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Phenotypic identification of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) subtypes using immunohistochemical markers has been developed from their molecular characteristics. Our objective was to evaluate the sensitivity of these markers in the definitive diagnosis of these lesions by core needle biopsies. A total of 239 needle biopsies paired with their surgical resection specimen (group A) or without an associated resection specimen (group B) were reviewed. Using a step-by-step algorithm after standard staining, appropriate immunostaining analyses were performed to determine the certainty of diagnosis of FNH, HNF1-inactivated HCA, inflammatory HCA, -catenin-activated HCA, or unclassified HCA. The diagnosis of FNH was certain or probable on routine stains in 53 of needle biopsies of group A, whereas after glutamine synthetase staining, the diagnosis was certain in 86.7 as compared with 100 on the corresponding surgical specimen (P=0.04). In needle biopsies of group A, the diagnosis of HCA was certain on routine stains in 58.6 as compared with 94.3 on surgical specimens. After specific immunostaining, diagnosis was established on biopsies with 74.3 certainty, including all HCA subtypes, with similar distribution in surgical specimens. For each “certain diagnosis” paired diagnostic test (biopsy and surgical specimen), a positive correlation was observed (P<0.001). No significant difference was observed between groups A and B for FNH (P=0.714) or for HCA subtypes (P=0.750). Compared with surgical specimens, immunohistochemical analysis performed on biopsies allowed the discrimination of FNH from HCA and the identification of HCA subtypes with good performance.

Inappropriate activation of the Wnt pathway resulting from β-catenin gene alterations has recently been implicated in the development of hepatocellular carcinoma (HCC). To explore the in vivoeffects of mutated β-catenin, HCC specimens from 32 patients carrying one or several tumors were screened for somatic mutations in exon 3 of the β-catenin gene, and the expression and subcellular localization of β-catenin was studied by immunohistochemistry. Missense mutations or interstitial deletions in β-catenin exon 3 were detected in 12 of 35 (34%) HCC samples. After immunostaining, most tumors exhibited increased membranous and/or cytoplasmic expression of β-catenin compared with adjacent nontumoral liver. Strong nuclear accumulation of β-catenin was observed either focally or uniformly in 15 of 35 (43%) tumor specimens, but not in cirrhotic nodules or dysplastic liver cells in adjacent liver. Aberrant nuclear expression of β-catenin was significantly associated with the presence of mutations in the β-catenin gene (P< 0.005). Moreover, nuclear β-catenin staining correlated significantly with increased Ki-67 proliferative index in tumor (P< 0.001) and seemed to be associated with poor outcome in patients with HCC. In conclusion, our data indicate that activation of the Wnt/β-catenin pathway in HCC results mainly from somatic mutations in the β-catenin gene and may promote tumor progression by stimulating tumor cell proliferation.

During chronic liver diseases, hepatic stellate cells (HSC) acquire a myofibroblastic phenotype, proliferate, and synthetize fibrosis components. Myofibroblastic HSC (mHSC) also participate to the regulation of intrahepatic blood flow, because of their contractile properties. Here, we examined whether human mHSC express natriuretic peptide receptors (NPR). Only NPR-B mRNA was identified, which was functional as demonstrated in binding studies and by increased cGMP levels in response to C-type natriuretic peptide (CNP). CNP inhibited mHSC proliferation, an effect blocked by the protein kinase G inhibitor 8-(4 chlorophenylthio)-cGMP and by the NPR antagonist HS-142-1 and reproduced by analogs of cGMP. Growth inhibition was associated with a reduction of extracellular signal-regulated kinase and c-Jun N-terminal kinase and with a blockade of AP-1 DNA binding. CNP and cGMP analogs also blunted mHSC contraction elicited by thrombin, by suppressing calcium influx. The relaxing properties of CNP were mediated by a blockade of store-operated calcium channels, as demonstrated using a calcium-free/calcium readdition protocol. These results constitute the first evidence for a hepatic effect of CNP and identify mHSC as a target cell. Activation of NPR-B by CNP in human mHSC leads to inhibition of both growth and contraction. These data suggest that during chronic liver diseases, CNP may counteract both liver fibrogenesis and associated portal hypertension.

Lower pulmonary tract cell populations collected by bronchoalveolar lavages (BAL) were evaluated in three groups of immunocompromised patients: HIV infected patients with Pneumocystis carinii(PC) pneumonitis (n = 22), or pneumonitis not related to PC (n = 29), and non-HIV-infected, immunocompromised patients with a PC pneumonitis (n = 18). In AIDS patients with PC pneumonitis, the cell populations were 59.3 ±4.5 percent alveolar macrophages (AM), 19.6 ±2.5 percent lymphocytes, 14.6 ±4.4 percent polymorphonuclear cells (PMN), and 10.3 ±3.6 percent eosinophils. In HIV-infected patients without PC pneumonitis, they were 76.5 ± 3.3 percent AM, 13 ± 2.1 percent lymphocytes, 9.2 ± 0.3 percent PMN, and 0.6 ± 0.2 percent eosinophils, and in non-HIV-infected, immunocompromised patients with PC pneumonitis, they were 43.9 ± 5.7 percent AM, 30.2 ± 4.3 percent lymphocytes, 20.4 ± 4.7 percent PMN, and 0.9 ± 0.4 percent eosinophils. The most striking finding was a marked BAL eosinophilia in AIDS patients with PC pneumonitis. The significance of this particular cellular pulmonary response to PC is not clear, and its consequences on the lung structures and/or PC require evaluation.

After liver transplantation for hepatitis C virus (HCV)-related cirrhosis, recurrent viral infection is almost constant, resulting in acute graft dysfunction in 30–75 of cases. Acute graft dysfunction in the post-transplant period may also be the result of various causes (such as rejection, CMV infection, sepsis, or technical problems). Therefore, the role of HCV rein fection is often difficult to document. The aim of this study was to assess the diagnostic value of serial HCV RNA quantitation in this setting.

Pneumocystis carinii (PC) has been recognized as frequently responsible for most opportunistic pulmonary infections occurring in immunocompromised AIDS and non-AIDS patients. Moreover, these patients can be considered at risk for secondary pulmonary alveolar proteinosis. Therefore, we have investigated the occurrence of associated secondary alveolar proteinosis and PC pneumonitis in AIDS and non-AIDS immunocompromised patients. In a series of 26 bronchoalveolar lavages (BAL) in patients with PCpneumonitis (19 AIDS and seven non-AIDS patients), we observed on light microscopy, in addition to the honeycombed material, areas of an extracellular material that had a different pattern which was suggestive of that described in alveolar proteinosis. A systematic ultrastructural study of these 26 BAL fluid samples demonstrated in each of them an accumulation of phospholipid surfactantlike extracellular material mixed or not with the PCcysts. In nine cases, the observation of lipoproteinaceous material on light microscopy and abundant phospholipid material with myelinlike and myelin tubular laminated structures on electron microscopy was highly suggestive of an associated pulmonary alveolar proteinosis (PAP). Such an accumulation of extracellular material was not observed in the 11 BAL fluid samples collected in immunocompromised patients (seven AIDS and four non-AIDS patients) without PCpneumonitis. These findings demonstrated a particular frequency of associated PAP with PCpneumonitis. These results raise important questions concerning (1) the consequence of such an alveolar accumulation of lipoproteinaceous material on the clinical status and prognosis of the pneumonitis, and (2) the mechanisms responsible for this accumulation.

The shortage of organ donors and the increased demand for liver transplantation has led to new strategies to increase the availability of liver grafts for transplantation. Occasionally, previous liver transplant recipients may experience brain death and become organ donors. Although this is a very rare situation, we and others have showed that reuse of liver grafts could be performed successfully within one week after transplantation. Late reuse has, however, not been reported to date. We report the first case in which a liver graft was successfully reused 13 years after the first transplantation.

The prevalence of pulmonary toxoplasmosis was assessed by a prospective analysis of 144 bronchoalveolar lavage (BAL) samples using competitive polymerase chain reaction (PCR) to avoid false-negative results due to PCR techniques. Six samples were excluded because they contained amplification reaction inhibitors. None of the samples from the 37 immunocompetent patients and only 1 sample (1.7%) from the 59 immunocompromised patients without human immunodeficiency virus infection were PCR-positive. In contrast, Toxoplasma gondii DNA was found in 6 (14%) of 42 samples from patients with AIDS. All 6 patients had 40 CD4 cells/µL and anti-Toxoplasma antibodies, and 5 had other sites of Toxoplasma infection. Six other AIDS patients who had received treatment for cerebral toxoplasmosis were PCR-negative. Thus, pulmonary toxoplasmosis is frequent in AIDS patients who have other sites of Toxoplasma infection and low CD4 lymphocyte counts and who are not receiving prophylaxis.