Currently there are three major problems in understanding drug-induced liver injury (DILI): (1) reliably establishing whether the liver disease was caused by the drug, or by another process; (2) ...determining the true incidence of and clinical risk factors for drug-induced hepatotoxicity; and (3) elaborating the mechanisms by which injury occurs to hepatocytes and other liver cells. We have focused here on the first two problems, as issues that may be amenable to actions in the near future, but the third may take substantially longer to work out. The first problem requires sufficient information for medical differential diagnosis. There are no pathognomonic indicators of DILI; even liver biopsy is not diagnostic. Making the correct attribution of causality requires analyzing the temporal relationship of drug exposure to illness and excluding all other possible causes. The second problem, determining incidence, cannot be done entirely adequately using currently available methods, whether by clinical trials, by spontaneous adverse event reports, or by retrospective epidemiologic studies. There is need for prospective safety studies to establish the true incidence of DILI caused by a drug, to identify risk factors for it, and to collect biologic materials for analytic studies toward better understanding mechanisms of DILI.
To study and report the clinical outcomes and patterns of failure after intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC).
The treatment outcomes of NPC patients treated with ...IMRT at Pamela Youde Nethersole Eastern Hospital between 2005 and 2007 were reviewed. The location and extent of locoregional failures were transferred to the pretreatment planning computed tomography for dosimetry analysis. Statistical analyses were performed on dose coverage and locoregional failures.
A total of 193 NPC patients were analyzed; 93% had Stage III/IV disease. Median follow-up was 30 months. Overall disease failure (at any site) developed in 35 patients. Among these, there were 23 distant metastases, 16 local failures, and 9 regional failures. Four of the locoregional failures were marginal. Dose conformity with IMRT was excellent. Patients with at least 66.5 Gy to their target volumes had significantly less locoregional failure. The 2-year local progression-free, regional progression-free, distant metastasis-free, and overall survival rates were 95%, 96%, 90%, and 92%, respectively.
Intensity-modulated radiotherapy provides excellent locoregional control for NPC. Distant metastasis remains the most difficult challenge, and more effective systemic agents should be explored for patients presenting with advanced locoregional diseases.
The most effective therapy currently available for treatment of chronic hepatitis C virus (HCV) is the combination of peginterferon and ribavirin. This study evaluated the effectiveness of this ...treatment in patients who were nonresponders to previous interferon-based therapy.
The first 604 patients enrolled in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial were evaluated. All were HCV RNA positive, previous nonresponders to interferon, with or without ribavirin, and had bridging fibrosis or cirrhosis on liver biopsy (Ishak fibrosis stage 3-6). Patients were retreated with peginterferon alfa-2a 180 microg/wk plus ribavirin 1000-1200 mg/day. Those with no detectable HCV RNA in serum at week 20 continued treatment for a total of 48 weeks and were then followed for an additional 24 weeks.
Thirty-five percent of patients had no detectable HCV RNA in serum at treatment week 20, and 18% achieved sustained virologic response (SVR). Factors associated with an SVR included previous treatment with interferon monotherapy, infection with genotypes 2 or 3, a lower AST:ALT ratio, and absence of cirrhosis. Reducing the dose of ribavirin from > or =80% to < or =60% of the starting dose during the first 20 weeks of treatment was associated with a decline in SVR from 21% to 11% (P < or = 0.05). In contrast, reducing the dose of peginterferon or reducing ribavirin after week 20, when HCV RNA was already undetectable, did not significantly affect SVR.
Selected nonresponders to previous interferon-based therapy can achieve SVR following retreatment with peginterferon alfa-2a and ribavirin.
Background & Aims
:
Progression of hepatic encephalopathy (HE) is a major determinant of outcome in acute liver failure (ALF). Our aim was to identify predictive factors of worsening HE, including ...the relation of encephalopathy with the systemic inflammatory response (SIRS) and infection.
Methods
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We included 227 consecutive patients with stage I-II HE prospectively enrolled in the U.S. Acute Liver Failure Study. Univariate and multivariate analysis of 27 variables at admission were performed separately for acetaminophen (n = 96) and nonacetaminophen (n = 131) etiologies.
Results
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On multivariate analysis, acquisition of infection during stage I-II HE (
P < 0.01), increased leukocyte levels at admission (
P < 0.01), and decreased platelet count (
P < 0.05) were predictive factors of worsening HE in the acetaminophen group. By contrast, only increased pulse rate (
P < 0.05) and AST levels (
P < 0.05) at admission were predictors in nonacetaminophen patients. In patients who progressed to deep HE, the first confirmed infection preceded progression in 15 of 19 acetaminophen patients compared with 12 of 23 nonacetaminophen patients. In patients who did not demonstrate positive microbiologic cultures, a higher number of components of SIRS at admission was associated with more frequent worsening of HE (25% vs. 35% vs. 50% for 0, 1, and ≥2 components of SIRS,
P < 0.05).
Conclusions
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This prospective evaluation points to infection and/or the resulting systemic inflammatory response as important factors contributing to worsening HE in ALF, mainly in patients with acetaminophen- induced ALF. The use of prophylactic antibiotics in these patients and the mechanisms by which infection triggers hepatic encephalopathy require further investigation.
Alpha-fetoprotein (AFP) has been useful in the diagnosis of hepatocellular carcinoma (HCC) but lacks specificity. We assessed serum AFP among patients with chronic hepatitis C and advanced fibrosis ...to establish predictors of AFP elevations and changes with antiviral therapy.
Serum AFP was measured at baseline and on therapy in patients in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C). AFP levels were correlated with patient demographic and clinical features.
Baseline AFP was ≥20
ng/mL in 191 of 1145 patients (16.6%). Mean AFP values were significantly higher in patients with cirrhosis than in those with bridging fibrosis (22.5 vs. 11.4
ng/mL,
P<0.0001). Factors independently associated with raised serum AFP in patients with cirrhosis were female gender, black race, decreased platelet count, increased serum AST/ALT ratio, serum ferritin, and Mallory bodies in liver biopsies. Serum AFP levels decreased significantly during therapy with pegylated interferon α-2a and ribavirin. HCC was identified in six subjects, only three of whom had AFP>20
ng/mL.
Among patients with advanced chronic hepatitis C, serum AFP values are frequently elevated, even in the absence of HCC. Factors associated with raised AFP include severity of liver disease, female gender and black race. Serum AFP levels decline during antiviral therapy.
Background Hospital outbreaks of epidemiologically important pathogens are usually caused by lapses in infection control measures and result in increased morbidity, mortality, and cost. However, ...there is no benchmark to compare the occurrence of hospital outbreaks across hospitals. Methods We implemented proactive infection control measures with an emphasis on timely education of health care workers and hospitalized patients at Queen Mary Hospital, a teaching hospital. Our benchmarked performance (outbreak episodes per 1 million patient discharges and 1 million patient-days) was compared with those of other regional public hospitals without these additional proactive measures in place between 2010 and 2014. Results During the study period, Queen Mary Hospital had 1 hospital outbreak resulting in 1.48 and 0.45 outbreak episodes per 1 million patient discharges and patient-days, respectively, values significantly lower than the corresponding overall rates in the 7 acute regional hospitals (24.26 and 6.70 outbreak episodes per 1 million patient discharges and patient-days, respectively; P < .001) and that of all 42 public hospitals in Hong Kong (41.62 and 8.65 outbreak episodes per 1 million patient discharges and patient-days, respectively; P < .001). Conclusions The results of this large study on benchmarked rate of hospital outbreaks per patient discharges or patient-days suggests that proactive infection control interventions may minimize the risk of hospital outbreaks.
Monitoring of intracranial pressure (ICP) in acute liver failure (ALF) is controversial as a result of the reported complication risk (∼20%) and limited therapeutic options for intracranial ...hypertension. Using prospectively collected information from 332 patients with ALF and severe encephalopathy, we evaluated a recent experience with ICP monitoring in the 24 centers constituting the U.S. ALF Study Group. Special attention was given to the rate of complications, changes in management, and outcome after liver transplantation (LT). ICP monitoring was used in 92 patients (28% of the cohort), but the frequency of monitoring differed between centers (P < 0.001). ICP monitoring was strongly associated with the indication of LT (P < 0.001). A survey performed in a subset of 58 patients with ICP monitoring revealed intracranial hemorrhage in 10.3% of the cohort, half of the complications being incidental radiological findings. However, intracranial bleeding could have contributed to the demise of 2 patients. In subjects listed for LT, ICP monitoring was associated with a higher proportion of subjects receiving vasopressors and ICP‐related medications. The 30‐day survival post‐LT was similar in both monitored and nonmonitored groups (85% vs. 85%). In conclusion, the risk of intracranial hemorrhage following ICP monitoring may have decreased in the last decade, but major complications are still present. In the absence of ICP monitoring, however, patients listed for LT appear to be treated less aggressively for intracranial hypertension. In view of the high 30‐day survival rate after LT, future studies of the impact of intracranial hypertension should also focus on long‐term neurological recovery from ALF. (Liver Transpl 2005;11:1581–1589.)
Knowledge of the presence of cirrhosis is important for the management of patients with chronic hepatitis C (CHC). Most models for predicting cirrhosis were derived from small numbers of patients and ...included subjective variables or laboratory tests that are not readily available. The aim of this study was to develop a predictive model of cirrhosis in patients with CHC based on standard laboratory tests. Data from 1,141 CHC patients including 429 with cirrhosis were analyzed. All biopsies were read by a panel of pathologists (blinded to clinical features), and fibrosis stage was determined by consensus. The cohort was divided into a training set (n = 783) and a validation set (n = 358). Variables that were significantly different between patients with and without cirrhosis in univariate analysis were entered into logistic regression models, and the performance of each model was compared. The area under the receiver-operating characteristic curve of the final model comprising platelet count, AST/ALT ratio, and INR in the training and validation sets was 0.78 and 0.81, respectively. A cutoff of less than 0.2 to exclude cirrhosis would misclassify only 7.8% of patients with cirrhosis, while a cutoff of greater than 0.5 to confirm cirrhosis would misclassify 14.8% of patients without cirrhosis. The model performed equally well in fragmented and nonfragmented biopsies and in biopsies of varying lengths. Use of this model might obviate the requirement for a liver biopsy in 50% of patients with CHC. In conclusion, a model based on standard laboratory test results can be used to predict histological cirrhosis with a high degree of accuracy in 50% of patients with CHC.
When Sertoli and germ cells were co-cultured in vitro in serum-free chemically defined medium, functional anchoring junctions such as cell-cell intermediate filament-based desmosome-like junctions ...and cell-cell actin-based adherens junctions (e.g. ectoplasmic specialization (ES)) were formed within 1-2 days. This event was marked by the induction of several protein kinases such as phosphatidylinositol 3-kinase (PI3K), phosphorylated protein kinase B (PKB; also known as Akt), p21-activated kinase-2 (PAK-2), and their downstream effector (ERK) as well as an increase in PKB intrinsic activity. PI3K, phospho (p)-PKB, and PAK were co-localized to the site of apical ES in the seminiferous epithelium of the rat testis in immunohistochemistry studies. Furthermore, PI3K also co-localized with p-PKB to the same site in the epithelium as determined by fluorescence microscopy, consistent with their localization at the ES. These kinases were shown to associate with ES-associated proteins such as β1-integrin, phosphorylated focal adhesion kinase, and c-Src by co-immunoprecipitation, suggesting that the integrin·laminin protein complex at the apical ES likely utilizes these protein kinases as regulatory proteins to modulate Sertoli-germ cell adherens junction dynamics via the ERK signaling pathway. To validate this hypothesis further, an in vivo model using AF-2364 (1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide) to perturb Sertoli-germ cell anchoring junction function, inducing germ cell loss from the epithelium in adult rats, was used in conjunction with specific inhibitors. Interestingly, the event of germ cell loss induced by AF-2364 in vivo was also associated with induction of PI3K, p-PKB, PAK-2, and p-ERK as well as a surge in intrinsic PKB activity. Perhaps the most important of all, pretreatment of rats with wortmannin (a PI3K inhibitor) or anti-β1-integrin antibody via intratesticular injection indeed delayed AF-2364-induced spermatid loss from the epithelium. In summary, these results illustrate that Sertoli-germ cell anchoring junction dynamics in the testis are regulated, at least in part, via the β1-integrin/PI3K/PKB/ERK signaling pathway.
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