been under investigations. The vaccine for hepatitis, in the form of primary prevention, is considered to be the most effective one inhibiting the development of liver disease. Furthermore, keeping away from hepatotoxic agents is another way for preventing liver cell injuries. Secondary prevention is to stop the developement of HCC in chronic liver diseases. Since the level of DNA in hepatitis B virus (HBV) hepatitis patients is closely related with the development of HCC, it is helpful to lower the DNA level using anti-viral agents. In addition, IFN, one of the anti-viral agents, can inhibit HCV hepatitis from tumorigenesis. Cyclo-oxygenase (COX)-2 inhibitors are also alleged to have a function in interrupting the development of HCC. Tertiary prevention means the prevention of recurrence of HCC after successful treatment. Because of high recurrence rate, the prevention of recurrence should be one of the important factors affecting the prognosis of HCC. Up to now, COX inhibitors, retinoic acids, vitamin K2, glycyrrhizin epigallocatechin-3-gallate (EGCG), and ginseng had been reported to be effective for the chemoprevention of HCC. Further studies are required for an advancement in the prevention of HCC.

A atuação da vitamina A e carotenóides na hepatocarcinogênese / The role of vitamin A and carotenoids in the liver carcinogenesis

O carcinoma hepatocelular (CHC) é um tumor maligno de baixo prognóstico. Evidências demonstrando a relaçãoentre nutrição e risco de desenvolvimento de câncer são freqüentes na literatura. Vários estudos epidemiológicostêm sugerido que o consumo freqüente de alimentos com elevado teor de carotenóides e vitamina A está associadoao risco reduzido de desenvolvimento de certos tipos de neoplasias. Objetivando verificar o volume de evidênciascientíficas da atuação da vitamina A e dos carotenóides no processo de hepatocarcinogênese, foram revisadosdados na literatura. Diversos estudos realizados até o momento apontam os retinóides como agentes que controlamtanto a diferenciação como a proliferação celular, podendo, dessa forma, serem úteis na quimioprevenção docâncer. Os mecanismos propostos pelos quais a vitamina A e os carotenóides exercem sua ação protetora incluemo aumento da função imunológica, dos canais de comunicação intercelular e da atividade antioxidante, apresentando ação inibitória nas lesões pré-neoplásicas. A quimioprevenção por meio da vitamina A ou carotenóides, pode resultar em melhor prognóstico e aumento de sobrevida para população de alto risco, tais como, pacientes com cirrose e CHC.

Symphytum officinale, sua toxicologia e a respectiva patogenesia registrada na literatura homeopatica / Symphytum officinale, its toxicology and respective pathogenesy found in the homeopathic literature

Symphytum officinale, ("confrey"), vegetal largamente utilizado em fitoterapia e, menos frequentemente, em homeopatia, apresenta alcaloides pirrolizidinicos em sua constituicao (licopsamina, intermedina e seus acetil-derivados e, ainda, sinfitina). Tais alcaloides sao hepatotoxicos podendo levar, em doses elevadas, ao surgimento de cancer hepatico. Tendo em vista as restricoes que vem sendo feitas ao uso de Symphytum officinale, mesmo em homeopatia, o autor sugere a retomada do estudo de sua patogenesia, porem, dentro de padroes e/ou protocolos rigidos e modernos

Carcinoma hepatocelular / Hepatocellular carcinoma

O carcinoma hepatocelular (CHC) é um dos tumores malignos mais freqüentes no mundo, sendo considerado pela OMS como problema de Saúde Pública em áreas de grande incidência do tumor, como Africa e Sudeste Asiático. Nesta revisäo seräo discutidos alguns aspectos do CHC, especialmente: a) a estreita relaçäo etiológica com o vírus da hepatite B, o mais universal agente etiológico, mas näo o único, havendo outros carcinogénicos e co-carcinogénicos que participam da gênese do tumor; b) a grande variaçäo na distribuiçäo geográfica do tumor, inclusive no Brasil, onde ele é mais freqüente no Norte e Nordeste; c) a singular associaçäo com a cirrose hepática, observada em todas as regiöes onde o tumor é diagnosticado; d) aspectos morfológicos do CHC, incluindo a nova classificaçäo macroscópica baseada nos padröes de crescimento do tumor e as características dos CHC pequenos; e) as manifestaçöes clínicas e alteraçöes laboratoriais, dando ênfase à avaliaçäo da alfa-feto-proteína, nem sempre elevada nos pacientes com CHC e aos métodos de imagenologia, especialmente a ultra-sonografia, como métodos para o diagnóstico precoce do CHC, o que melhora o prognóstico, sendo importante o seguimento de pacientes de alto risco (cirróticos HBsAg positivos) com aqueles métodos. Finalmente seräo feitos comentários sobre terapêutica, quando esta é possível, e sobre a perspectiva de prevençäo da ocorrência do tumor pelo aumento na utilizaçäo da vacina contra o VHB