Biomedical subjects

Milton J Finegold

Publications and source records attributed to Milton J Finegold.

At least 19 recordsLinked to original sources

PubMed2026

Asynchronous transitions from high-risk hepatoblastoma to carcinoma.

BACKGROUND & AIMS: Most pediatric hepatocellular tumors are classified as hepatoblastoma (HB) or hepatocellular carcinoma (HCC), yet a subset exhibits mixed histological and molecular features. These hepatoblastomas with carcinoma features (HBCs) include cases provisionally designated as hepatocellular neoplasm-not otherwise specified (HCN-NOS). Their biology remains poorly understood, with unresolved questions about their cellular composition and outcomes. It is unclear whether HBCs comprise hybrid cells with combined HB and HCC characteristics (HBC cells) or admixtures of distinct HB and HCC cells. We characterized the biology, etiology, cellular composition, and evolutionary dynamics of HBCs. METHODS: We performed multi-omics profiling - including single-nucleus RNA sequencing, single-nucleus DNA sequencing, and multi-region longitudinal bulk RNA and DNA sequencing - to characterize HBC composition, evolution, and treatment response. Two-thirds of our samples were post-chemotherapy resections. RESULTS: HBCs comprise heterogeneous mixtures of HB-like, HBC-like, and HCC-like molecular cell types. Outcomes in HBC are significantly worse than in HB, and HBC cells are more chemoresistant than HB cells, with resistance shaped by their cell identity, genetic alterations, and embryonic differentiation stage. HBC cells originate from HB cells that were arrested at early hepatic stem cell development stages because of aberrant WNT signaling activation. Inhibition of WNT signaling promoted differentiation and enhanced sensitivity to chemotherapy. Furthermore, each analyzed HBC reflected a dynamic process of multiple HB-to-HBC and HBC-to-HCC transitions, underscoring their evolutionary complexity. A limitation of our study is our inability to pinpoint the role of chemotherapy-induced genome modifications. CONCLUSIONS: Multi-omics profiling of HBCs revealed key insights into their biology and composition, demonstrating that they originate from HB precursors at early hepatic stem cell development stages and that their differentiation arrest depends on sustained aberrant WNT signaling activity. IMPACT AND IMPLICATIONS: Hepatoblastomas with carcinoma features (HBCs) represent a poorly understood subset of pediatric liver tumors with mixed characteristics of hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Using multi-omics profiling, we show that HBCs comprise heterogeneous mixtures of HB-like, intermediate HBC-like, and HCC-like cell populations that arise from HB precursors arrested at early hepatic stem cell developmental stages due to aberrant WNT signaling. This differentiation arrest contributes to chemoresistance and poorer clinical outcomes compared with HB. Importantly, pharmacologic inhibition of WNT signaling promoted differentiation and increased chemotherapy sensitivity, suggesting a potential therapeutic strategy. These findings refine the biological classification of HBCs and highlight differentiation-based treatment approaches for this aggressive tumor subtype.

Multiomics↗

PubMed2006

Treatment of solid organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lymphocytes (CTLs).

We have investigated the in vivo safety, efficacy, and persistence of autologous Epstein Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) for the treatment of solid organ transplant (SOT) recipients at high risk for EBV-associated posttransplantation lymphoproliferative disease (PTLD). EBV-CTLs generated from 35 patients expanded with normal kinetics contained both CD8 and CD4 lymphocytes and produced significant specific killing of autologous EBV-transformed B lymphoblastoid cell lines (LCLs). Twelve SOT recipients at high risk for PTLD, or with active disease, received autologous CTL infusions without toxicity. Real-time polymerase chain reaction (PCR) monitoring of EBV-DNA showed a transient increase in plasma EBV-DNA suggestive of lysis of EBV-infected cells, although there was no consistent decrease in virus load in peripheral-blood mononuclear cells. Interferon-gamma enzyme-linked immunospot (ELISPOT) assay and tetramer analysis showed an increase in the frequency of EBV-responsive T cells, which returned to preinfusion levels after 2 to 6 months. None of the treated patients developed PTLD. One patient with liver PTLD showed a complete response, and one with ocular disease has had a partial response stable for over one year. These data are consistent with an expansion and persistence of adoptively transferred EBV-CTLs that is limited in the presence of continued immunosuppression but that nonetheless produces clinically useful antiviral activity.

Antigens, Viral↗

PubMed2006

Diverse patterns of cell-specific gene expression in response to glucocorticoid in the developing small intestine.

Although glucocorticoids are known to elicit functional maturation of the gastrointestinal tract, the molecular mechanisms of glucocorticoid action on the developing intestine have not been fully elucidated. Our previous microarray studies identified 66 transcripts as being rapidly induced in the jejunum following dexamethasone (Dex) administration to suckling mice. Now we report the specific cellular location of a subset of these transcripts. Mouse pups at P8 received Dex or vehicle and intestinal segments were collected 3-4 h later. Robotic-based in situ hybridization (ISH) was performed with digoxygenin-labeled riboprobes. Transcripts studied included Ndrg1, Sgk1, Fos, and two unknown genes (Gene 9 and Gene 36). As predicted, ISH revealed marked diversity of cellular expression. In small intestinal segments, Sgk1 mRNA was in all epithelial cells; Fos mRNA was confined to epithelial cells at the villus tip; and Ndrg1 and Gene 36 mRNAs were localized to epithelial cells of the upper crypt and villus base. The remaining transcript (Gene 9) was induced modestly in villus stroma and strongly in the muscle layers. In the colon, Ndrg1, Sgk1, and Gene 36 were induced in all epithelial cells; Gene 9 was in muscle layers only; and Fos was not detectable. For jejunal segments, quantitation of ISH signals in tissue from Dex-treated and vehicle-treated mice demonstrated mRNA increases very similar to those measured by Northern blotting. We conclude that glucocorticoid action in the intestine reflects diverse molecular mechanisms operating in different cell types and that quantitative ISH is a valuable tool for studying hormone action in this tissue.

Animals↗

PubMed2006

Increased liver pathology in hepatitis C virus transgenic mice expressing the hepatitis B virus X protein.

Transgenic mice expressing the full-length HCV coding sequence were crossed with mice that express the HBV X gene-encoded regulatory protein HBx (ATX mice) to test the hypothesis that HBx expression accelerates HCV-induced liver pathogenesis. At 16 months (mo) of age, hepatocellular carcinoma was identified in 21% of HCV/ATX mice, but in none of the single transgenic animals. Analysis of 8-mo animals revealed that, relative to HCV/WT mice, HCV/ATX mice had more severe steatosis, greater liver-to-body weight ratios, and a significant increase in the percentage of hepatocytes staining for proliferating cell nuclear antigen. Furthermore, primary hepatocytes from HCV, ATX, and HCV/ATX transgenic mice were more resistant to fas-mediated apoptosis than hepatocytes from nontransgenic littermates. These results indicate that HBx expression contributes to increased liver pathogenesis in HCV transgenic mice by a mechanism that involves an imbalance in hepatocyte death and regeneration within the context of severe steatosis.

Animals↗

PubMed2006

Severe dysplasia in children with familial adenomatous polyposis: rare or simply overlooked?

BACKGROUND/PURPOSE: Because severe dysplasia and carcinoma in children with familial adenomatous polyposis (FAP) younger than 18 years is rare, earlier surgical intervention is not common. The purpose of this study is to report the prevalence of dysplasia and carcinoma among children with FAP in our institution. METHODS: From 1998 through 2004, children 18 years or younger with FAP that underwent total proctocolectomy at a large children's hospital were retrospectively reviewed. RESULTS: Eleven children underwent surgery for FAP. The mean age at surgery was 13 +/- 3.2 years. Approximately half of the patients who underwent preoperative endoscopy had evidence of dysplasia. Nine (82%) patients had dysplasia on preoperative biopsy and/or operative specimen, and 3 (27%) of these patients had severe dysplasia or carcinoma in situ. Four of the 5 patients without symptoms had evidence of dysplasia. No patients had invasive carcinoma. CONCLUSION: We observed a higher incidence of severe colonic dysplasia in young children with FAP compared with the current literature. A significant number of patients with dysplasia at surgery had no symptoms and no evidence of dysplasia on preoperative endoscopic biopsies. These data suggest that earlier intervention in children with FAP may be beneficial and should be investigated further.

Adenomatous Polyposis Coli↗

PubMed2006

GLP-2 receptor localizes to enteric neurons and endocrine cells expressing vasoactive peptides and mediates increased blood flow.

BACKGROUND & AIMS: Glucagon-like peptide-2 (GLP-2) is a nutrient-responsive hormone that exerts diverse actions in the gastrointestinal tract, including enhancing epithelial cell survival and proliferation, mucosal blood flow, and nutrient uptake and suppressing gastric motility and secretion. These actions are mediated by the G-protein-coupled receptor, GLP-2R. Cellular localization of the GLP-2R and the nature of its signaling network in the gut, however, are poorly defined. Thus, our aim was to establish cellular localization of GLP-2R and functional connection to vascular action of GLP-2 in the gut. METHODS: Intestinal cellular GLP-2R localization was determined with real-time, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) of laser capture microdissected subtissue and fluorescence in situ hybridization and also with double and/or triple immunostaining of human and pig tissue using a validated GLP-2R polyclonal antibody. Superior mesenteric arterial blood flow and intestinal eNOS expression and phosphorylation were measured in TPN-fed pigs acutely (4 h) infused with GLP-2. RESULTS: We show that the porcine GLP-2R mRNA was expressed in the villus epithelium and myenteric plexus. GLP-2R protein was co-localized by confocal immunohistochemistry with serotonin in enteroendocrine cells and also with endothelial nitric oxide synthase (eNOS)-expressing and vasoactive intestinal polypeptide-positive enteric neurons. In neonatal pigs, GLP-2 infusion dose-dependently stimulated intestinal blood flow and coordinately upregulated the expression of intestinal eNOS mRNA, protein, and phosphorylation (eNOS-Ser1117). CONCLUSIONS: We conclude that the GLP-2-induced stimulation of blood flow is mediated by vasoactive neurotransmitters that are colocalized with GLP-2R in 2 functionally distinct cell types within the gastrointestinal tract.

Animals↗

PubMed2006

Improved hepatic transduction, reduced systemic vector dissemination, and long-term transgene expression by delivering helper-dependent adenoviral vectors into the surgically isolated liver of nonhuman primates.

Helper-dependent adenoviral vectors (HDAds) are attractive vectors for liver-directed gene therapy because they can mediate sustained, high-level transgene expression without chronic toxicity. However, high vector doses are required to achieve efficient hepatic transduction by systemic delivery because of a nonlinear dose response. Unfortunately, such high doses result in systemic vector dissemination and dose-dependent acute toxicity with potentially severe and lethal consequences. We hypothesize that the threshold to efficient hepatic transduction may be circumvented by delivering the vector into the surgically isolated liver via the portal vein. Total hepatic isolation was achieved by occluding hepatic inflow from the portal vein and hepatic artery and by occluding hepatic venous outflow at the inferior vena cava. We demonstrate in nonhuman primates that this approach resulted in significantly higher efficiency hepatic transduction with reduced systemic vector dissemination compared with systemic intravascular delivery. This method of delivery was associated with transient acute toxicity, the severity of which was variable. Importantly, stable, high levels of transgene expression were obtained for at least 665 days for one baboon and for at least 560 days for two baboons with no evidence of long-term toxicity.

Adenoviruses, Human↗

PubMed2006

Hepatitis C viral recurrence in a pediatric patient following liver transplantation.

Hepatitis C virus (HCV) infections are known to have a more benign course in children than in adults. Although the natural history of HCV recurrence after liver transplantation has been well studied in adult patients, much less is known about HCV recurrence after liver transplantation in pediatric patients. Herein, we report a case of a pediatric patient with HCV presumably acquired through vertical transmission. She underwent liver transplantation at 14 yr of age. The first three yr after liver transplantation were uneventful. However, in the past 12 months she has been hospitalized twice after developing ascites, hematemesis and esophagogastroduodenoscopy (EGD)-documented esophageal varices. Post-transplant biopsy has demonstrated chronic inflammation complicated with active hepatitis C and stage 2-3 scarring. This case report demonstrates the need for further epidemiologic studies to study the natural history of the rate of HCV recurrence after liver transplantation in the pediatric population.

Adolescent↗

PubMed2006

Rotavirus viremia and extraintestinal viral infection in the neonatal rat model.

Rotaviruses infect mature, differentiated enterocytes of the small intestine and, by an unknown mechanism, escape the gastrointestinal tract and cause viremia. The neonatal rat model of rotavirus infection was used to determine the kinetics of viremia, spread, and pathology of rotavirus in extraintestinal organs. Five-day-old rat pups were inoculated intragastrically with an animal (RRV) or human (HAL1166) rotavirus or phosphate-buffered saline. Blood was collected from a subset of rat pups, and following perfusion to remove residual blood, organs were removed and homogenized to analyze rotavirus-specific antigen by enzyme-linked immunosorbent assay and infectious rotavirus by fluorescent focus assay or fixed in formalin for histology and immunohistochemistry. Viremia was detected following rotavirus infection with RRV and HAL1166. The RRV 50% antigenemia dose was 1.8 x 10(3) PFU, and the 50% diarrhea dose was 7.7 x 10(5) PFU, indicating that infection and viremia occurred in the absence of diarrhea and that detecting rotavirus antigen in the blood was a more sensitive measure of infection than diarrhea. Rotavirus antigens and infectious virus were detected in multiple organs (stomach, intestines, liver, lungs, spleen, kidneys, pancreas, thymus, and bladder). Histopathological changes due to rotavirus infection included acute inflammation of the portal tract and bile duct, microsteatosis, necrosis, and inflammatory cell infiltrates in the parenchymas of the liver and lungs. Colocalization of structural and nonstructural proteins with histopathology in the liver and lungs indicated that the histological changes observed were due to rotavirus infection and replication. Replicating rotavirus was also detected in macrophages in the lungs and blood vessels, indicating a possible mechanism of rotavirus dissemination. Extraintestinal infectious rotavirus, but not diarrhea, was observed in the presence of passively or actively acquired rotavirus-specific antibody. These findings alter the previously accepted concept of rotavirus pathogenesis to include not only gastroenteritis but also viremia, and they indicate that rotavirus could cause a broad array of systemic diseases in a number of different organs.

Animals↗

PubMed2006

Consequences of copper accumulation in the livers of the Atp7b-/- (Wilson disease gene) knockout mice.

Wilson disease is a severe genetic disorder associated with intracellular copper overload. The affected gene, ATP7B, has been identified, but the molecular events leading to Wilson disease remain poorly understood. Here, we demonstrate that genetically engineered Atp7b-/- mice represent a valuable model for dissecting the disease mechanisms. These mice, like Wilson disease patients, have intracellular copper accumulation, low-serum oxidase activity, and increased copper excretion in urine. Their liver pathology developed in stages and was determined by the time of exposure to elevated copper rather than copper concentration per se. The disease progressed from mild necrosis and inflammation to extreme hepatocellular injury, nodular regeneration, and bile duct proliferation. Remarkably, all animals older than 9 months showed regeneration of large portions of the liver accompanied by the localized occurrence of cholangiocarcinoma arising from the proliferating bile ducts. The biochemical characterization of Atp7b-/- livers revealed copper accumulation in several cell compartments, particularly in the cytosol and nuclei. The increase in nuclear copper is accompanied by marked enlargement of the nuclei and enhanced DNA synthesis, with these changes occurring before pathology development. Our results suggest that the early effects of copper on cell genetic material contribute significantly to pathology associated with Atp7b inactivation.

Adenosine Triphosphatases↗

PubMed2005

Impaired TGF-beta responses in peripheral T cells of G alpha i2-/- mice.

Null mutation of heterotrimeric G protein alpha2 inhibitory subunit (Galphai2) induces Th1-skewed hyperimmune responses in the colon, leading to chronic colitis and the development of colonic adenocarcinoma. However, the underlying molecular mechanisms and cellular basis, in particular, for the role of Galphai2 in regulating immune responses, are poorly understood. We show here that peripheral T cells from Galphai2-deficient mice do not respond normally to the inhibitory effects of TGF-beta on proliferation and cytokine production, revealing a previously unappreciated cross-talk between these two signaling pathways. Lack of Galphai2 resulted in decreased phosphorylation of Smad2 and Smad3 in T cells at the basal levels as well as at the late but not early phase of TGF-beta stimulation, which appears to be ascribed to differential expression of neither cell surface TGF-beta receptors nor Smad7. The altered phosphorylation of Smad proteins involves phospholipase C-mediated signaling, a downstream signaling molecule of Galphai2, because phospholipase C inhibitors could restore Smad2 and Smad3 phosphorylation in Galphai2(-/-) T cells at levels comparable to that in wild-type T cells. Moreover, adoptive transfer of Galphai2-deficient T cells into immunocompromised mice rendered an otherwise resistant mouse strain susceptible to trinitrobenzesulfonic acid-induced colitis, suggesting that an impaired response of Galphai2-deficient T cells to TGF-beta may be one of the primary defects accounting for the observed colonic Th1-skewed hyperimmune responses. These findings shed new lights on the molecular and cellular basis of how Galphai2 down-regulates immune responses, contributing to the maintenance of mucosal tolerance.

Adoptive Transfer↗

PubMed2005

Developmental expression and function of aldehyde reductase in proximal tubules of the kidney.

Aldehyde reductase reduces a wide variety of toxic and physiological aldehydes with a marked preference for negatively charged substrates such as glucuronate. Reduction of glucuronate to gulonate is a step in inositol catabolism, a process specific to the kidney cortex. Administration of the aldehyde reductase inhibitor AL-1576 to mice increases urinary output of glucuronate and decreases output of vitamin C. Aldehyde reductase mRNA with a 319-bp 5'-untranslated region is expressed ubiquitously in murine tissues. A new isoform with a short 64-bp 5'-untranslated region is found predominantly in the kidney, resulting in 10-fold higher enzymatic activity observed in this organ compared with other tissues. A moderate level of the new transcript is found in liver, intestine, and stomach, whereas brain, heart, lung, spleen, ovary, and testis have low to insignificant levels. The short transcript is absent during embryonic development and is first observed in the murine kidney on postnatal day 6. The abundance of the short transcript and enzyme activity increase sigmoidally with age; the sharpest increase occurs during the third week of life. As shown by immunohistochemistry, aldehyde reductase expression is limited to the proximal tubules and parietal epithelium of Bowman's capsule. In the mouse, the intensity of staining in tubules increases with age, suggesting that induction of aldehyde reductase expression is part of renal tubular maturation. The human kidney also exhibits proximal tubular localization and the two mRNA transcripts of aldehyde reductase. Immunoreactive protein is present in the 9-wk-old fetal kidney, indicating that the induction of aldehyde reductase in humans occurs early in development.

Aldehyde Reductase↗

PubMed2005

Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector.

Crigler-Najjar syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by a deficiency of uridine diphospho-glucuronosyl transferase 1A1. Current therapy relies on phototherapy to prevent kernicterus, but liver transplantation presently is the only permanent cure. Gene therapy is a potential alternative, and recent work has shown that helper-dependent adenoviral (HD-Ad) vectors, devoid of all viral coding sequences, induce prolonged transgene expression and exhibit significantly less chronic toxicity than early-generation Ad vectors. We used a HD-Ad vector to achieve liver-restricted expression of human uridine diphospho-glucuronosyl transferase 1A1 in the Gunn rat, a model of the human disorder. Total plasma bilirubin levels were reduced from >5.0 mg/dl to <<1.4 mg/dl for >2 yr after a single i.v. administration of vector expressing the therapeutic transgene at a dose of 3 x 10(12) viral particles per kg. HPLC analysis of bile from treated rats showed the presence of bilirubin glucuronides at normal WT levels >2 yr after one injection of vector, and i.v. injection of bilirubins IIIalpha and XIIIalpha in the same animals revealed excess bilirubin-conjugating capacity. There was no significant elevation of liver enzymes (alanine aminotransferase) and only transient, moderate thrombocytopenia after injection of the vector. A clinically significant reduction in serum bilirubin was observed with a dose as low as 6 x 10(11) viral particles per kg. We conclude that complete, long-term correction of hyperbilirubinemia in the Gunn rat model of Crigler-Najjar syndrome can be achieved with one injection of HD-Ad vector and negligible chronic toxicity.

Adenoviridae↗

PubMed2005

Accelerated transition from the double-positive to single-positive thymocytes in G alpha i2-deficient mice.

Deletion of alpha i2 subunit of heterotrimeric G proteins induces a 2-4-fold increase in the proportions of CD4 and CD8 single-positive (SP) thymocytes as compared with wild-type littermates, but how G alpha i2 is involved in thymocyte development is unknown. To determine a role for G alpha i2 in a specific developmental stage of thymocyte differentiation, we studied the ontogeny of thymocytes in G alpha i2-deficient mice. Our data show that an accelerated transition from the double-positive (DP) to SP thymocytes, rather than impairment in thymic emigration, accounts for a high proportion of the SP thymocytes in the absence of G alpha i2. Lack of G alpha i2 greatly augmented a response of thymocytes to TCR-mediated stimulation, as evidenced by enhanced proliferation of the DP thymocytes upon ligation of the TCRs. The augmented response may be the reason behind the expedited transition from the DP to SP thymocytes in the animal. In accordance with this, effects of G alpha i2 deficiency on CD8 or CD4 SP thymocyte differentiation required engagement of the TCRs with either MHC class I or MHC class II molecule. The abnormal thymocyte development resulted in an increase in positive selection, altered usage of TCR Vbeta gene, aberrant development of CD4+ CD25+ T regulatory cells and untimely thymic involution, the contribution of which to colitis development in the animal is discussed. These findings reveal a previously unappreciated role for G alpha i2 protein in clonal selection and functionality of thymocytes.

Animals↗

PubMed2005

Cytogenetic evaluation of a large series of hepatoblastomas: numerical abnormalities with recurring aberrations involving 1q12-q21.

Hepatoblastoma is a malignant embryonal liver tumor that occurs almost exclusively in infants and very young children. Previous cytogenetic studies of hepatoblastoma have investigated small series or individual cases. This report is on the cytogenetics of a large series of 111 hepatoblastoma specimens, with cytogenetic results consecutively karyotyped over a 12-year period. Abnormal karyotypes were observed in 55 cases (approximately 50% of the total). Numerical aberrations were observed in 41 cases (36% of the total), particularly trisomies of chromosomes 2, 8, and 20. Chromosome losses were less common than chromosome gains. Structural abnormalities were observed in 43 cases (39% of the total). Unbalanced translocations resulting in trisomy 1q and involving breakpoints at 1q12-21 were the most common structural abnormality, observed in 20 tumors (18% of total cases); the corresponding translocated chromosome was highly varied. The previously reported t(1;4) was observed in seven cases. Most tumors with translocations involving 1q12-21 also displayed numerical chromosome aberrations, the most common of which were chromosomal trisomies, whereas tumors with other structural rearrangements had fewer numerical abnormalities.

Chromosome Aberrations↗

PubMed2005

Nested stromal epithelial tumor of the liver: six cases of a distinctive pediatric neoplasm with frequent calcifications and association with cushing syndrome.

Rare cases of nonhepatocytic mixed stromal and epithelial tumors of the liver with associated calcification and ossification have been described previously. We report 6 similar cases in children, including 2 cases associated with ectopic ACTH production. The patients were between 2 and 14 years of age at diagnosis. All tumors presented as a solitary liver mass with no extrahepatic involvement. Two adolescent females with palpable abdominal tumors presented with Cushing syndrome that abated after excision of the tumors. The other children had tumors identified incidentally on imaging studies or at laparotomy. All tumors were well circumscribed, ranging in size from 4.0 to 30.0 cm in greatest diameter. Histologically, they shared an organoid arrangement of cellular nests that were comprised of an admixture of both spindled and epithelioid cells. These cellular nests were surrounded by a band of delicate myofibroblasts and set in a dense fibrous stroma that contained slit-like to dilated blood vessels. A variable proliferation of bile ducts extended from the fibrous stroma and focally surrounded the cellular nests. One case showed a sheet-like overgrowth of the nested cells with associated necrosis. The cellular nest cells were immunoreactive for EMA, CD56, neuron specific enolase, pan-cytokeratin (4 of 6 cases), vimentin (5 of 6 cases), and WT-1 amino terminus (4 of 6 cases). Cytokeratin and EMA stained mostly epithelioid nest cells, with vimentin and WT-1 staining predominantly the spindled nest cells. The 3 cases from adolescent females showed immunoreactivity for ACTH in the nested cell population but not in the surrounding stromal cells. Immunohistochemical stains for synaptophysin and chromogranin were negative in all cases. Psammomatous calcifications were present focally in 2 cases and were extensive in 3 cases. Ossification or osteoid formation was present in 4 cases. The 1 patient whose tumor had sheet-like overgrowth of the nested cell population had a local recurrence with multiple hepatic nodules 1 year following the original resection. A 2-year-old patient has been subsequently diagnosed with nephroblastomatosis and Wilms tumor of the kidney. Follow-up information was available in an additional 3 patients with no tumor recurrence or metastatic disease at 2, 3, and 14 years.

Adolescent↗

PubMed2005

Cellular immunity to Epstein-Barr virus in liver transplant recipients treated with rituximab for post-transplant lymphoproliferative disease.

The evaluation of long-term cellular immunity to EBV in pediatric orthotopic liver transplant (OLT) recipients after treatment with the humanized anti-CD20 monoclonal antibody (Rituximab) has not yet been explored. At our institution, one child with EBV-related mononucleosis-like syndrome and five children with polymorphic-EBV-PTLD occurring 6-88 months after OLT were treated with Rituximab. Treatment was well tolerated. All children achieved complete remission. After Rituximab, B-lymphocytes were undetectable in the peripheral blood and EBV-load, monitored with real-time PCR, decreased to undetectable levels in all children from >4000 copies/microg DNA at diagnosis. Four to eight months after Rituximab, EBV-load increased (>4000 copies/microg DNA) in four children, and PTLD recurred in three. Their frequency of EBV-specific T-cell precursors, measured by Elispot analysis, remained lower than in healthy controls. Rituximab effectively induced regression of PTLD in OLT recipients. However, EBV-specific T-cell immunocompetence, which may be crucial for the long-term control of EBV-mediated proliferation, did not improve.

Antibodies, Monoclonal↗

PubMed2005

Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents.

OBJECTIVES: Fatty liver is a common cause of liver disease in children. However, the epidemiology of pediatric fatty liver is limited to single-center case series of nonalcoholic fatty liver disease (NAFLD). Obesity and insulin resistance are major established risk factors for NAFLD. The role of gender, race, and ethnicity on the prevalence of fatty liver in obese children is unknown. METHODS: We recruited obese 12th-grade participants from the Child and Adolescent Trial for Cardiovascular Health in California, Louisiana, Minnesota, and Texas. Serum samples were collected at school when the participants were well. Alanine aminotransferase (ALT) was measured by kinetic enzymatic assay, and ALT >40 U/L was defined as abnormal. Causes of abnormal ALT other than NAFLD were excluded by serum testing. RESULTS: A total of 127 obese students (73 female, 54 male) had a mean BMI of 35.2 kg/m2. Unexplained ALT elevation was present in 23% of participants overall. The mean ALT for participants with normal values was 28 U/L and for participants with an abnormal ALT was 56 U/L. Abnormal ALT was significantly more prevalent in boys (44%) than in girls (7%). The prevalence of abnormal ALT differed significantly by race and ethnicity (Hispanic: 36%; white: 22%; black: 14%). Serum ALT value was significantly predicted by the combination of gender, race/ethnicity, and BMI. After controlling for gender and BMI, Hispanic ethnicity significantly predicted greater ALT than black race. CONCLUSIONS: In a national, school-based sample of obese adolescents, boys were 6 times more likely than girls to have an unexplained elevated ALT. Given that participants were well and causes of chronic liver disease were excluded, we speculate that obese adolescent boys have an increased prevalence of fatty liver compared with obese adolescent girls. This population-based study also supports the hypothesis that NAFLD is more common in Hispanic adolescents. These findings have implications for both disease screening and studies of fatty liver pathophysiology.

Adolescent↗