ABSTRACT Intrahepatic biliary proliferations represent a spectrum from reactive (ductular reaction, some with atypical architecture), hamartomatous (von Meyenburg complex), benign (bile duct adenoma) and precursor/borderline entities (biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct) to fully malignant (cholangiocarcinoma) neoplasms. Clinical pictures and even imaging patterns may be similar, requiring refined studies aiming at histopathological and immunohistochemistry for more precise diagnosis, essential for correct patient management. This article discusses updated concepts and definitions of most relevant entities aiming more specifically at the differential diagnosis in practice, focusing on morphology and immunohistochemistry, with a discussion of potential markers to help distinguishing between benign and malignant lesions.

RESUMO As proliferações biliares intra-hepáticas representam um espectro que abrange desde entidades reativas (reação ductular, algumas com arquitetura atípica), hamartomatosas (complexo de von Meyenburg), benignas (adenoma de ductos biliares) e precursoras/limítrofes (neoplasia intraepitelial biliar, neoplasia papilar intraductal de ducto biliar) até neoplasias totalmente malignas (colangiocarcinoma). Os quadros clínicos e até mesmo os padrões de imagem podem ser semelhantes, exigindo estudos refinados visando critério histológicos e imuno-histoquímicos para diagnósticos mais precisos, essenciais para o correto manejo do paciente. Este artigo discute conceitos atualizados e definições das entidades mais relevantes visando mais especificamente ao diagnóstico diferencial na prática, com foco na morfologia e imuno-histoquímica, com discussão de potenciais marcadores para ajudar na distinção entre lesões benignas e malignas.

ABSTRACT BACKGROUND: Peritoneal carcinomatosis in gastric cancer is considered a fatal disease, without expectation of definitive cure. As systemic chemotherapy is not sufficient to contain the disease, a multimodal approach associating intraperitoneal chemotherapy with surgery may represent an alternative for these cases. AIMS: The aim of this study was to investigate the role of intraperitoneal chemotherapy in stage IV gastric cancer patients with peritoneal metastasis. METHODS: This study is a single institutional single-arm prospective clinical trial phase II (NCT05541146). Patients with the following inclusion criteria undergo implantation of a peritoneal catheter for intraperitoneal chemotherapy: Stage IV gastric adenocarcinoma; age 18–75 years; Peritoneal carcinomatosis with peritoneal cancer index<12; Eastern Cooperative Oncology Group 0/1; good clinical status; and lab exams within normal limits. The study protocol consists of four cycles of intraperitoneal chemotherapy with paclitaxel associated with systemic chemotherapy. After treatment, patients with peritoneal response assessed by staging laparoscopy undergo conversion gastrectomy. RESULTS: The primary outcome is the rate of complete peritoneal response. Progression-free and overall survivals are other outcomes evaluated. The study started in July 2022, and patients will be screened for inclusion until 30 are enrolled. CONCLUSIONS: Therapies for advanced gastric cancer patients have been evaluated in clinical trials but without success in patients with peritoneal metastasis. The treatment proposed in this trial can be promising, with easy catheter implantation and ambulatory intraperitoneal chemotherapy regime. Verifying the efficacy and safety of paclitaxel with systemic chemotherapy is an important progress that this study intends to investigate.

RESUMO RACIONAL: A carcinomatose peritoneal no câncer gástrico é considerada uma doença fatal, sem expectativa de cura definitiva. Como a quimioterapia sistêmica não é suficiente para conter a doença, uma abordagem multimodal associando a quimioterapia intraperitoneal à cirurgia pode representar uma alternativa para esses casos. OBJETIVOS: Investigar o papel da quimioterapia intraperitoneal em pacientes com câncer gástrico estágio IV com metástases peritoneais. MÉTODOS: Trata-se de um ensaio clínico prospectivo unicêntrico, braço único, fase II (NCT05541146). Pacientes com os seguintes critérios de inclusão serão submetidos à implantação de cateter peritoneal para quimioterapia intraperitoneal: adenocarcinoma gástrico estágio IV; idade 18-75 anos; carcinomatose peritoneal com índice de câncer peritoneal<12; ECOG 0/1; bom estado clínico e exames laboratoriais dentro da normalidade. O protocolo do estudo consiste em 4 ciclos de quimioterapia intraperitoneal com Paclitaxel associado à quimioterapia sistêmica. Após o tratamento, os pacientes com resposta peritoneal avaliada por laparoscopia serão submetidos à gastrectomia de conversão. RESULTADOS: O desfecho primário é a taxa de resposta peritoneal completa. A sobrevida livre de progressão e global são outros desfechos avaliados. O estudo foi iniciado em julho de 2022 e os pacientes serão selecionados para inclusão até que 30 sejam inscritos. CONCLUSIONS: Terapias para pacientes com câncer gástrico avançado foram avaliadas em ensaios clínicos, mas sem sucesso em pacientes com metástase peritoneal. O tratamento proposto neste estudo pode ser promissor, com fácil implantação do cateter e regime de quimioterapia intraperitoneal ambulatorial. Verificar a eficácia e segurança do Paclitaxel associado à quimioterapia sistêmica é um progresso importante que o presente estudo pretende investigar.

RESUMO - RACIONAL: Pelo menos 12 linfonodos (LNs) devem ser examinados após a ressecção cirúrgica do câncer de cólon. Como é difícil encontrar LNs pequenos, fixadores de clareadores de gordura foram propostos, mas não há consenso sobre a melhor opção. OBJETIVO: Verificar se a solução de Carnoy (SC) aumenta o número de LNs obtidos em espécimes de câncer de cólon esquerdo. MÉTODOS: Ensaio prospectivo randomizado (clinictrials.gov: NCT02629315) com 60 pacientes com adenocarcinoma de cólon esquerdo submetidos à retossigmoidectomia. As amostras foram randomizadas para fixação com SC ou formalina tamponada neutra a 10% (NBF). Após a dissecção, a gordura pericólica do grupo NBF foi imersa em SC e redissecada (Revisão). O endpoint primário foi o número total de LNs recuperados. RESULTADOS: O número médio de LNs foi de 36,6 e 26,8 para os grupos CS e NBF, respectivamente (p=0,004). O número de casos com <12 LNs foi 0 (CS) e 3 (NBF, p=0,237). A duração da dissecção foi semelhante. LNs foram recuperados em todos os casos durante a revisão (média de 19, intervalo: 4-37), representando quase 40% dos LNs deste braço do estudo. Após a revisão, nenhum caso no braço NBF permaneceu com <12 LNs. Dois pacientes tiveram LNs metastáticos encontrados durante a revisão (não ocorreu upstaging). CONCLUSÃO: Em comparação com NBF, a SC aumenta a contagem de LNs em espécimes de câncer de cólon. Após a análise patológica convencional, a fixação da gordura pericólica com SC e a realização de uma segunda dissecção aumentaram o número de LNs.

ABSTRACT - BACKGROUND: At least 12 lymph nodes (LNs) should be examined following surgical resection of colon cancer. As it is difficult to find small LNs, fat clearing fixatives have been proposed, but there is no consensus about the best option. AIM: The objective of this study was to verify if Carnoy’s solution (CS) increases the LN count in left colon cancer specimens. METHODS: A prospective randomized trial (clinicaltrials.gov registration: NCT02629315) with 60 patients with left colon adenocarcinoma who underwent rectosigmoidectomy. Specimens were randomized for fixation with CS or 10% neutral buffered formalin (NBF). After dissection, the pericolic fat from the NBF group was immersed in CS and re-dissected (Revision). The primary endpoint was the total number of LNs retrieved. RESULTS: Mean LN count was 36.6 and 26.8 for CS and NBF groups, respectively (p=0.004). The number of cases with <12 LNs was 0 (CS) and 3 (NBF, p=0.237). The duration of dissection was similar. LNs were retrieved in all cases during the revision (mean: 19, range: 4-37), accounting for nearly 40% of the LNs of this arm of the study. After the revision, no case was found in the NBF arm with <12 LNs. Two patients had metastatic LNs during the revision (no upstaging occurred). CONCLUSION: Compared to NBF, CS increases LN count in colon cancer specimens. After conventional pathologic analysis, fixing the pericolic fat with CS and performing a second dissection substantially increased the number of LNs.

RESUMO - RACIONAL: Apesar do avanço nas terapias, o prognóstico de pacientes com câncer gástrico (CG) avançado permanece ruim. Vários estudos demonstraram a expressão do receptor de estrogênio alfa (REa), porém seu significado no CG permanece controverso. OBJETIVO: relatar uma série de casos de CG com expressão de REa-positivo, e descrever suas características clínicopatológicas e prognóstico. MÉTODOS: Avaliamos retrospectivamente os pacientes com CG submetidos à gastrectomia com intenção curativa entre 2009 e 2019. A expressão do REa foi avaliada por imuno-histoquímica por meio da construção de microarranjos de tecido (TMA). Pacientes com adenocarcinoma gástrico ERa-negativos serviram como grupo comparação. RESULTADOS: No período selecionado, foram identificados 6 (1,8%) CG REa-positivos entre os 345 CG analisados. Todos os ERa-positivos eram homens, com idades entre 34-78 anos, tinham CG do tipo difuso de Lauren e pN+. Comparado aos REa-negativos, os CG REa-positivos associaram-se a maior diâmetro (p=0,031), gastrectomia total (p=0,012), tipo de Lauren difuso/misto (p=0,012), presença de invasão perineural (p=0,030) e metástase linfonodal (p=0,215). O estágio final foi o IIA em um caso; IIIA em três e IIIB em dois casos. Entre os 6 pacientes REa -positivos, 3 tiveram recorrência da doença (peritoneal) e morreram. Não houve diferença significativa na sobrevida entre os grupos REa-positivo e negativo. CONCLUSÃO: A expressão do REa é menos comum no CG, estando associada à histologia difusa e presença de metástases linfonodal, podendo servir como um marcador relacionado à progressão tumoral e pior prognóstico. Além disso, uma alta taxa de recorrência peritoneal foi observada em pacientes ERa-positivos.

ABSTRACT - BACKGROUND: Despite advances in therapies, the prognosis of patients with advanced gastric cancer (GC) remains poor. Several studies have demonstrated the expression of estrogen receptor alpha (ERa); however, its significance in GC remains controversial. AIM: The present study aims to report a case series of GC with ERa-positive expression and describe their clinicopathological characteristics and prognosis. METHODS: We retrospectively evaluated patients with GC who underwent gastrectomy with curative intent between 2009 and 2019. ERa expression was assessed by immunohistochemistry through tissue microarray construction. Patients with ERa-negative gastric adenocarcinoma served as a comparison group. RESULTS: During the selected period, 6 (1.8%) ERa-positive GC were identified among the 345 GC patients analyzed. All ERa-positive patients were men, aged 34-78 years, and had Lauren diffuse GC and pN+ status. Compared with ERa-negative patients, ERa-positive patients had larger tumor size (p=0.031), total gastrectomy (p=0.012), diffuse/mixed Lauren type (p=0.012), presence of perineural invasion (p=0.030), and lymph node metastasis (p=0.215). The final stage was IIA in one case, IIIA in three cases, and IIIB in two cases. Among the six ERa-positive patients, three had disease recurrence (peritoneal) and died. There was no significant difference in survival between ERa-positive and ERa-negative groups. CONCLUSIONS: ERa expression is less common in GC, is associated with diffuse histology and presence of lymph node metastasis, and may be a marker related to tumor progression and worse prognosis. Also, a high rate of peritoneal recurrence was observed in ERa-positive patients.

ABSTRACT Hepatitis E Virus (HEV) is an infection known worldwide for its asymptomatic and self-limited course in most cases. Some cases progressing to chronicity have been described in immunosuppressed patients, especially in recipients of solid organ transplants. We evaluated laboratory parameters of HEV infection (HEV RNA, anti-HEV IgM and anti-HEV IgG) through enzyme-linked immunosorbent assay (Elisa), confirmed by immunoblotting, in a cohort of 294 patients who received liver transplants at the HCFMUSP (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo). Laboratory and demographic data were collected from the entirety of the transplanted population. Hepatic biopsies of 122 patients transplanted due liver failure secondary to hepatitis C (HCV), with or without serological or molecular markers of HEV, were analyzed according to METAVIR score. Out of 24 (8.2%) patients tested positive for anti-HEV IgG, six (2%) were positive for anti-HEV IgM and 17 (5.8%) for HEV RNA. Of the patients transplanted because of HCV infection, 95 (77.8%) had received treatment including ribavirin for at least six months before blood sample collection. Among patients transplanted due to HCV cirrhosis who tested positive for anti-HEV IgG, only three (37.5%) showed fibrosis beyond stage 2, while five (41.7%) of the HEV RNA-positive patients had liver fibrosis beyond stage 2. Overall, the prevalence of HEV in the post-hepatic transplant scenario appears to be low, and, at least histologically, seemingly not harmful. We conclude that, although some studies reported a risk of HEV chronification, patients who had their livers transplanted due to HCV and showed serological or molecular markers of HEV did not have higher levels of fibrosis compared to patients who showed no indications of HEV infection at the time of the analysis.

RESUMO Racional: A presença de metástase em linfonodos é um dos indicadores prognósticos mais importantes no câncer gástrico. As micrometástases têm sido estudadas como fator prognóstico no câncer gástrico, sendo relacionadas à diminuição da sobrevida global e aumento do risco de recidiva da doença. Entretanto, sua identificação é limitada pela metodologia convencional, uma vez que podem não ser identificadas pela rotina histopatológica por meio da coloração de H&E. Objetivo: Investigar a presença de células tumorais ocultas através de imunoistoquimica utilizando as citoqueratinas (CK) AE1/AE3 em pacientes com câncer gástrico com linfonodos histologicamente classificados como negativos por H&E. Métodos: Quarenta pacientes (T1-T4N0) submetidos à gastrectomia potencialmente curativa com linfadenectomia D2 foram avaliados. A presença de metástases, micrometástases e células tumorais isoladas foram correlacionadas com características clínicopatológicas e impacto no estadiamento. Os depósitos tumorais nos linfonodos foram classificados de acordo com o sistema TNM (7º TNM). Resultados: Um total de 1439 linfonodos foi obtido (~36 por paciente). Células tumorais foram detectadas por imunoistoquimica em 24 linfonodos de 12 pacientes (30%). As células neoplásicas estavam presentes na forma isolada ou em cluster. Invasão tumoral (p=0,002), venosa (p=0,016), linfática (p=0,006) e perineural (p=0,04), assim como resposta linfocítica peritumoral (p=0,012) foram correlacionadas com linfonodos CK-positivos que originalmente eram negativos à H&E. Dois pacientes tiveram o estadiamento alterado, migrando do estádio IB para IIA. Quatro dos 28 CK-negativos (14,3%) e três dos 12 CK-positivos (25%) tiveram recorrência da doença (p=0,65). Conclusão: A imunoistoquimica é meio eficaz para a detecção de células tumorais ocultas em linfonodos, podendo ser recomendada para melhor determinar o estágio do tumor. Ela pode ser útil como técnica complementar à rotina de H&E, de modo a fornecer melhor estadiamento patológico.

ABSTRACT Background: The presence of lymph nodes metastasis is one of the most important prognostic indicators in gastric cancer. The micrometastases have been studied as prognostic factor in gastric cancer, which are related to decrease overall survival and increased risk of recurrence. However, their identification is limited by conventional methodology, since they can be overlooked after routine staining. Aim: To investigate the presence of occult tumor cells using cytokeratin (CK) AE1/AE3 immunostaining in gastric cancer patients histologically lymph node negative (pN0) by H&E. Methods: Forty patients (T1-T4N0) submitted to a potentially curative gastrectomy with D2 lymphadenectomy were evaluated. The results for metastases, micrometastases and isolated tumor cells were also associated to clinicopathological characteristics and their impact on stage grouping. Tumor deposits within lymph nodes were defined according to the tumor-node-metastases guidelines (7th TNM). Results: A total of 1439 lymph nodes were obtained (~36 per patient). Tumor cells were detected by immunohistochemistry in 24 lymph nodes from 12 patients (30%). Neoplasic cells were detected as a single or cluster tumor cells. Tumor (p=0.002), venous (p=0.016), lymphatic (p=0.006) and perineural invasions (p=0.04), as well as peritumoral lymphocytic response (p=0.012) were correlated to CK-positive immunostaining tumor cells in originally negative lymph nodes by H&E. The histologic stage of two patients was upstaged from stage IB to stage IIA. Four of the 28 CK-negative patients (14.3%) and three among 12 CK-positive patients (25%) had disease recurrence (p=0.65). Conclusion: The CK-immunostaining is an effective method for detecting occult tumor cells in lymph nodes and may be recommended to precisely determine tumor stage. It may be useful as supplement to H&E routine to provide better pathological staging.

OBJECTIVE: Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation. METHODS: Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups. RESULTS: Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01). CONCLUSION: The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.

Histology is the gold standard for diagnosing acute rejection and hepatitis C recurrence after liver transplantation. However, differential diagnosis between the two can be difficult. We evaluated the role of C4d staining and quantification of hepatitis C virus (HCV) RNA levels in liver tissue. This was a retrospective study of 98 liver biopsy samples divided into four groups by histological diagnosis: acute rejection in patients undergoing liver transplant for hepatitis C (RejHCV+), HCV recurrence in patients undergoing liver transplant for hepatitis C (HCVTx+), acute rejection in patients undergoing liver transplant for reasons other than hepatitis C and chronic hepatitis C not transplanted (HCVTx-). All samples were submitted for immunohistochemical staining for C4d and HCV RNA quantification. Immunoexpression of C4d was observed in the portal vessels and was highest in the HCVTx- group. There was no difference in C4d expression between the RejHCV+ and HCVTx+ groups. However, tissue HCV RNA levels were higher in the HCVTx+ group samples than in the RejHCV+ group samples. Additionally, there was a significant correlation between tissue and serum levels of HCV RNA. The quantification of HCV RNA in liver tissue might prove to be an efficient diagnostic test for the recurrence of HCV infection.

BACKGROUND AND AIMS: Although there is much known about liver diseases, some aspects remain unclear, such as the nature of the differences between the diseases observed in newborn infants and those in adults. For example, how do newborns respond to duct epithelial cell injury? Do the stellate cells in newborns respond similarly to those in adults during biliary obstruction? METHODS: Ninety newborn Wistar rats aged six days, weighing 8.0 - 13.9 g each, and 90 adult rats weighing 199.7 - 357.0 g each, were submitted to bile duct ligation. After surgery, they were randomly divided and sacrificed on the 3rd, 5th, 7th, 14th, 21st or 28th day post-bile duct ligation. Hepatic biopsies were obtained and immunohistochemical semi-quantification of desmin and α-SMA expression was performed in hepatic stellate cells and in myofibroblasts in the portal space, and between the portal space and the liver lobule. RESULTS: Desmin expression in the myofibroblast cells post-bile duct ligation was higher in young rats, reaching its peak level in a shorter time when compared to the adult animals. The differences between the groups for α-SMA expression were less significant than for desmin. CONCLUSIONS: These findings indicate that there is an increase in the number of collagen-producing myofibroblast cells in young animals, suggesting that there is more intense fibrosis in this population. This finding may explain why young animals with bile duct obstruction experience more intense portal fibrosis that is similar to the pathology observed in the livers of newborns with biliary atresia.

OBJETIVOS: A regeneração hepática é um processo complexo não completamente elucidado. O modelo mais utilizado para o estudo desse fenômeno é a hepatectomia a 70% em ratos adultos. Não há trabalhos utilizando modelos em animais em crescimento. Desta forma, os objetivos deste estudo foram: 1. padronizar dois modelos de hepatectomia parcial e regeneração hepática utilizando ratos recém-nascidos e recém-desmamados; 2. estudar a evolução do peso do fígado remanescente e as alterações histológicas do parênquima hepático nos dias subseqüentes à hepatectomia parcial. MÉTODOS: Cinqüenta ratos recém-nascidos e quarenta e quatro ratos recém-desmamados foram submetidos à hepatectomia a 70%. Após laparotomia mediana, foi realizada compressão bilateral no abdome superior do animal, levando à exteriorização dos lobos hepáticos direito medial, esquerdo medial e esquerdo lateral, que foram ligados na base e ressecados em bloco. Os animais foram sacrificados logo após a hepatectomia e no 1º,2º,3º,4º, e 7º dias após a cirurgia. O peso corpóreo e do fígado foram determinados, e o parênquima hepático submetido à análise histológica. RESULTADOS: Os índices de mortalidade dos animais recém-nascidos e recém-desmamados foram 30% e 0% respectivamente. Em ambos os grupos, houve uma diminuição significativa na massa hepática logo após a hepatectomia, com recuperação completa no sétimo dia de pós-operatório. O parênquima hepático dos animais recém-nascidos apresentou acentuada esteatose no segundo dia. O fígado do animal recém-desmamado exibiu figuras mitóticas mais precoces e mais numerosas que o do recém-nascido. CONCLUSÕES: Os modelos de hepatectomia parcial em ratos recém-nascidos e recém-desmamados são factíveis e podem ser usados para estudos da regeneração hepática. Embora semelhante, o processo de regeneração hepática em animais em crescimento não é igual ao do animal adulto.

OBJECTIVES: Liver regeneration is a complex process that has not been completely elucidated. The model most frequently used to study this phenomenon is 70% hepatectomy in adult rats; however, no papers have examined this effect in developing animals. The aims of the present study were: 1) to standardize two models of partial hepatectomy and liver regeneration in newborn suckling and weaning rats, and 2) to study the evolution of remnant liver weight and histological changes of hepatic parenchyma on the days that follow partial hepatectomy. METHODS: Fifty newborn and forty-four weaning rats underwent 70% hepatectomy. After a midline incision, compression on both sides of the upper abdomen was performed to exteriorize the right medial, left medial and left lateral hepatic lobes, which were tied inferiorly and resected en bloc. The animals were sacrificed on days 0 (just after hepatectomy), 1, 2, 3, 4 and 7 after the operation. Body and liver weight were determined, and hepatic parenchyma was submitted to histological analysis. RESULTS: Mortality rates of the newborn and weaning groups were 30% and 0%, respectively. There was a significant decrease in liver mass soon after partial hepatectomy, which completely recovered on the seventh day in both groups. Newborn rat regenerating liver showed marked steatosis on the second day. In the weaning rat liver, mitotic figures were observed earlier, and their amount was greater than in the newborn. CONCLUSIONS: Suckling and weaning rat models of partial hepatectomy are feasible and can be used for studies of liver regeneration. Although similar, the process of hepatic regeneration in developing animals is different from adults.

RACIONAL: Em razão dos riscos relacionados ao tratamento prolongado com prednisona e azatioprina, tenta-se a retirada dessas drogas em pacientes com hepatite auto-imune em remissão. Como há alta taxa de recidiva, a maioria dos pacientes recebe tratamento por tempo indefinido. OBJETIVO: Avaliar a segurança e a eficácia do tratamento de manutenção com cloroquina na prevenção de recidiva da hepatite auto-imune. MÉTODOS: O tratamento convencional foi suspenso após obtenção de remissão bioquímica e histológica. Difosfato de cloroquina foi administrado, 250 mg diariamente, por pelo menos 12 meses ou até a ocorrência de recidiva, definida pela elevação dos níveis de aminotransferases em, pelo menos, duas vezes acima dos valores normais. RESULTADOS: Quatorze pacientes foram consecutivamente tratados e comparados com 18 controles históricos. Houve chance de 6,49 vezes maior de recidiva nos pacientes do grupo de controles históricos, quando comparados com os pacientes do grupo tratado com o difosfato de cloroquina. (72,2% versus 23,5%; P = 0.031). CONCLUSÕES: O grupo tratado com cloroquina teve menor freqüência de recidivas da hepatite auto-imune. Difosfato de cloroquina foi seguro em pacientes com hepatite auto-imune e cirrose hepática sem descompensação clínica, na dose de 250 mg diariamente e até 2 anos de uso. Esses resultados preliminares estimulam a realização de estudos controlados, comparando cloroquina com placebo ou com o tratamento de manutenção.

BACKGROUND: Due to the risks related to long-term treatment with prednisone and azathioprine, most clinicians try to withdraw these drugs when patients with autoimmune hepatitis are in remission. However, there is a high probability of relapse, and most patients end up receiving maintenance treatment. AIM: To evaluate the safety and efficacy of maintenance treatment with chloroquine in the prevention of autoimmune hepatitis relapses. METHODS: Classical treatment was stopped after achievement of biochemical and histological remission of autoimmune hepatitis. Chloroquine diphosphate, 250 mg daily, was given for at least 12 months or until the occurrence of relapses defined by levels of aminotransferases at least twice the upper normal values. RESULTS: Fourteen patients were consecutively treated and compared with 18 historical controls. There was a 6.49 (1.38-30.30) greater chance of relapse in the historical controls when compared with patients treated with chloroquine (72.2% x 23.5%; 0.031). CONCLUSIONS: The group treated with chloroquine had a lower frequency of relapses. Chloroquine was safe in patients with autoimmune hepatitis and hepatic cirrhosis without decompensation, on 250 mg daily up to 2 years. These preliminary results provide a basis for upcoming controlled studies comparing chloroquine with placebo or for maintenance treatment with prednisone and/or azathioprine for the prevention of autoimmune hepatitis relapses.

Hepatite C é uma doença de evolução progressiva. A maioria dos pacientes tem nível de ALT elevada e 25% apresentam níveis normais. Os com ALT normal geralmente são do gênero feminino e sem associação entre genótipo e gravidade de lesão hepática. O exame histopatológico mostra geralmente ausência de ou leve fibrose (cerca de 20% tem fibrose), embora cirrose já tenha sido relatada. Visando estimar a prevalência, características demográficas, genotípicas e anatomopatológicas em pacientes com ALT normal, realizamos um estudo de série com 68 casos com diagnóstico de hepatite C crônica. Os pacientes foram selecionados de janeiro de 1977 a abril de 2002. Encontrou-se uma prevalência de 13,8% (45,6% masculinos). A média de idade foi 39 +/- 13 anos. Predomínio de genótipo 1 (84,8%), seguido pelo 3 (8,5%) e 2 (6,7%). Encontramos fígado reacional em 52,9% das biópsias, atividade periportal de 0-1 em 85,3% e atividade periportal de 2-4 em 14,7%. Apresentaram atividade estrutural de 0 a 1 73,5% e 26,5% com atividade estrutural de 2 a 4, sendo que 29% da amostra apresentou APP > 2 e AE > 1; 73,5% não apresentaram esteatose. Nossos dados reforçam a necessidade de biópsia em pacientes com hepatite C e níveis de ALT normais.

Hepatitis C virus infection evolves progressively persisting in the majority of patients (85%). Most patients have high ALT (alanine aminotransferase) levels and approximately 25% normal ALT. The latter are usually female and there is no association between genotype and severity of hepatic lesion. Histologic analysis usually shows small lesion and absence or low amount of fibrosis, despite cirrhosis having been reported. Aiming at assessing prevalence, demographic, genotypical and anatomopathological characteristics in patients with normal ALT levels, we have carried out a study of 68 chronic hepatitis C patients between January 1997 and April 2000. There was a prevalence of 13.8% chronic hepatitis C patients with normal ALT levels, 45.6% of which were male and 54.4% female, the mean age being 38 +/- 13 years. We found a predominance of genotype 1 in 84.7% of the patients, genotype 2 in 6.8% and genotype 3 in 10.7%. In 52.9% of the cases liver biopsies revealed liver reaction, periportal activity score 0-1 was observed in 85.3% of the patients and score 2-4 was seen in 14.7%. Structural activity score 0-1 was seen in 73.5% of the patients and score 2-4 in 26.5% of them. Periportal activity > 2 and structural activity > 1 was seen in 29%, but steatosis was not seen in 73.5%. Our results suggest the need to revisit for liver biopsy practice in patients with Chronic Hepatitis C and normal transaminases.

O carcinoma hepatocelular (CHC) é um importante tipo de câncer relacionado etiologicamente a alguns vírus, carcinógenos químicos e outros fatores ambientais que causam danos crônicos ao fígado em humanos. A freqüência de mutação do gene p53 em CHC é altamente heterogênea (0-52%) nos diversos países. OBJETIVO: O objetivo deste estudo foi determinar, imuno-histologicamente, a freqüência da expressão anômala de p53 em CHCs em pacientes cirróticos versus não-cirróticos, bem como em displasia hepática e hiperplasia adenomatosa. Para isso, foram estudados 84 pacientes com carcinoma hepatocelular ou cirrose. RESULTADOS: Foram detectadas expressões do p53 alterado em 58,3% dos pacientes com CHC graus III-IV, contrastando com os 22,2% dos pacientes com CHC graus I-II (p = 0,02). Áreas não tumorais, tanto nas proximidades do CHC como nos 30 casos de cirrose não mostraram expressão nuclear alterada do p53, mesmo nas displasias ou hiperplasias adenomatosas. Quando se considerou HBV, HCV ou alcoolismo nos casos estudados, não se encontrou diferença significativa. CONCLUSÃO: A elevada freqüência de imuno-expressão de p53 nesta população é próxima à relatada na China e África, tornando necessárias outras pesquisas para explicar as diferenças com os CHC estudados na Europa e na América do Norte.

Hepatocellular carcinoma (HCC) is an important type of cancer etiologically related to some viruses, chemical carcinogens and other host or environmental factors associated to chronic liver injury in humans. The tumor suppressor gene p53 is mutated in highly variable levels (0-52%) of HCC in different countries. OBJECTIVE: The objective of the present study was to compare the frequency of aberrant immunohistochemical expression of p53 in HCC occurring in cirrhotic or in non-cirrhotic patients as well as in liver cell dysplasia and in adenomatous hyperplasia. We studied 84 patients with HCC or cirrhosis. RESULTS: We detected p53 altered immuno-expression in 58.3% of patients in Grade III-IV contrasting to 22.2% of patients in Grade I-II (p = 0.02). Nontumorous areas either in the vicinity of HCC or in the 30 purely cirrhotic cases showed no nuclear p53 altered expression, even in foci of dysplasia or adenomatous hyperplasia. No significant difference was found among cases related to HBV, HCV or alcohol. CONCLUSION: The high frequency of p53 immunoexpression in this population is closer to those reported in China and Africa, demanding further studies to explain the differences with European and North American reports.