The proposed risk-score grading predicted the survival differences extremely well. Estimated survival as determined by the Cox proportional hazards model was similar to that determined by the Kaplan-Meier method. Verification and further improvements of the proposed system are awaited by other centers or international collaborative studies.

Invasive aspergillosis occurred in 26 liver transplant recipients since 1990 at five liver transplant centers. The median time to onset was 17 days after transplantation. Twenty-seven percent of the patients had undergone retransplantation. Invasive aspergillosis occurred significantly earlier after transplantation in smokers than in nonsmokers (P=0.017). Patients with late-onset aspergillosis (occurring after posttransplant day 90) were more likely to have had prior cytomegalovirus infection than those with early-onset aspergillosis (occurring within 90 days of transplantation) (67% vs. 10%, respectively, P=0.013). Only 8% of the patients had received additional corticosteroids or OKT3, which suggests that augmented immunosuppression may not be a relevant risk factor for invasive aspergillosis in the 1990s due to less frequent use of these agents. The median serum bilirubin level of the patients was 21.8 mg/dl, 85% of the patients had renal insufficiency, and 54% were on dialysis before the onset of invasive aspergillosis, which suggest that overall severity of illness, including poorly functioning hepatic allograft and renal failure may be the major determinants of disease occurrence. Overall mortality was 92% (24/26). No difference in mortality could be shown for the patients who received amphotericin B versus liposomal amphotericin B preparations (100% vs. 89%); however, the mean time to death after the initiation of therapy was 20 days in patients who received amphotericin B and 43 days in those who received liposomal amphotericin B preparations.

The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists regarding the cellular origin of human liver parenchymal tissue generation during embryonic development, homeostasis or repair. Here we report the existence of a hepatobiliary hybrid progenitor (HHyP) population in human foetal liver using single-cell RNA sequencing. HHyPs are anatomically restricted to the ductal plate of foetal liver and maintain a transcriptional profile distinct from foetal hepatocytes, mature hepatocytes and mature BECs. In addition, molecular heterogeneity within the EpCAM + population of freshly isolated foetal and adult human liver identifies diverse gene expression signatures of hepatic and biliary lineage potential. Finally, we FACS isolate foetal HHyPs and confirm their hybrid progenitor phenotype in vivo. Our study suggests that hepatobiliary progenitor cells previously identified in mice also exist in humans, and can be distinguished from other parenchymal populations, including mature BECs, by distinct gene expression profiles.

No abstract

A total of 103 cases of hepatocellular carcinoma (HCC) arising in native livers discovered at the time of transplantation underwent allelic loss analysis. HCC mutational allelotyping targeted 10 genomic loci (1p, 3p, 5q, 7q, 8q, 9p, 10q, 17p, 17q, 18q)

Immunosuppressive-associated leukoencephalopathy is a significant complication of cyclosporine (CsA) or tacrolimus therapy. However, the precise time of onset, role of putative risk factors, differences, if any, in presentation in various types of organ transplantation and outcome of this entity, remain poorly defined. Fifty cases of immunosuppressive-associated leukoencephalopathy reported in the literature in organ transplant recipients, were reviewed. Of 50 cases, 31 occurred in liver, 8 in renal, 6 in lung, and 5 in heart transplant recipients. Median time to onset was 28 days (range 3-1512 days); 82% occurred within 90 days of transplantation. Lesions tended to occur earlier in the liver transplant recipients, compared with other organ transplant recipients (median 9 vs. 29 days, P=.19). Seizures 74%, altered mental status 50%, and visual abnormalities 28% were the most frequently presenting features. Ten percent of the patients had fever with no documented source of infection. Systemic hypertension (P=.001), and lesions in the presence of therapeutic drug levels (P=.11) were more likely to occur with CsA than tacrolimus. Neuroimaging and clinical abnormalities were reversible on cessation or reduction of CsA or tacrolimus in all but two cases. Resolution of neurologic signs/symptoms occurred a median of 4 days and neuroimaging abnormalities in a median of 20 days on reduction/cessation of the drug. Immunosuppressive-associated leukoencephalopathy is a unique entity that can usually be diagnosed on the basis of its distinctive time of onset, and clinical and neuroimaging characteristics, and it is potentially reversible if promptly diagnosed. Despite identical clinical presentation of this syndrome in the recipients of CsA and tacrolimus, above noted variations in risk factors suggest that a difference in pathophysiologic mechanism may exist.

Patients with human immunodeficiency virus (HIV) most often have hepatitis C virus (HCV) or hepatitis B (HBV) virus coinfection, or both, as a cause of their liver disease. Recent survival statistics show that patients infected with HIV treated with highly active antiretroviral therapy (HAART) can expect a significant prolongation of life by interfering with the natural progression of HIV to aquired immune deficiency syndrome (AIDS). Therefore, HIVpositive patients experiencing complications of liver failure are at greater immediate risk of dying from their end-stage liver disease (ESLD) rather than their HIV. Many transplant centers still consider HIV infection as a contraindication for orthotopic liver transplantation (OLT). At our two institutions, we believe that patients with HIV suffering from ESLD should be considered for OLT. This study evaluates the survival of patients undergoing OLT with HIV under HAART therapy. OLT was performed in 16 patients with HIV suffering from ESLD as a result of chronic HCV, chronic HBV, or fulminant hepatic failure (FHF). Collected data include patient demographics, patient and graft survival, pre-OLT assessments, and postoperative complications (including opportunistic infections). Ten patients at Pittsburgh and 6 patients at Miami received OLT. Of the 16 patients who received OLT, 14 remain alive to date. Thirteen of 16 patients are more than 12 months post-OLT, whereas the last patient is currently 6 months post-OLT. Five patients at Miami and 9 of 10 patients at Pittsburgh received HAART therapy before OLT, although 2 of the Pittsburgh patients had their HAART therapy discontinued before OLT because of significant liver dysfunction. The pre-OLT viral loads were undetectable in 13 of 16 patients. The cluster determinant (CD)4 count was less than 200 in 6 patients and greater than 100 in 2 patients before OLT. In all patients, CD4 counts increased above 200 in the post-OLT period. Tacrolimus toxicity associated with the pharmacologic inhibition of cytochrome p450 metabolism caused by protease inhibitors occurred in 6 patients after OLT. Six patients (38%) experienced acute cellular rejection immediately after OLT. Our experience suggests that OLT is effective in selected HIV-positive patients suffering from ESLD. Patient and graft survival was similar to non-HIV-positive patients suffering from the same indications for OLT. Acute cellular rejection was no less frequent that seen in non-HIV-positive patients. Given the complex pharmacologic interactions between the protease inhibitors and tacrolimus, careful monitoring, and attention is required to prevent toxicity or underdosing. (Liver Transpl 2003;9:239-247.)

The gross and histopathologic characteristics of 212 nonfibrolamellar hepatocellular carcinomas (HCCs) discovered in native livers removed at the time of liver transplantation were correlated with features of invasive growth and tumorfree survival. The results show that most HCCs begin as small well-differentiated tumors that have an increased proliferation rate and induce neovascularization, compared with the surrounding liver. But at this stage, they maintain a near-normal apoptosis/mitosis ratio and uncommonly show vascular invasion. As tumors enlarge, foci of dedifferentiation appear within the neoplastic nodules, which have a higher proliferation rate and show more pleomorphism than surrounding better-differentiated areas. Vascular invasion, which is the strongest predictor of disease recurrence, correlates significantly with tumor number and size, tumor giant cells and necrosis, the predominant and worst degree of differentiation, and the apoptosis/mitosis ratio. In the absence of macroscopic or large vessel invasion, largest tumor size (P < .006), apoptosis/mitosis ratio (P < .03), and number of tumors (P < .04) were independent predictors of tumor-free survival and none of 24 patients with tumors having an apoptosis/mitosis ratio greater than 7.2 had recurrence. A minority of HCCs (<15%) quickly develop aggressive features (moderate or poor differentiation, low apoptosis/mitosis ratio, and vascular invasion) while still small, similar to flat carcinomas of the bladder and colon. In conclusion, hepatic carcinogenesis in humans is a multistep and multifocal process. As in experimental animal studies, aggressive biologic behavior (vascular invasion and recurrence) correlates significantly with profound alterations in the apoptosis/mitosis ratio and with architectural and cytologic alterations that suggest a progressive accumulation of multiple genetic abnormalities. (HEPATOLOGY 2001;34: 502-510.)