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L Ferrell

Publications and source records attributed to L Ferrell.

At least 37 records · Page 2Linked to original sources
PubMed1997

Nomenclature of chronic hepatitis: the new look.

The new recommendations for nomenclature, grading, and staging of chronic hepatitis and related biliary and other disorders are attempts to standardize the criteria and simplify the terminology used in making these diagnoses. It is hoped that an emphasis on the etiology as part of the diagnosis will eliminate the previous association with poor prognosis that was implied with a diagnosis of CAH. The inclusion of a system of grading and staging, whether it is numerical or descriptive, simple or complex, matters less than the need for it to communicate important information about the degree of necroinflammatory activity (grade) and the extent of the disease (stage of fibrosis) that are likely factors of prognostic and therapeutic significance.

Hepatitis↗
PubMed1996

Treatment of patients with pineoblastoma with high dose cyclophosphamide.

The outcome for patients with pineoblastoma has historically been very poor, with most patients dying of disseminated disease despite irradiation. Furthermore, the low incidence of this tumor has hindered progress toward defining better treatment strategies. Here we report the activity and toxicity of cyclophosphamide administered as a single agent at a dose schedule of 2 g/m2/day for 2 successive days at monthly intervals for a maximum of four courses. Eight patients were evaluated, six newly diagnosed and two recurrent. Amongst the six newly diagnosed patients, there were three patients demonstrating partial responses, and three had stable disease throughout the cyclophosphamide treatment period. All six patients are alive and disease free after further therapy. One patient with recurrent disease demonstrated tumor progression on cyclophosphamide, and the other had stable disease throughout the cyclophosphamide treatment period. Both patients subsequently died of progressive disease. The major toxicity of high dose cyclophosphamide was hematopoietic, with one patient requiring a dose reduction after three courses due to prolonged thrombocytopenia. One patient was also withdrawn from treatment with cyclophosphamide due to impaired pulmonary function. This study demonstrates the activity of high dose cyclophosphamide in the treatment of pineoblastoma and may serve as basis for the design of future studies of this tumor.

Adolescent↗
PubMed1996

Successful treatment of childhood pilocytic astrocytomas metastatic to the leptomeninges with high-dose cyclophosphamide.

Leptomeningeal dissemination of childhood pilocytic astrocytoma (PA) is a rare event with little information available regarding therapy. We report here four children with disseminated PA whom we treated with high doses of cyclophosphamide with clinical benefit. The patients were aged 2.5 to 8 years. Three patients presented with PA localized in the posterior fossa, initially treated with surgical resection (n = 3) and radiotherapy (n = 1). Leptomeningeal dissemination occurred at 32, 44, and 8 months from diagnosis, respectively. The fourth patient presented with an optic pathway tumor with leptomeningeal dissemination at diagnosis. At commencement of cyclophosphamide therapy, disease was present in the subarachnoid space (intracranial, n = 2; spinal, n = 4), cerebral ventricles (n = 2), and primary site (n = 3). Histology was identical at diagnosis and recurrence in the two biopsied cases and cerebrospinal fluid was negative in all cases. Treatment was with cyclophosphamide 4-5 g/m2/cycle given every 4 weeks for a total of two cycles (n = 1) and four cycles (n = 3). One patient achieved disease stabilization (duration 27 months at the time of publication) and three patients experienced significant reductions in tumor burden. Subsequent intrathecal therapy was administered to two patients. Two patients developed disease progression at 10 and 9 months from cessation of chemotherapy. The one re-treated patient responded to further, lower dose, cyclophosphamide. This is the first report of the use of high dose cyclophosphamide for disseminated PA. The recurrence of disease in two cases with a further response to lower dose cyclophosphamide has implications for the optimal duration of therapy for these low grade, aggressive tumors.

Antineoplastic Agents, Alkylating↗
PubMed1996

Severity of liver disease in liver transplantation recipients with hepatitis C virus infection: relationship to genotype and level of viremia.

Infection with hepatitis C virus (HCV) genotype 1b has been reported to be associated with more severe posttransplantation liver disease than infection with non-1b genotypes. To address this issue, we evaluated the outcome in 124 patients who underwent liver transplantation for chronic HCV infection. The HCV genotype and/or serotype responsible for infection was determined by four different methods. HCV RNA was detected in serum samples by polymerase chain reaction (PCR) amplification, and quantified by branched DNA assay. Disease severity was expressed as a histological score (which included grading of portal inflammation, lobular activity, fibrosis, and cytopathic changes). Median duration of histological follow-up was 25 months (range 1-75 months). Genotype was assignable in 112 (92.5%) patients. Genotypes responsible for infection were as follows: 1a = 32.2%, 1b = 27.3%, 2a = 7.4%, 2b = 8.3%, 3a = 14%, and mixed infection (more than one subtype) = 3.3%. Level of viremia, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and total histological score were not significantly different in patients infected with type 1b compared with patients infected with other genotypes. While duration of histological follow-up was greater in patients infected with type lb versus other types (P = .02), by univariate and multivariate analysis neither HCV genotype (lb versus others), level of viremia nor duration of histological follow-up were associated with disease severity. Moreover, there was no significant difference in the actuarial graft survival in patients infected with type lb compared with that of patients infected with non-lb types (82% and 87% at 3 years, respectively). Reanalysis using HCV genotype 1 showed no association with disease severity, graft survival, and patient survival. We conclude that HCV genotype 1 and subtype 1b are not associated with disease severity or graft survival in liver transplantation recipients.

Adult↗
PubMed1996

Interferon alfa for recurrent hepatitis B infection after liver transplantation.

Reinfection with hepatitis B virus (HBV) after liver transplantation is nearly universal in patients not receiving immunoprophylaxis. Because reinfection reduces graft and patient survival, treatment of recurrent infection is important. Interferon alfa (IFN-alpha) is an effective therapy for chronic hepatitis B infection in immunocompetent patients, but its efficacy in transplant recipients has not been established. Fourteen liver transplant recipients with recurrent hepatitis B infection (hepatitis B surface antigen [HBsAg] positive in serum; hepatitis on biopsy) were treated with IFN-alpha 2b (Intron A; Schering Inc, Kenilworth, NJ) 3 million units (MU) three times weekly for 23.5 weeks (median, range 4 to 41). The primary endpoint was loss of HBV DNA by the b-DNA assay (a virological response). Before treatment, all patients were HBV DNA positive and 9 were hepatitis B e antigen (HBeAg) positive. Pretreatment HBV DNA levels were 6,760 MEq/mL (median, range 2.0 to 11,888 MEq/mL). HBV DNA levels decreased significantly with treatment (P = .03). Four patients had a complete and sustained virological response. Virological responses did not consistently correlate with biochemical response because of concomitant hepatitis C. Two patients had a serological response; 1 lost HBeAg, another lost HBeAg and HBsAg. All responders remained HBV DNA negative in follow-up (mean, 32 months; range, 23 to 40), but 1 patient required retransplantation for cirrhosis. Of the nonresponders, 1 patient required retransplantation for chronic rejection, 3 required retransplantation for recurrent hepatitis B, 3 died with recurrent hepatitis B, and 3 are alive and remain HBV DNA positive. IFN-alpha can induce a sustained serological (14%) and virological response (29%) in liver transplant recipients with recurrent HBV infection.

Hepatitis B↗
PubMed1996

Liver transplantation improves survival of rats bearing hepatoma-3924A.

There was interest in developing a rat model of hepatocellular carcinoma with tumor dissemination that would respond to liver transplantation. Thus, a model of intrahepatic hepatoma implantation with micrometastases was developed by modifying a previously reported technique in the ACI rat. The pattern of tumor growth permits surgical resection with liver transplantation if done early in the course of disease. In addition, this model results in a reproducible rate of pulmonary metastatic disease. The pulmonary metastatic rate (number of rats developing pulmonary metastases) was 45.5% (n = 11) 2 weeks following intrahepatic tumor implantation and rose to 100% at the fifth week (n = 7). To examine the long-term outcome of animals with tumor, 46 animals were followed until death or 100 days after tumor implantation. Of these animals, 67.4% died from tumor within 100 days, all with pulmonary metastases. Several of the animals that were followed long term had advanced liver tumor as well, with intraperitoneal spread and ascites. To evaluate the effect of orthotopic liver transplantation (OLTX) in this model, syngeneic OLTX was performed 16 days after intrahepatic tumor implantation (n = 11). OLTX improved the 100-day survival of the recipients from 32.6% (control group) to 80.0% (P < 0.05). None of the long-term survivors had evidence of tumor on postmortem examination. The mechanisms responsible for decreased metastases following syngeneic liver transplantation are being investigated. The influence of immunosuppression, more advanced stage of tumor at the time of OLTX, and chemotherapeutic agents on this survival benefit could be be investigated with this model.

Animals↗
PubMed1996

Hepatitis G virus infection in patients with hepatitis C virus infection undergoing liver transplantation.

BACKGROUND & AIMS: Hepatitis G virus (HGV) is transmissible by blood transfusion, but its role in chronic liver disease is unknown. The aim of this study was to determine the prevalence of HGV infection in patients infected with hepatitis C virus (HCV) undergoing transplantation and evaluate the effects of HGV coinfection on the course of posttransplantation HCV infection. METHODS: One hundred twenty-four patients infected with HCV undergoing liver transplantation were studied. Serum samples were tested for HCV and HGV RNA; HCV RNA was quantitated by branched DNA assay, and HCV genotype was determined. RESULTS: The prevalence of pretransplantation and posttransplantation HGV infection was 24% and 28%, respectively. Pre-transplantation HGV infection was positively correlated with posttransplantation HGV infection (P < 0.001). Pretransplantation clinical features were not different in patients infected with HCV with and without HGV infection. Posttransplantation HCV RNA levels were not significantly different in patients with and without HGV coinfection, but HCV genotype 1b was more frequent in patients with HGV coinfection. There were no differences in the histological severity of posttransplantation liver disease, graft, and patient survival between patients with and without HGV infection. CONCLUSIONS: Although HGV coinfection is frequent in patients with end-stage HCV disease undergoing liver transplantation, there is no association between the presence of HGV coinfection and the severity of liver disease post-transplantation, graft, or patient survival.

Adult↗
PubMed1996

Low proliferative activity in macroregenerative nodules: evidence for an alternate hypothesis concerning human hepatocarcinogenesis.

UNLABELLED: Macroregenerative nodules are commonly thought to be hyperplastic lesions, deriving both their large size and premalignant potential from an increased proliferative rate. We have previously suggested an alternate model of macroregenerative nodule development in which neither size nor premalignant potential of macroregenerative nodules would depend on increased proliferation. We tested this hypothesis by examining the proliferative activity in macroregenerative and surrounding cirrhotic nodules. METHODS: Eighteen macroregenerative nodules, including five type I and 13 type II, were immunostained for proliferating cell nuclear antigen (PCNA). Type II macroregenerative nodules included ten with diffuse large (7) or small (3) liver cell dysplasia only and eight containing nodule-in-nodule lesions. Five nodule-in-nodule lesions met the histologic criteria for hepatocellular carcinoma. PCNA labeling indices (PCNA-LIs; percentage positive hepatocyte nuclei/500 randomly counted cells) were determined in macroregenerative nodules and the four largest adjacent cirrhotic nodules. Nodule-in-nodule lesions were assessed separately from the background macroregenerative nodule. RESULTS: 4/5 type I and 12/13 type II macroregenerative nodules (exclusive of NIN lesions) had PCNA-LIs lower than the mean of surrounding cirrhotic nodules. All nodule-in-nodule lesions, whether atypical or overtly malignant, had PCNA-LIs greater than any surrounding nodules. In conclusion, macroregenerative nodules have PCNA-LIs indistinguishable from, and often lower than, surrounding cirrhotic nodules. Increased proliferative activity only occurs with the development of atypia and transition to hepatocellular carcinoma. CONCLUSION: Macroregenerative nodules derive neither their size nor their premalignant potential from on-going rapid proliferation, a finding consistent with our alternate hypothesis of macroregenerative nodule development.

Carcinoma, Hepatocellular↗
PubMed1995

Increased efficacy of CSA following rearterialization in the rat OLTX model.

Many investigators presently use a rat orthotopic liver transplant (OLTX) model without rearterialization of the graft. Rearterialization has been demonstrated to have a variable effect on the rejection response in various strain combinations. However, there are little data on the effects in a model with immunosuppression. The influence of rearterialization on the efficacy of cyclosporine (CSA) in such a model was examined, with the hypothesis that rearterialization may alter the rejection response and efficacy of cyclosporine. OLTX was performed between adult male D Agouti rats and Lewis rats. Rearterialization was performed between the recipient and donor celiac axis, and CSA was delivered at 1 mg/kg/day by continuous infusion for 14 days postoperatively. Treatment groups consisted of no rearterialization/no CSA, rearterialization/no CSA, no rearterialization/CSA, and rearterialization/CSA. Survival time and histology of liver grafts were measured. Rearterialization itself did not prolong survival in this strain combination (median survival no rearterialization/no CSA is 11 days versus median survival rearterialization/no CSA is 10 days). The addition of CSA at this dose without rearterialization also did not prolong survival (median survival no rearterialization/CSA is 15.5 days). The combination of CSA with rearterialization did prolong survival significantly (median survival rearterialization/CSA is 22 days; P < 0.05 versus the other three groups). The mechanism of this increased efficacy is unknown, but may involve altered MHC antigen expression, altered metabolism of CSA, decreased toxicity of CSA, or decreased nonspecific inflammation in the rearterialized grafts.

Animals↗
PubMed1995

Macroregenerative nodules in cirrhosis are not associated with elevated serum or stainable tissue alpha-fetoprotein.

We have explored the relationship of serum alpha-fetoprotein and macroregenerative nodules (MRNs), possible precursor lesions of hepatocellular carcinoma (HCC), and sought to demonstrate alpha-fetoprotein (AFP) expression in these nodules. One hundred and sixty-eight sequential adult cirrhotic resected livers were examined and MRNs were identified by standard criteria. Pretransplant serum AFP was available for 158 of these patients (normal < 20 ng/ml). One hundred and seventy-two randomly selected lesions, including ordinary and atypical MRNs, some containing microfoci of HCC, and HCCs were stained for AFP by immunohistochemistry. In the series, 12 cases had grossly apparent HCCs, four associated with high serum alpha-fetoprotein (p < 0.006). Forty-four cases had MRNs, 32 without grossly apparent HCC. Five of these 32 cases were associated with high serum AFP (not significant). Immuno-staining for AFP was seen in three specimens of HCC and in a cirrhotic nodule from a patient without HCC, but not in MRNs. 1) Neither the presence of MRNs--whether ordinary, atypical, or containing micro-foci of HCC--nor that of gross HCC is ruled out by a normal serum AFP. 2) Elevated serum AFP is not associated with the presence of MRNs. 3) MRNs rarely stain for tissue AFP.

Adenoma, Liver Cell↗
PubMed1995

Malignant liver tumors that mimic benign lesions: analysis of five distinct lesions.

The diagnosis of malignant liver tumors has long been an important part of surgical pathology, but now with improved radiographic and biopsy techniques, the appropriate pathological identification and differentiation of malignant from benign liver lesions has become even more critical. This review discusses five examples of malignant lesions that may be underdiagnosed as benign: well-differentiated hepatocellular carcinoma, fetal and macrotrabecular hepatoblastoma, well-differentiated cholangiocarcinoma, Kaposi's sarcoma, and epithelioid hemangioendothelioma.

Acquired Immunodeficiency Syndrome↗
PubMed1994

The increased efficacy and decreased nephrotoxicity of a cyclosporine liposome.

A potential approach to avoid the complications of systemic immunosuppression is to deliver immunosuppressive agents locally to the site of the allograft. Liposomes are phospholipid particles that allow delivery of drugs preferentially to the reticuloendothelial system. Since the liver is a primary component of the RES, we hypothesized that liposome technology could be utilized to deliver immunosuppressive agents locally to a transplanted liver, thereby avoiding the complications of systemically delivered immunosuppression. We evaluated this hypothesis with a prototypic cyclosporine liposome in a rat model. Pharmacokinetic studies of this liposome indicated earlier clearance from the systemic circulation and increased hepatic uptake relative to the standard intravenous form of CsA. Decreased nephrotoxicity was also shown in an ischemic kidney model in the rat. The immunosuppressive efficacy of this liposome was also tested in a rat liver transplant model. There was a significant increase in survival compared with standard intravenous CsA when both drugs were administered at a dose of 1.75 mg/kg/day for seven days posttransplant (P < .05, CsA liposome-treated versus CsA/saline-treated). There were no demonstrable early toxic effects or late toxic effects observed with follow-up to 100 days. These data indicate that CsA liposomes have potential for use as an immunosuppressive agent with increased efficacy and decreased nephrotoxicity relative to the commercially available form of intravenous CsA. This improved therapeutic index of a locally targeted drug may lead to fewer complications attributed to systemic immunosuppression.

Animals↗
PubMed1994

"Occult" hepatitis B virus as source of infection in liver transplant recipients.

Hepatitis B virus (HBV) infection almost always recurs after liver transplantation in patients who were surface antigen (HBsAg) positive before surgery but apparent de novo acquisition of infection in a transplant setting has not previously been reported. We have used sensitive techniques to elucidate the origin of such infections in patients in a California transplantation programme. We tested post-transplant serum from 207 patients who had been HBsAg negative and found 20 to be HBsAg positive. The origin of infection was identified in 7 patients, being occult pre-transplant infection in 5 and occult infection in the donor in 2. No pre-transplant patient nor donor with demonstrable HBV DNA had serological markers of hepatitis B. Post-transplant HBV DNA was present in serum from 19 patients. Analysis of the variable pre-S region of HBV demonstrated 100% sequence homology between recipient liver and post-transplant serum (2 patients) and between donor serum and recipient post-transplant serum (2). There was only 84% homology between the 2 different patients infected with subtype adw. 19 patients are alive, 9 without histological evidence of hepatitis (mean follow-up 33 months), and survival was significantly greater than that of a group with recurrent HBV infection. Apparent acquisition of HBV infection with liver transplantation is not rare, and may be due to occult pre-transplant infection or occult infection in the donor. The post-transplant outcome of this infection tends to be benign but our findings do underscore the clinical relevance of HBV infection in the absence of serological markers.

Adolescent↗
PubMed1994

Interferon-alpha therapy for hepatitis C virus infection after liver transplantation.

The aims of this pilot study were to evaluate the safety and efficacy of interferon-alpha 2b for treatment of hepatitis C virus infection in liver transplant recipients, to monitor changes in hepatitis C virus RNA levels with treatment and to determine pretreatment parameters predictive of a complete response. Eighteen patients with documented hepatitis C virus viremia and histological evidence of hepatitis after liver transplantation received 3 million units of alpha interferon three times weekly for at least 4 mo. Pretreatment serum aminotransferase levels were at least 1.5 times the upper limit of normal and no patient had concomitant hepatitis B virus infection. Response to therapy was defined as normalization of both aspartate and alanine aminotransferase at the end of treatment. Five patients (28%) had a complete response, whereas 13 (72%) had persistent elevation of one or both aminotransferases (nonresponders). At the end of therapy, hepatitis C virus RNA levels were reduced in both responders and nonresponders (p = 0.043 and 0.039, respectively by Wilcoxon signed rank test). After cessation of treatment, aminotransferases remained normal in four of five responders but serum hepatitis C virus RNA levels returned to pretreatment levels in responders and nonresponders. There was no significant change in histological score with therapy. Responders were more likely than nonresponders to have low pretreatment hepatitis C virus RNA levels and low serum bilirubin (p = 0.0004 and 0.0077, respectively). Responders tended to have a prolonged interval between transplantation and initiation of therapy (p = 0.10 by rank logistic regression analysis). Side effects resulted in early cessation of therapy in two patients and dose reduction in six.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1994

Quantitation of hepatitis C virus RNA in liver transplant recipients.

BACKGROUND/AIMS: Hepatitis C virus (HCV) infection is common in liver transplant recipients, yet the effects of immunosuppression on HCV RNA levels and the relationship of HCV RNA levels to hepatic damage have not been studied. METHODS: To explore these issues, we measured HCV RNA in serum by polymerase chain reaction amplification and branched DNA assay from 100 HCV-infected patients undergoing liver transplantation. RESULTS: Mean posttransplant levels were 16-fold higher than pretransplant values (7,935,000 and 496,000 Eq/mL, respectively; n = 65; P < 0.0001). Patients with high pretransplant levels had higher mean posttransplant levels than those with low pretransplant levels (17,119,000 and 6,504,000 Eq/mL, respectively; P = 0.064). Posttransplant levels were similar in patients with recurrent and acquired infection and were independent of time of sampling. Fifty percent of patients with HCV infection had normal liver biopsy specimens, and there was no strong relationship between level of viremia and degree of hepatic damage. CONCLUSIONS: HCV RNA levels increase markedly following liver transplantation. The frequent finding of viremia in the absence of histological hepatitis suggests that a "carrier state" is common. Absence of allograft damage in some (despite high levels of viral RNA) suggests that in immunosuppressed patients, HCV infection may be tolerated without direct hepatic damage.

Base Sequence↗
PubMed1994

Hepatocellular nodules in the cirrhotic liver: diagnostic features and proposed nomenclature.

Large nodules occurring within cirrhotic livers are not necessarily indicative of hepatocellular carcinoma. They actually fall into three distinct histologic categories, which have been labeled in different ways by different investigators. Standardized nomenclature under consideration by the World Congress of Gastroenterology is outlined here, as are the diagnostic features, therapy, and prognosis for these lesions.

Carcinoma, Hepatocellular↗
PubMed1993

Cirrhosis of undefined pathogenesis: absence of evidence for unknown viruses or autoimmune processes.

To examine whether unknown viruses or autoimmune processes contribute to the development of cryptogenic liver disease, we studied 48 patients undergoing liver transplantation who had non-A, non-B cirrhosis; non-blood-borne cirrhosis of unknown etiology; or autoimmune cirrhosis. After the diagnosis of hepatitis C virus infection was established by the presence of viral antibodies or viral RNA, patients were reclassified into three groups: hepatitis C virus infection, autoimmune cirrhosis and cryptogenic cirrhosis. Explant histological appearance, incidence of posttransplant hepatitis and immunological features were compared in the three groups. Thirty-one percent of patients had neither hepatitis C virus infection nor classical autoimmune cirrhosis and were classified as having cryptogenic cirrhosis. Unlike histological appearance in hepatitis C virus infection but similar to that in autoimmune cirrhosis, explant histological appearance of cryptogenic cirrhosis showed inactive cirrhosis with little inflammation. After transplantation, histological hepatitis of the allograft was demonstrated in 44% of patients with hepatitis C infection but in no patient with autoimmune or cryptogenic cirrhosis. The autoimmune score, developed from clinical criteria associated with autoimmune liver disease, was significantly lower in cryptogenic cirrhosis and hepatitis C virus infection than in autoimmune cirrhosis. Autoantibodies--including antinuclear antibodies, smooth muscle antibodies and liver-kidney microsomal antibodies--were not commonly present in serum of patients with cryptogenic cirrhosis, whereas antibodies to soluble liver antigens were found with increased frequency in this entity. We conclude that in many patients with liver disease, no pathogenesis can be identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoimmune Diseases↗