RESUMO
The aim of this study was to assess the reversibility of cirrhosis after therapy in a large series of patients with cirrhosis from various etiologies. We performed a retrospective study of 113 patients with biopsy-proven cirrhosis who underwent specific therapy and follow-up biopsies. Two pathologists performed blinded analyses of indirect biochemical and morphological signs of cirrhosis. Fourteen (12.4%) of the 113 cirrhotic patients had biopsy-proven disappearance of cirrhosis, defined as a decrease of 2 or greater in their METAVIR fibrosis score: 8 were related to hepatitis C virus, 3 to hepatitis B virus, and 3 to autoimmune cirrhosis. Necro-inflammatory activity decreased from 2.4 +/- 0.65 to 0.85 +/- 0.9 (P = .004), and fibrosis from 4 to 1.7 +/- 0.61 (P = .001). Prothrombin time (n = 1), platelet count (n = 2), serum albumin level (n = 2), and ultrasound abnormalities (n = 6) normalized in patients who had initial abnormalities. Hyaluronic acid and procollagen type III serum level decreased in all. In the 11 patients with regression of viral cirrhosis, 2 were nonresponders and 9 were responders, including 2 relapsers. The 3 patients with regressive autoimmune cirrhosis were complete responders to immunosupressive therapy. Using repeated liver biopsies, clinicobiochemical, radiologic, and endoscopic tests, we provide evidence for potential reversibility of cirrhosis after long-lasting suppression of the necro-inflammatory activity of liver disease.
Assuntos
Cirrose Hepática/terapia , Biópsia , Hepatite B/complicações , Hepatite C/complicações , Humanos , Ácido Hialurônico/sangue , Fígado/patologia , Cirrose Hepática/patologia , Cirrose Hepática Alcoólica/terapia , Masculino , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Estudos Retrospectivos , Resultado do TratamentoRESUMO
In recent years, mycoses have emerged as important infections in clinical practice. This phenomenon is explained by the ever growing number of immunocompromised patients and the increasing number of people travelling in areas where fungal diseases are endemic. Head and neck infections are common in disseminated mycoses and may simulate carcinoma or cause upper airway obstruction. The most frequent causative yeasts or yeast-like organisms include Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum var capsulatum, Blastomyces dermatitidis, Paracoccidioides brasiliensis and Coccidioides immitis. Other causative fungal pathogens include Aspergillus fumigatus and less frequently, Rhizopus oryzae and Rhinosporidium seeberi. Since in most cases their pathophysiology is similar, those microorganisms share a common clinical pathological presentation. Symptoms such as dysphonia or dysphagia associated with hyperplastic and ulcerative lesions on endoscopic examination should prompt biopsies. A purulent or granulomatous inflammatory tissue reaction with pseudoepitheliomatous hyperplasia warrants caution since it may lead to a mistaken diagnosis of carcinoma. The pathologist must look carefully for microorganisms with Grocott and PAS stains. The causative agent can be identified if the pathologist is aware of the risk. Positive culture is needed to institute adequate treatment.
Assuntos
Candidíase/patologia , Criptococose/patologia , Histoplasmose/patologia , Mucormicose/patologia , Micoses/patologia , Aspergilose/patologia , Coccidioidomicose/patologia , Humanos , Micoses/classificaçãoRESUMO
The aim of this retrospective study was to determine the potential reversibility of hepatitis C virus (HCV) cirrhosis with the combined antifibrotic effects of interferon-alpha and the increasing frequency of sustained virologic response. Sixty-four HCV-cirrhotic immunocompetent patients who underwent antiviral therapies (interferon-alpha with or without ribavirin) and pretreatment and posttreatment liver biopsies were included (group 1). Resolution of cirrhosis was defined as a decrease in the fibrosis score from 4 to 2 or less by the Metavir score after blinded analysis by 2 independent pathologists. An additional group of 4 HCV-infected dialysis patients (group 2) who had received antiviral treatment, among whom 3 underwent a combined renal and liver transplantation allowing the analysis of the whole liver, was also studied. In 5 (all stage Child A) of the 64 cirrhotic patients (7.8%), the final biopsy showed only F2 to portal and periportal fibrosis with rare fibrous septa without nodule formation. Four of these 5 were complete sustained responders (negative PCR and normal ALT), and 1 was a relapser. In group 2, reversibility of cirrhosis was observed in 3 of the 4 patients and was clearly shown in 2 patients by the analysis of the whole-liver examination at the time of the hepatectomy preceding the transplantation. In conclusion, long-lasting suppression of the necroinflammatory activity of liver disease and/or antifibrogenetic effects of interferon-alpha may allow regression of cirrhosis.
Assuntos
Antivirais/uso terapêutico , Hepatite Viral Humana/tratamento farmacológico , Interferons/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Ribavirina/uso terapêutico , Adulto , Quimioterapia Combinada , Feminino , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite Viral Humana/complicações , Hepatite Viral Humana/patologia , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND/AIMS: Alcohol consumption accelerates the appearance of liver fibrosis and hepatocellular carcinoma in patients with chronic hepatitis C virus (HCV) infection, but the mechanisms of these interactions are unknown. We therefore investigated the effects of chronic ethanol consumption in HCV core protein-expressing transgenic mice. METHODS: Ethanol was progressively added (up to 20%) to the drinking water that was given ad libidum. RESULTS: In vivo fatty acid oxidation was not inhibited by ethanol consumption and/or HCV core expression. Both chronic ethanol consumption and HCV core expression decreased hepatic lipoprotein secretion and caused steatosis, but had no additive effects on lipoprotein secretion or steatosis. However, chronic ethanol consumption and HCV core protein additively increased lipid peroxidation and acted synergistically to increase the hepatic expression of transforming growth factor-beta (TGF-beta) and, to a less extent, tumor necrosis factor-alpha (TNF-alpha). CONCLUSIONS: HCV core protein expression and chronic alcohol consumption have no effects on in vivo fatty acid oxidation and do not additively impair hepatic lipoprotein secretion, but additively increase hepatic lipid peroxidation and synergistically increase hepatic TNF-alpha and TGF-beta expression. These effects may be involved in the activation of fibrogenesis and the development of hepatocellular carcinoma in patients cumulating alcohol abuse and HCV infection.
Assuntos
Hepacivirus/genética , Antígenos do Núcleo do Vírus da Hepatite B/genética , Hepatopatias Alcoólicas/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Necrose Tumoral alfa/genética , Animais , Depressores do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Etanol/farmacologia , Ácidos Graxos/metabolismo , Fígado Gorduroso/metabolismo , Expressão Gênica/efeitos dos fármacos , Antígenos do Núcleo do Vírus da Hepatite B/metabolismo , Peroxidação de Lipídeos , Lipoproteínas/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
The HIP/PAP (=human Reg-2) C-type lectin encoding gene is activated in primary liver cancers. In normal liver, the protein is undetectable in normal mature hepatocytes and found only in some ductular cells, representing potential hepatic progenitor cells. The aim of this study was to examine the consequences of human HIP/PAP expression in the liver of transgenic mice. We demonstrated that HIP/PAP stimulated liver regeneration after partial hepatectomy. To further investigate the enhanced liver regeneration observed in vivo, primary cultures of hepatocytes were used to evaluate the mitogenic and anti-apoptotic properties of HIP/PAP. HIP/PAP increased hepatocyte DNA synthesis and protected hepatocytes against TNF-alpha plus actinomycin-D-induced apoptosis. HIP/PAP anti-apoptotic effects against TNF-alpha were clearly demonstrated when protein kinase A activity was specifically inhibited by KT5720, and HIP/PAP stimulated PKA-dependent phosphorylation of the proapoptotic Bad protein at Ser-112, suggesting that HIP/PAP may compete with cAMP to stimulate PKA activity. Overall, our results led us to propose a new role for a C-type lectin, HIP/PAP, as a hepatic cytokine that combines mitogenic and anti-apoptotic functions regarding hepatocytes, and consequently acts as a growth factor in vivo to enhance liver regeneration.
Assuntos
Antígenos de Neoplasias/fisiologia , Apoptose , Biomarcadores Tumorais/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Lectinas Tipo C/fisiologia , Regeneração Hepática , Proteínas , Transdução de Sinais , Animais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , DNA/biossíntese , Dactinomicina/toxicidade , Hepatectomia , Hepatócitos/metabolismo , Humanos , Lectinas Tipo C/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitógenos/fisiologia , Proteínas Associadas a Pancreatite , Fosforilação , Serina/metabolismo , Fator de Necrose Tumoral alfa/toxicidade , Proteína de Morte Celular Associada a bclRESUMO
Fibromatosis is a rare benign soft-tissue tumor of fibroblastic origin arising from the aponeurotic structures. Preoperative diagnosis of fibromatosis of the deep cervical fascia is difficult from clinical presentation alone. We report a case of a tumor of the cervical fascia space for which the radiologic appearance did not exhibit specific characteristics. Critical analysis of the radiologic images combined with fine-needle aspiration findings were helpful in suggesting preoperatively the diagnosis of fibromatosis, which was confirmed histologically after surgical resection.
Assuntos
Fáscia , Fibroma/patologia , Neoplasias de Cabeça e Pescoço/patologia , Adulto , Fibroma/cirurgia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , MasculinoRESUMO
BACKGROUND/AIMS: The analysis of hepatitis B virus (HBV) X protein genetic variability and is correlation with liver disease severity have only been addressed, so far, on whole liver extracts. We have studied, therefore, the HBV X protein (HBx) gene sequence in morphologically well-characterised tumour and non-tumour liver cells from patients with HBV-related hepatocellular carcinoma. METHODS: Using laser capture microdissection (LCM), we picked up six to eight groups of tumour and non-tumour hepatocytes in serial frozen sections from six patients. After global DNA preamplification followed by HBx-specific polymerase chain reaction, the HBx gene was sequenced in each group of microdissected cells. We also validated the quantification of HBV-DNA in microdissected hepatocytes using HBV Amplicor. RESULTS: Heterogeneous mutations in HBx gene were found in distinct cirrhotic nodules and tumour areas from the same patient. Mutations at aa 127, 130 and 131 were frequently detected but there was no distinct point mutation profile between tumour and non-tumour samples. In contrast, deletions in HBx gene, which were found in five/six patients, were more frequent in tumour-derived sequences (6/18) than in non-tumour-derived sequences (1/20). CONCLUSIONS: We have shown that LCM provides a direct insight of intrahepatic HBV infection. Using this technique, we demonstrated the persistence of distinct HBx encoding sequences in clonally expanding cells, thus supporting the hypothesis that HBx deletions may be implicated in liver carcinogenesis.
Assuntos
Carcinoma Hepatocelular/virologia , Vírus da Hepatite B/genética , Hepatite B/virologia , Neoplasias Hepáticas/virologia , Transativadores/genética , Adulto , Idoso , Sequência de Aminoácidos , Carcinoma Hepatocelular/patologia , DNA Viral/análise , Deleção de Genes , Hepatite B/patologia , Humanos , Imuno-Histoquímica , Lasers , Neoplasias Hepáticas/patologia , Masculino , Microdissecção , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação Puntual , Proteínas Virais Reguladoras e AcessóriasRESUMO
Donor-specific induction of tolerance was previously achieved in the diabetic rat by intrathymic injection of pancreatic islets. It allowed a secondary islet graft in any site without immunosuppression. Since total pancreatic graft in man is metabolically more proficient than islet graft, we attempted tolerance induction for total vascularized pancreas transplantation in diabetic BN recipient rats by an intrathymic bone marrow cell (BMC) injection from Lewis donor rats, associated to an antilymphocyte antibody (ALS) administration. Control groups consisted of isogenic grafts, allogenic grafts without tolerance induction and allogenic grafts with ALS alone. In all grafted groups, mean blood glucose and plasma insulin were normalised within 24 h. Graft rejection (clinically suggested by diabetes recurrence and later confirmed by histology) appeared at 18 +/- 2 postoperative days in the absence of intrathymic BMC injection and at 36 +/- 8 days in the group with BMC injection (p < 0.05). Intrathymic bone marrow graft was successful in delaying rejection in our study.
Assuntos
Transplante de Medula Óssea , Diabetes Mellitus Experimental/cirurgia , Transplante de Pâncreas , Pâncreas/fisiopatologia , Timo/fisiopatologia , Animais , Transplante de Medula Óssea/métodos , Rejeição de Enxerto/patologia , Injeções , Masculino , Pâncreas/patologia , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Condicionamento Pré-Transplante , Tolerância ao Transplante , Transplante HomólogoAssuntos
Carcinoma Hepatocelular/complicações , Degeneração Hepatolenticular/diagnóstico , Cirrose Hepática/complicações , Neoplasias Hepáticas/complicações , Fatores Etários , Idoso , Autopsia , Carcinoma Hepatocelular/patologia , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/patologia , Humanos , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , MasculinoRESUMO
The 18q chromosome arm is frequently lost in advanced head and neck squamous cell carcinoma. Twenty-four microsatellite markers located on chromosome 18q were genotyped in 145 primary tumors and 10 cell lines in order to identify putative tumor suppressor genes implicated in tumor progression. Two different minimal common regions of loss (MCRL) were identified at 18q22 and 18q23 respectively. To refine and delineate boundaries of an homozygous deletion found in one cell line, 44 extra markers located at 18q22 were analysed and the homozygous deletion was precisely defined within a critical region of 4.9 Mb. Four known genes (CDH7, CDH19, DNAM-1, FLJ23594) located in this critical region and two EST clusters (Hs.96900, Hs.98628) were selected for further investigations. For these six genes, genomic structures were established, somatic mutations were screened in 20 HNSCC and 10 cell lines and transcription levels were determined in eight cell lines. No somatic mutations were found in any of the candidate genes analysed (57 coding exons). However, differential transcription levels were observed for CDH19 and Hs.96900 in head and neck cancer cell lines supporting their putative involvement through down regulation mechanisms in head and neck cancer progression.
Assuntos
Carcinoma de Células Escamosas/genética , Cromossomos Humanos Par 18 , Neoplasias de Cabeça e Pescoço/genética , Deleção de Sequência , Genes Supressores de Tumor , HumanosRESUMO
The role of the hepatitis B virus X protein (HBx) in the pathogenesis of hepatitis B virus (HBV) infection remains unclear. HBx exhibits pleiotropic biological effects, whose in vivo relevance is a matter for debate. In the present report, we have used a combination of HBx-expressing transgenic mice and liver cell transplantation to investigate the in vivo impact of HBx expression on liver cell proliferation and viability in a regenerative context. We show that moderate HBx expression inhibits liver regeneration after partial hepatectomy in HBx-expressing transgenic mice. We also demonstrate that the transplantation of HBx-expressing liver cells, isolated from HBx transgenic mice, is sufficient to inhibit overall recipient liver regeneration after partial hepatectomy. Moreover, the injection of serum samples drawn from HBx-expressing transgenic mice mimicked the inhibitory effect of HBx on liver regeneration. Finally, the incubation of primary rat hepatocytes with the supernatant of HBx-expressing liver cells inhibits cellular DNA synthesis. Taken together, our results demonstrate a paracrine inhibitory effect of HBx on liver cell proliferation and lead us to propose HBV as one of the few viruses implicated in human cancer which act, at least in part, through paracrine biological pathways.
Assuntos
Vírus da Hepatite B/metabolismo , Fígado/metabolismo , Comunicação Parácrina , Transativadores/metabolismo , Animais , Divisão Celular , Células Cultivadas , Feminino , Expressão Gênica , Vírus da Hepatite B/genética , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Fígado/citologia , Fígado/virologia , Regeneração Hepática , Masculino , Camundongos , Camundongos SCID , Camundongos Transgênicos , Ratos , Ratos Wistar , Transativadores/genética , Transgenes , Células Tumorais Cultivadas , Proteínas Virais Reguladoras e AcessóriasRESUMO
It is still unclear as to whether the gene expression profile in HCV- or HBV-related HCC exhibits a degree of specificity and whether the development of HCC in a context of cirrhosis influences this gene profile. To address these issues, the expression profiles of 15 cases of HCC were analysed using cDNA macroarray. A global analysis and hierarchical clustering, demonstrated the heterogeneity of HCC patterns, with a majority of down-regulated genes. Statistical analysis clearly showed a distinction between the gene expression profiles of HCV- and HBV-related HCC. HBV-associated HCC exhibited involvement of different cellular pathways, those controlling apoptosis, p53 signalling and G1/S transition. In HCV-related HCC we identified a more heterogenous pattern with an over-expression of the TGF-beta induced gene. In HCC developing on non-cirrhotic tissues, beta-catenin encoding gene and genes implicated in the PKC pathway were specifically up-regulated. In addition, our investigation highlighted a distinct profiles of TGF-beta superfamily encoding genes in well, moderately or poorly differentiated HCC. Overall, our study supports the hypothesis that despite the heterogeneity of the HCC pattern, the large-scale screening of gene expression may provide data significant to our understanding of the mechanism of liver carcinogenesis.
Assuntos
Carcinoma Hepatocelular/genética , Expressão Gênica , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Perfilação da Expressão Gênica , Hepacivirus , Vírus da Hepatite B , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Hibridização de Ácido Nucleico/métodos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
New biomarkers of pancreatic adenocarcinoma are needed to improve the early detection of this deadly disease. We performed surface enhanced laser desorption ionization (SELDI) mass spectrometry using ProteinChip technology (Ciphergen Biosystems, Fremont, CA) to screen for differentially expressed proteins in pancreatic juice. Pancreatic juice samples obtained from patients undergoing pancreatectomy for pancreatic adenocarcinoma were compared with juice samples from patients with other pancreatic diseases. We identified a peak approximately 16,570 daltons present in the pancreatic juice from 10/15 (67%) of the patients with pancreatic adenocarcinoma and in the pancreatic juice from 1/7 (17%) of the patients with other pancreatic diseases. Using a ProteinChip immunoassay, we identified this differentially expressed protein as hepatocarcinoma-intestine-pancreas/pancreatitis-associated-protein I (HIP/PAP-I), a protein released from pancreatic acini during acute pancreatitis and overexpressed in hepatocellular carcinoma. We then quantified by ELISA the pancreatic juice HIP/PAP-I levels in 43 patients (28 with pancreatic adenocarcinoma, 15 with other pancreatic diseases) and the serum HIP/PAP-I levels in 98 patients (53 with pancreatic adenocarcinoma, 45 with other pancreatic diseases or healthy individuals). HIP/PAP-I levels were significantly higher in both the pancreatic juice (P < 0.001) and in the serum (P < 0.001) of patients with pancreatic adenocarcinoma compared with the control group. HIP/PAP-I levels were approximately 1000-fold higher in pancreatic juice compared with serum and the magnitude of the difference between the pancreatic adenocarcinoma group and the control group was greater in the pancreatic juice samples (143.75 +/- 235.52 microg/ml versus 6.04 +/- 7.59 microg/ml) than in the serum samples (99.96 +/- 140.66 ng/ml versus 35.25 +/- 28.44 ng/ml). In our study, patients with pancreatic juice HIP/PAP-I levels > or= 20 microg/ml were 21.9 times (95% confidence interval, 3.5-136.5; P < 0.001) more likely to have pancreatic adenocarcinoma than patients with levels <20 microg/ml. Immunolabeling of tissue sections revealed that the HIP/PAP-I protein was strongly expressed in acini adjacent to the invasive adenocarcinoma, but it was only rarely (1/30; 3%) expressed in the neoplastic epithelium, which suggests that the main source of HIP/PAP-I release in the pancreatic juice is acini. This low level of HIP/PAP-I expression in pancreatic adenocarcinoma was confirmed by reverse transcription-PCR: only 1 (5%) of 19 pancreatic cancer cell lines expressed HIP/PAP-I transcripts. Taken together, these data suggest that pancreatic juice measurement of HIP/PAP-I may help to identify patients with pancreatic adenocarcinoma.