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Biomedical subjects

Emma E Furth

Publications and source records attributed to Emma E Furth.

At least 37 records · Page 2Linked to original sources
PubMed2004

Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome.

Appropriate patient selection is crucial in ensuring acceptable outcomes from orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). The United Network for Organ Sharing (UNOS) has elected to prioritize HCC patients for OLT based on criteria of tumor burden. However, it is unclear whether these criteria correlate with outcome, or with the pathobiological features associated with tumor recurrence. Therefore, we analyzed 109 consecutive patients undergoing OLT for HCC at our center, to determine the utility of present selection criteria in predicting outcome. Pathologic tumor staging of the explanted liver was based on the American Tumor Study Group modified tumor node metastases (pTNM) classification system. Multifocality was defined as >4 tumor nodules on explant. Survival analysis was performed using Kaplan-Meier and Cox proportional hazards regression methods. At a median follow-up of 18.9 months, the overall mortality was 19% with 15 patients (14%) dying of recurrent HCC. Kaplan-Meier 1, 3 and 5-year survival rates were 89.5%, 68%, and 65%, respectively. Recurrence-free rates of 1, 3, and 5 years were 89%, 75%, and 65%, respectively. On univariate analysis, the factors found to be significantly associated with recurrence of HCC were explant features of macrovascular invasion, tumor size (per centimeter increase), pTNM stage (per 1-stage increase), and pre-transplant serum alphafetoprotein (AFP) >300 ng/mL. In defining a threshold level, we found that explant tumor diameter > or =3 cm, and those tumors classified as at least pT3 on pathological examination, were significantly associated with recurrence (P =.01 and.03, respectively). Tumor size on explant was found to be strongly correlated with multifocality (P =.017) and vascular invasion (P =.02). Patients exceeding pathological UNOS criteria were 3.1 times more likely to have recurrence of HCC (P =.03). In conclusion, we found that tumor size appears to be a surrogate marker for negative pathobiological predictors of outcome, i.e., vascular invasion and multifocality. Present UNOS selection criteria for HCC based on tumor burden appear to provide adequate discriminatory power in predicting outcome of OLT.

Adult↗
PubMed2004

The role of beta-catenin, TGF beta 3, NGF2, FGF2, IGFR2, and BMP4 in the pathogenesis of mesenteric sclerosis and angiopathy in midgut carcinoids.

A subset of midgut carcinoids (MCs) result in mesenteric angiopathy (MA) and bowel infarction as a consequence of vascular compression caused by extensive mesenteric sclerosis (MS). The goal of this study was to determine whether the level of expression of several fibrosing-related growth factors was related to the finding of MA and/or MS in MCs. Eighteen cases of MC, 6 with both extensive MS and MA (group I), 5 with extensive MS only (group II), and 7 with ordinary MS only (group III), were analyzed for immunoexpression of beta-catenin, transforming growth factor-beta 2 (TGF beta 2), nerve growth factor 2 (NGF2), fibroblast growth factor 2 (FGF2), insulin growth factor receptor (IGFR), and bone morphogenic protein 4 (BMP4) in formalin-fixed, paraffin-embedded sections. Standard immunohistochemical technique was used following antigen retrieval. Immunostaining was scored semiquantitively as the product of the percentage and intensity (0 to 2+) of the immunostaining, giving a possible range of 0 to 200. One-way analysis of variance and Mann-Whitney nonparametric analyses were used for statistical analysis. The mean scores of immunoreactivity of each factor in groups I, II, and III were as follows: 135, 174, and 147 for beta-catenin (cytoplasmic reactivity only); 106, 112, and 92 for TGF beta 3; 1.67, 32, and 36 for NGF-2; 2.5, 48, and 55 for FGF-2; 19, 112, and 66 for IGFR2; 140, 45, and 52 for BMP4. There were significant differences in NGF-2 immunoreactivity between groups I and III (P = 0.0023) and in BMP4 immunoreactivity between groups I and II (P = 0.017) and groups I and III (P = 0.022). All MCs expressed high levels of membranous beta-catenin, moderate levels of TGF beta 3 and IGFR2, and low levels of FGF-2, with no significant differences seen among the groups. MCs with prominent MS and MA (group I) expressed significantly higher BMP4 than those in groups II and III, suggesting a potential role of BMP4 in the pathogenesis of MA. The level of NGF-2 expression was significantly lower in group I than in group III, possibly indicating abnormal angiogenesis in the formation of angiopathy.

Carcinoid Tumor↗
PubMed2004

Pattern of ischemia reperfusion injury in a mouse orthotopic liver transplant model.

BACKGROUND: The molecular pathways of ischemic injury after liver transplantation are complex and difficult to dissect because of the presence of many variables. Transgenic and genetically deficient strains of mice provide ideal models for the study of the contribution of a single gene product in biological processes in vivo. Although well described in rats, prolonged preservation has not been studied in a mouse model of orthotopic liver transplantation (mOLT). The aim of this study was to establish a model of cold ischemia and reperfusion injury in mOLT and describe the pattern of the regenerative response to various lengths of cold storage. MATERIALS AND METHODS: mOLT was performed using a syngeneic combination. Grafts were preserved at 4 degrees C in University of Wisconsin (Viaspan) solution for increasing periods of cold preservation. After cold storage, the liver grafts were transplanted and recipient survival was monitored. Hepatocellular injury was determined by histology, and the regenerative response was quantitated by interleukin 6 upregulation and DNA replication. RESULTS: Long-term survival was 100%, 100%, 88%, and 0% for cold preservation of 1, 4, 8, and 16 h, respectively. Grafts with short preservation times (1 and 4 h) demonstrated limited injury and a weak regenerative response, with slight IL-6 early upregulation and minimal cell division. Eight hours of cold ischemia resulted in prominent injury and an intense regenerative response accompanied by significant IL-6 upregulation and DNA synthesis. Sixteen hours of storage resulted in all recipients succumbing to liver failure, with histology showing extensive hepatic necrosis. CONCLUSIONS: This study demonstrated the feasibility of using the mOLT model for the study of molecular mechanisms associated with recovery from cold ischemia and reperfusion injury. Increasing lengths of cold ischemia correlate with progressive tissue damage whereas recovery is associated with a regenerative response that correlates with the severity of injury.

Animals↗
PubMed2004

Redistribution of thorotrast into a liver allograft several years following transplantation: a case report.

Thorotrast was used as a radiographic contrast agent in the United States from about 1930 to the mid-1950 s. Its use was discontinued when it was recognized that its radioactivity caused long-term deleterious effects. Such long-term sequelae of intravascular Thorotrast injection include, most notably, hepatic and hematologic malignancies and hepatic fibrosis. Some patients who had received Thorotrast subsequently received liver transplants. However, it was not known whether or not Thorotrast could become redistributed within the new allograft. A single report in 1994 demonstrated that radioactivity was detected by gamma-ray spectroscopy in liver allografts shortly after transplantation. No report has identified Thorotrast in the allografts of long-term transplant survivors, and the redistribution of Thorotrast into allografts has not been documented histologically or by electron microscopy. We report a case of recurrent Thorotrast into a liver allograft 10 years post-transplant. We evaluated the native liver and allograft specimens for the presence of thorium utilizing light microscopy, electron microscopy and electron X-ray microanalysis. This case report demonstrates for the first time the redistribution of Thorotrast into a long-surviving liver allograft using histologic, electron microscopic and X-ray microanalysis techniques.

Cholangitis, Sclerosing↗
PubMed2004

Percutaneous ablation of VX2 carcinoma-induced liver tumors with use of ethanol versus acetic acid: pilot study in a rabbit model.

PURPOSE: Acetic acid has been employed as a chemical ablation agent for liver tumors because of its superior diffusion characteristics compared with ethanol and the resulting requirement for smaller volumes and fewer injection sessions. Early tissue changes were compared after injection of acetic acid and ethanol in a rabbit model of hepatocellular carcinoma. MATERIALS AND METHODS: VX2 tumors were created in the left lobe of the liver in 11 male New Zealand White rabbits. Each animal underwent a midline minilaparotomy to expose the tumor-laden left lobe, followed by injection of 1.0 mL of 100% ethanol (n = 5) or 50% acetic acid (n = 6) with use of a 20-gauge infusion needle. Animals were killed 30 minutes after surgery; explanted livers were sectioned and examined for gross and microscopic changes. RESULTS: Injection of each agent produced rapid diffusion through tumor and surrounding hepatic parenchyma, with immediate protein precipitation manifested by blanching as a result of coagulation effect. The sizes of coagulation zones, expressed as mean products of the maximum perpendicular diameters of tumoral diffusion, were 13.0 cm(2) +/- 9.4 and 1.3 cm(2) +/- 1.8 for acetic acid and ethanol, respectively (P =.049). No differences in histologic changes were seen between agents. CONCLUSIONS: In this animal model, acetic acid produced significantly larger zones of tumor coagulation compared with ethanol when injected into VX2 carcinoma in equal volumes. Further evaluation is necessary before these findings can be extrapolated to a clinical setting.

Acetic Acid↗
PubMed2004

Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes.

The Werner and Bloom syndromes are caused by loss-of-function mutations in WRN and BLM, respectively, which encode the RecQ family DNA helicases WRN and BLM, respectively. Persons with Werner syndrome displays premature aging of the skin, vasculature, reproductive system, and bone, and those with Bloom syndrome display more limited features of aging, including premature menopause; both syndromes involve genome instability and increased cancer. The proteins participate in recombinational repair of stalled replication forks or DNA breaks, but the precise functions of the proteins that prevent rapid aging are unknown. Accumulating evidence points to telomeres as targets of WRN and BLM, but the importance in vivo of the proteins in telomere biology has not been tested. We show that Wrn and Blm mutations each accentuate pathology in later-generation mice lacking the telomerase RNA template Terc, including acceleration of phenotypes characteristic of latest-generation Terc mutants. Furthermore, pathology not observed in Terc mutants but similar to that observed in Werner syndrome and Bloom syndrome, such as bone loss, was observed. The pathology was accompanied by enhanced telomere dysfunction, including end-to-end chromosome fusions and greater loss of telomere repeat DNA compared with Terc mutants. These findings indicate that telomere dysfunction may contribute to the pathogenesis of Werner syndrome and Bloom syndrome.

Animals↗
PubMed2003

Inhibition of colon tumor progression and angiogenesis by the Ink4a/Arf locus.

The Ink4a/Arf locus is frequently methylated in colon carcinoma and other common human cancers, suggesting that the locus may play a broad, as yet poorly defined,role inhibiting tumor progression. We examined the influence of the locus in mice with multiple intestinal neoplasia (Min). Colon tumors in 3-month-old Min mice that were null for the Ink4a/Arf locus (-/-) were moderately larger than in Ink4a/Arf-wild-type (+/+) animals (P = 0.032). More strikingly, one-half of the -/- colon tumors were grossly red in color, whereas most of the +/+ tumors were white (P = 0.0025). This color difference remained statistically significant after normalizing for tumor area (P = 0.016). On histological analysis, -/- colon tumors displayed more RBCs near the tumor surface, twice the number of functional vessels, and features of carcinoma in situ not found in +/+ tumors. Biochemical analyses showed that red tumors had higher hemoglobin and vascular endothelial growth factor (VEGF) content than white tumors. Surprisingly, the small intestinal tumor burden was actually lower in -/- animals, and none of these tumors were red, underscoring the importance of tissue context in the function of the locus. These results provide direct evidence that the Ink4a/Arf locus inhibits colon tumor progression. The enhanced vascularity of the -/- tumors is particularly significant in light of the clinical importance of this property in the detection, recurrence, and therapy of colon tumors.

Animals↗
PubMed2003

Molecular and immunohistochemical analysis of intraductal papillary neoplasms of the biliary tract.

Intraductal papillary neoplasms (IPNs) of the biliary tract are uncommon lesions that may be solitary or may spread extensively along the biliary tree. Some biliary IPNs are histologically and radiologically similar to intraductal papillary mucinous tumors (IPMNs) of the pancreas and present a risk for progression to invasive cholangiocarcinoma. Unlike pancreatic IPMNs, little is known about their molecular pathogenesis. We studied 14 biliary IPNs (including 5 cases with associated invasive cholangiocarcinoma) for genetic alterations in the APC/beta-catenin pathway, K-ras oncogene mutations, p53/chromosome 17p alterations, and Dpc4/18q alterations. Immunohistochemistry was performed for beta-catenin, p53, and Dpc4, and microdissected tissue was analyzed using direct DNA sequencing for exon 1 of K-ras and exon 3 of beta-catenin and allelic loss assays on chromosomes 5q, 17p, and 18q. Activating mutations in codon 12 of the K-ras oncogene were present in 4 of 14 (29%) biliary IPNs. Of these 4 cases, 2 patients had associated invasive cholangiocarcinoma, and identical K-ras mutations were present in both the intraductal and invasive components. Allelic loss on chromosome 18q was present in 4 of 13 informative cases (31%); however, no loss of normal Dpc4 expression was detected by immunohistochemistry. Nuclear accumulation of beta-catenin protein was demonstrated in 3 of 12 cases (25%); however, there were no beta-catenin gene mutations, and allelic loss on 5q was present in only 1 of 10 informative cases (10%). Both immunohistochemistry for p53 and 17p allelic loss assays were negative. Biliary IPNs therefore demonstrate a K-ras gene mutation frequency that is lower than that previously reported for pancreatic IPMNs, but similar to that reported for hepatic cholangiocarcinomas. The presence of K-ras mutations in 2 purely intraductal neoplasms, and identical K-ras mutations in 2 cases with both intraductal and invasive components, suggests that these mutations arise early in tumorigenesis. Finally, the frequency of allelic loss on 18q suggests that a locus on 18q is involved in the molecular pathogenesis of biliary IPNs, but this locus is not DPC4.

Adult↗
PubMed2003

Influence of ethnicity in the outcome of hepatitis C virus infection and cellular immune response.

This study was performed to examine the immunologic basis for the apparent ethnic difference in clinical outcome of hepatitis C virus (HCV) infection between African Americans (AA) and Caucasian Americans (CA). To this end, we recruited 99 chronically HCV-infected and 31 spontaneously HCV-cleared subjects for clinical, virologic, and immunologic analysis. In particular, CD4-proliferative T-cell response to genotype 1-derived HCV antigens (core, NS3-NS5) was examined in 82 patients chronically infected with genotype 1 (54 AA, 28 CA) and in all HCV-cleared subjects (14 AA, 17 CA). HCV-specific Th1 response also was examined in 52 chronic and 13 recovered subjects. Our results showed that HCV clearance was associated with a vigorous HCV-specific Th1 response irrespective of ethnic origin. Although the HCV-specific CD4 T-cell response clearly was weaker during chronic infection, AA ethnicity in this setting was associated with a significantly greater CD4-proliferative T-cell response to HCV, particularly to the nonstructural antigens (22% AA vs. 0% CA, P =.007) as well as better clinical parameters of liver disease. Interestingly, most HCV-specific CD4 T-cell proliferative responses in AA patients were unaccompanied by concurrent interferon gamma (IFN-gamma) production, suggesting a dysregulated virus-specific, CD4 T-cell effector function during chronic HCV infection. In conclusion, our results suggest that host ethnicity does influence the clinical outcome and antiviral T-cell response during HCV infection. AA ethnicity is associated with a more robust antiviral CD4 T-cell response than CA ethnicity, although these T cells are limited in direct virus or disease control due to their dysfunctional nature.

Black People↗
PubMed2003

Oxyntic mucosa pseudopolyps: a presentation of atrophic autoimmune gastritis.

Gastric polyps are often present in the setting of atrophic gastritis. Although the majority of these polyps are nonneoplastic, such as hyperplastic polyps, neoplastic polyps may be present. We discuss nine cases that illustrate an additional nonneoplastic cause of polyps in atrophic gastritis. Specifically, preserved islands of relatively normal oxyntic mucosa in a background of gastric atrophy may appear polypoid endoscopically. The patients (seven women, two men, mean age 64 years) presented with nonspecific abdominal or reflux symptoms (n = 8) and diarrhea (n = 1). Five of five patients tested were confirmed to have hypergastrinemia, and three of three patients tested had antiparietal cell antibodies. Biopsies from the gastric body or fundus of our nine patients showed fragments of atrophic mucosa and separate fragments of preserved oxyntic mucosa. Based upon the histologic characteristics of the atrophic fundic and relatively normal antral biopsies, the gastric atrophy appeared to be of autoimmune-type. The relatively preserved oxyntic glands showed parietal cell hypertrophy and focal mild chronic inflammation. The number of polyps observed endoscopically ranged from less than five to multiple/diffuse. Three patients had persistent nodularities in their stomachs for 1, 3, and 7 years of their follow-up. Our study shows that some patients with atrophic gastritis, autoimmune-type, may present with gastric polyps/nodules that represent relatively preserved oxyntic mucosa. This presentation may be more common than is presently recognized because biopsies of the polyps alone will not show histologic features of atrophic gastritis or reveal the etiology of the polyp itself. Although a limited number of previous studies have suggested this type of polypoid presentation may represent "early" atrophic gastritis, its persistence in three of our patients argues against this hypothesis.

Adult↗
PubMed2003

Lymphoplasmacytic chronic cholecystitis and biliary tract disease in patients with lymphoplasmacytic sclerosing pancreatitis.

Lymphoplasmacytic sclerosing pancreatitis (LPSP) represents a distinctive form of chronic pancreatitis characterized by diffuse fibroinflammatory infiltrates that can involve both the pancreatic ducts and acinar parenchyma. Several cases of inflammatory infiltrates within the gallbladder have been reported in association with LPSP, but the spectrum of gallbladder pathology in patients with LPSP has not been systematically reviewed. Many patients with LPSP have distal CBD fibrosis, strictures, and inflammation, features that overlap somewhat with primary sclerosing cholangitis (PSC). In PSC, a pattern of gallbladder pathology termed "diffuse acalculous lymphoplasmacytic chronic cholecystitis" has been previously described as showing a triad of diffuse, mucosal-based, plasma cell-rich inflammatory infiltrates. We studied 20 gallbladders from patients with LPSP and compared them with 20 gallbladders in PSC, 20 gallbladders with chronic cholelithiasis, and 10 gallbladders from patients with benign (non-LPSP) pancreatic disease. The following features were evaluated: degree and composition of mucosal inflammation and deep (mural) inflammation, lymphoid nodules, metaplasia, dysplasia/neoplasia, fibrosis, muscular hypertrophy, Rokitansky-Aschoff sinuses, and cholesterolosis. The majority (60%) of gallbladders in LPSP contained moderate or marked inflammatory infiltrates and lymphoid nodules, frequencies similar to PSC but significantly higher than in chronic cholelithiasis and benign non-LPSP pancreatic disease. LPSP gallbladders received the highest scores for deep inflammation of all groups, and 35% of LPSP gallbladders showed transmural chronic cholecystitis. Overall, "diffuse lymphoplasmacytic chronic cholecystitis" was present in 50% of PSC cases and 25% of LPSP cases, but in only 5% of chronic cholelithiasis and none of non-LPSP benign pancreatic disease. Mucosal inflammation in LPSP gallbladders correlated significantly with the presence of inflammation in the extrapancreatic portion of the CBD. These findings suggest that inflammatory pathology of the gallbladder is frequently associated with LPSP and that it is part of the spectrum of biliary tract disease in these patients, rather than a simple reflection of the pancreatitis itself.

Adolescent↗
PubMed2003

Diffuse lymphoplasmacytic chronic cholecystitis is highly specific for extrahepatic biliary tract disease but does not distinguish between primary and secondary sclerosing cholangiopathy.

Previous studies of gallbladder pathology in primary sclerosing cholangitis (PSC) have suggested that a distinctive histologic triad ("diffuse lymphoplasmacytic acalculous cholecystitis," composed of diffuse, mucosal-based, dense lymphoplasmacytic infiltrates) is commonly present in gallbladders of patients with PSC and is relatively specific for that disease. However, prior control populations have included only patients with cholecystitis/cholelithiasis and hepatitis, and have not evaluated patients with non-PSC-associated extrahepatic biliary tract disease. We recently observed cases of diffuse lymphoplasmacytic chronic cholecystitis in a subset of patients with biliary tract disease associated with lymphoplasmacytic sclerosing pancreatitis and among patients undergoing Whipple resection for pancreatic head malignancy, suggesting that diffuse lymphoplasmacytic chronic cholecystitis is not specific for PSC. We studied 20 gallbladders from patients with obstructive jaundice due to malignancies of the pancreatic head, duodenum, or ampulla and 5 gallbladders from patients with choledocholithiasis, and compared them with 20 gallbladders from patients with PSC and 20 gallbladders with cholelithiasis. The following histologic features were evaluated: degree of mucosal and deep inflammation, lymphoid nodules, epithelial metaplasia, muscular hypertrophy, Rokitansky-Aschoff sinuses, fibrosis, and cholesterolosis. Gallbladders in malignancy-associated obstructive jaundice were nearly identical to gallbladders in PSC with respect to scores for mucosal inflammation, lymphoid nodules, and frequency of diffuse lymphoplasmacytic chronic cholecystitis (60% vs. 50%, respectively). PSC gallbladders, however, were significantly more likely to contain focal or extensive epithelial metaplasia (P = 0.01). The cholelithiasis control group was characterized by lack of significant mucosal inflammation in the majority of cases (95%) and frequent Rokitansky-Aschoff sinuses, fibrosis, and muscular hypertrophy. Gallbladders in the choledocholithiasis group showed overlapping histologic features with PSC/malignancy-associated obstructive jaundice and cholelithiasis. These results suggest that a pattern of diffuse lymphoplasmacytic chronic cholecystitis is highly specific for extrahepatic biliary tract disease but does not distinguish between primary and secondary cholangiopathies.

Adolescent↗
PubMed2003

Detachable balloon-modified reducing stent to treat hepatic insufficiency after transjugular intrahepatic portosystemic shunt creation.

A patient developed severe hepatic insufficiency after creation of a transjugular intrahepatic portosystemic shunt, which was treated unsuccessfully with a constrained Wallstent ("reducing stent"). After a failed attempt at occluding the shunt with an occlusion balloon, a detachable balloon was placed at the portal end of the constrained stent. This balloon-modified reducing stent reduced flow while maintaining shunt patency, and the patient's hepatic insufficiency improved. She went on to undergo successful liver transplantation several months later.

Aged↗
PubMed2003

Peroxisome proliferator-activated receptor gamma expression in follicular-patterned thyroid lesions. Caveats for the use of immunohistochemical studies.

To determine its usefulness as a specific diagnostic marker for follicular carcinomas (FCs) vs other follicular-patterned thyroid lesions and possible application to fine-needle aspiration specimens, we immunohistochemically studied peroxisome proliferator-activated receptor gamma (PPAR gamma) expression in histologic sections (FC, 13 cases; follicular adenoma [FA], 11; follicular variant of papillary carcinoma [FVPC], 9) and surrounding thyroid tissue by using a PPAR gamma monoclonal antibody. Positivity (detected by nuclear staining) was scored as absent, weak, moderate, or strong. When only moderate or strong nuclear staining was considered positive, 9 FCs (69%), 3 FAs (27%), and 2 FVPCs (22%) demonstrated positive nuclear immunoreactivity. The sensitivity and specificity of immunohistochemical detection of PPAR gamma expression in FCs were 69% and 75%, respectively. In nonlesional surrounding tissue, moderate to strong positive staining was seen in focal areas of chronic lymphocytic thyroiditis in 6 of 33 cases (FC, 2; FA, 3; FVPC, 1); diffuse moderate staining was detected in surrounding tissue in the absence of lymphocytic thyroiditis in 4 cases (12%; FC, 3; FA, 1). Staining in the follicular-patterned lesions and surrounding nonlesional thyroid was specific with peptide blocking experiments. PPAR gamma expression is not a specific marker for FCs, and its detection in nonlesional thyroid tissue suggests limited usefulness as a diagnostic marker for follicular-patterned lesions in general.

Adenocarcinoma, Follicular↗
PubMed2002

The role of passenger leukocyte genotype in rejection and acceptance of rat liver allografts.

BACKGROUND: Although graft-resident passenger leukocytes are known to mediate acute rejection by triggering direct allorecognition, they may also act in an immunomodulatory fashion and play an important role in tolerance induction. Our purpose in the current study was to utilize rat bone marrow chimeras to evaluate the role of the genotype of passenger leukocytes in both acute rejection and tolerance of liver allografts. METHODS: The fate of livers bearing donor-type, recipient-type, and third-party passenger leukocytes was evaluated in the MHC class I and II mismatched rejector combination ACI-->LEW and the acceptor combination PVG-->DA. RESULTS: We report that although treatment of ACI liver donors with lethal irradiation does not lead to prolongation of graft survival in the ACI-->LEW strain combination, ACI livers bearing recipient-type (LEW) or third-party passenger leukocytes (BN) are rejected at a significantly slower rate. We confirm that lethal irradiation of PVG donor animals leads to abrogation of tolerance induction with acute rejection of their livers by DA recipients. However, the majority of PVG livers carrying donor-type (PVG), recipient-type (DA), or third-party (LEW) passenger leukocytes are accepted for >100 days. These DA recipients develop immune tolerance to the donor parenchyma (PVG). CONCLUSIONS: Our findings demonstrate that long-term acceptance of liver allografts and tolerance induction is not dependent on the presence of donor-type passenger leukocytes and can be achieved with organs carrying donor-type, recipient-type, or third-party passenger leukocytes. The importance of the MHC framework on the surface of passenger leukocytes as a critical regulator of the immune response after transplantation of chimeric organs is substantiated by the delayed tempo of rejection of ACI livers bearing recipient-type or third-party passenger leukocytes in the ACI-->LEW strain combination.

Animals↗
PubMed2002

A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD) is an inborn error of urea synthesis that has been considered as a model for liver-directed gene therapy. Current treatment has failed to avert a high mortality or morbidity from hyperammonemic coma. Restoration of enzyme activity in the liver should suffice to normalize metabolism. An E1- and E4-deleted vector based on adenovirus type 5 and containing human OTC cDNA was infused into the right hepatic artery in adults with partial OTCD. Six cohorts of three or four subjects received 1/2 log-increasing doses of vector from 2 x 10(9) to 6 x 10(11) particles/kg. This paper describes the experience in all but the last subject, who experienced lethal complications. Adverse effects included a flu-like episode and a transient rise in temperature, hepatic transaminases, thrombocytopenia, and hypophosphatemia. Humoral responses to the vector were seen in all research subjects and a proliferative cellular response to the vector developed in apparently naive subjects. In situ hybridization studies showed transgene expression in hepatocytes of 7 of 17 subjects. Three of 11 subjects with symptoms related to OTCD showed modest increases in urea cycle metabolic activity that were not statistically significant. The low levels of gene transfer detected in this trial suggest that at the doses tested, significant metabolic correction did not occur.

Adenoviruses, Human↗
PubMed2002

Efficacy, safety, and clinical outcomes of endoscopic mucosal resection: a study of 101 cases.

BACKGROUND: Endoscopic mucosal resection (EMR) is an alternative to surgery for removal of superficial neoplastic lesions of the GI tract. The aim of this study was to assess the safety, efficacy, and clinical outcomes of EMR. METHODS: Data from consecutive EMR procedures performed by using suction cap-assisted and/or saline solution-assisted snare resection techniques over a 45-month period were reviewed retrospectively. EUS was performed before EMR in the majority of cases. Immediate and delayed complications were recorded. Survival was assessed in patients with carcinoma or high-grade dysplasia on final histopathology in whom EMR achieved complete resection. RESULTS: One hundred one lesions were removed by EMR in 92 patients. Indications were adenoma (67%), high-grade dysplasia (13%), intramucosal carcinoma (11%), and lesions of uncertain histopathology (10%). Locations were esophagus 19%, stomach 14%, duodenum 27%, rectum 12%, and colon 29%. Suction cap-assisted technique was used in 26% and saline solution-assisted polypectomy in 74% of cases. Complete resection was achieved in 89%. For complete resection, 17% required more than 1 session. Post-EMR histopathology was adenoma 47%, high-grade dysplasia 13%, carcinoma 16%, carcinoid 3%, benign 19%, and low-grade dysplasia 3%. EMR resulted in upgrading of histopathologic staging to carcinoma or high-grade dysplasia in 44%. Bleeding was the only complication (early 16, delayed 6). The median cancer-free survival in patients with adenocarcinoma who underwent complete resection by EMR was 27 months (interquartile range: 17-28 months). CONCLUSION: EMR achieves complete resection in a majority of patients but is associated with a higher risk of bleeding compared with standard polypectomy. EMR changes pathologic stage in a significant number of patients. Survival data are encouraging, but long-term follow-up studies are needed.

Adult↗