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Biomedical subjects

John A Goss

Publications and source records attributed to John A Goss.

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↗
PubMed2007

A pooled analysis of posttransplant survival following combined heart-liver transplantation.

Because no single center has accumulated a large experience with this complex operation, the effectiveness of combined orthotopic heart transplantation (OHT) and orthotopic liver transplantation (OLT) in achieving long-term survival has been unknown. Cases of OHT-OLT were pooled from a U.S. transplant recipient registry and from previously published literature. Aggregate data from these sources was used for survival analysis. Thirty-six patients having undergone OHT-OLT were listed in the national registry; the one- and five-year patient survival rates of these patients were 88% and 78%, respectively. Many patients remain alive at 8+ years after transplantation. An analysis of the pooled results of previously-published cases estimated a one-year patient survival rate of 84%. In selected disease processes, OHT-OLT can correct underlying metabolic deficiencies. While rarely indicated, OHT-OLT is a successful treatment for patients with end-stage heart and liver disease, with survival comparable to that seen after isolated orthotopic heart or orthotopic liver transplantation.

Adolescent↗
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

Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure.

BACKGROUND: Orthotopic liver transplantation (OLT) is an effective treatment for fulminant hepatic failure (FHF), but postOLT mortality is higher for patients with FHF than for patients with other indications for OLT. In the current study, a large cohort of patients who underwent OLT for FHF was evaluated to develop and validate a system useful for estimating postOLT patient survival. METHODS: The 1,457 patients who underwent OLT for FHF in the United States between 1988 and 2003 were enrolled through the UNOS database. This group was divided into a modeling group (n=972) and a crossvalidation group (n=486). With a multivariate regression analysis, the modeling group was used to identify clinical parameters that had a significant association with postOLT survival. This regression analysis was used to create a scoring system that was subsequently assessed in the crossvalidation group. RESULTS: Four risk factors were identified with the multivariate analysis: 1) body mass index > or = 30 kg/m2; 2) serum creatinine > 2.0 mg/dL; 3) recipient age > 50 years old; and 4) history of life support. By assigning points based on the number of risk factors present, the scoring system was able to differentiate between low-risk patients (5-year survival, 81%) and high-risk patients (5-year survival, 42%). The relative risk of postOLT mortality increased by approximately 150% for each additional point. CONCLUSION: The scoring system risk-stratified the crossvalidation group and accurately predicted postOLT survival. A scoring system utilizing clinical and demographic information readily available prior to OLT may help predict the probability of survival after OLT for FHF.

Adult↗
PubMed2006

The pediatric end-stage liver disease (PELD) model as a predictor of survival benefit and posttransplant survival in pediatric liver transplant recipients.

The pediatric end-stage liver disease (PELD) model accurately estimates 90-day waitlist mortality for pediatric liver transplant candidates, but it has been unclear if PELD can identify patients who will derive survival benefit from undergoing liver transplantation (LT), if it correlates with posttransplant survival, or if it can identify patients for whom LT would be futile. Pediatric patients who underwent LT between 2001 and 2004 were enrolled through the United Network for Organ Sharing Organ Procurement and Transplant Network database. Survival benefit was measured in terms of life-years gained during the first year after LT. Complete data were available for 1,247 patients: 53% were listed as Status 1 at the time of orthotopic liver transplantation (OLT), while the remaining 47% had PELD scores. Only in patients with a PELD of 17+ or those designated as United Network for Organ Sharing Status 1 derived a survival benefit within 1 year of LT; patients with a PELD score of < or = 16 did not. In addition, a statistically significant association was seen between 1-year post-OLT survival and PELD at LT (P = 0.03). No "threshold" PELD score, beyond which risk of post-LT mortality increased dramatically, was apparent. In conclusion, pediatric patients with a PELD score of 17+ derive survival benefit early after LT, and increasing PELD scores are associated with increasing transplant benefit after liver transplantation. PELD does correlate with posttransplant survival but should not be used as a marker for futility.

Algorithms↗
PubMed2006

The natural history of hepatitis C virus in pediatric liver transplant recipients.

Although rare in the pediatric population, the natural history of hepatitis C virus (HCV) recurrence in pediatric patients undergoing orthotopic liver transplantation (OLT) for end-stage liver disease secondary to HCV has not been well described. We performed an analysis of all 67 pediatric patients (< 17 years old) who have undergone OLT for HCV in the United States between 1/1988 and 6/2005. The 67 pediatric patients received a total of 83 OLTs for HCV. Following initial OLTs performed for HCV, the patient and allograft survival rates were 71.6% and 55.0%, respectively, at 5 years. Following retransplantation these rates decreased to 55.0% and 33.8%, respectively, following retransplantation. Recipients were listed for retransplantation after 31.3% of all OLTs, and overall recipients were retransplanted after 19.3% of OLTs. The overwhelming majority of retransplants were performed for HCV recurrence. A mean of 1.2 OLTs were performed per patient for HCV. The median time between OLTs for HCV was 290 days. In conclusion, the risk of HCV recurrence in pediatric OLT recipients is high and is associated with a high rate of retransplantation. Still, OLT represents the only treatment option that may achieve long-term survival in pediatric patients with end-stage liver disease secondary to HCV that is recalcitrant to medical management.

Adolescent↗
PubMed2006

The effect of whole organ pancreas transplantation and PIT on diabetic complications.

Diabetes mellitus is a leading cause of morbidity and mortality in the Western world. Currently, the only forms of beta-cell replacement are whole organ pancreas transplantation and pancreatic islet transplantation. Whole organ transplantation has demonstrated benefits in prevention and reversal of diabetic complications with sustainable long-term outcomes. Pancreatic islet transplantation continues to be a field that needs further study to ascertain the true benefit of islet transplantation for diabetic complications. This can only be achieved with improvement in long-term islet allograft survival.

Diabetes Complications↗
PubMed2006

Resolution of medically resistant hypothyroidism after liver transplantation for hepatic hemangioendothelioma.

Hepatic hemangioendothelioma (HHE) is a rare vascular tumor in neonates and may cause high-output cardiac failure and coagulopathy, and rarely has been associated with hypothyroidism. Hepatic hemangioendothelioma treatment options consist of corticosteroids, alpha-interferon, surgical resection, and liver transplantation. Herein, we report the case of a 6-week-old female neonate that presented with an HHE that involved all segments of the liver, resulting in respiratory failure and severe hypothyroidism that was recalcitrant to exogenous L-thyroxine therapy. After failure of medical and supportive therapy for the HHE, the patient underwent a cadaveric orthotopic liver transplantation that resulted in successful treatment of the severe hypothyroidism, respiratory failure, and cardiac symptoms. The patient is currently 1-year posttransplantation and disease free with normal thyroid function.

Female↗
PubMed2006

Impact of pretransplant growth retardation in pediatric liver transplantation.

OBJECTIVE: Malnutrition frequently complicates end-stage liver disease and orthotopic liver transplantation (OLT) in pediatric patients. Pretransplant malnutrition has been associated with increased post-OLT mortality and length of stay in adults. The relationship between pre-OLT nutritional status and post-OLT outcomes in pediatric liver transplant recipients, however, is not well studied. METHODS: The records of 65 pediatric patients who underwent OLT at a single institution were reviewed. Univariate analyses were used to investigate the relationship between anthropomorphic data (expressed as z-scores) and post-OLT hospital length-of-stay, hospital costs and clinical outcomes. A multivariate model was then used to identify peri-OLT variables independently correlated with post-OLT length-of-stay. RESULTS: A decreased height z-score was correlated with an increased post-OLT hospital length-of-stay (r = -0.30; P = 0.015) and increased hospital costs (r = -0.49; P = 0.0004). The mean length-of-stay was 20.5 days for patients with a height z-score of <-1.5 and 10.7 days for patients with a height z-score of >1.5 (P = 0.038). Likewise, hospital costs were about $40,000 higher (25% increased) for patients with growth retardation. A weak direct correlation was seen between weight z-score and post-OLT length-of-stay (r = 0.18; P = 0.15). Height z-score, biliary atresia and pre-OLT protime were independently and significantly correlated with post-OLT length-of-stay in a multivariate model. CONCLUSIONS: Height z-score is a better indicator of pretransplant malnutrition than weight z-score. Pretransplant growth retardation is associated with increased post-OLT hospital length-of-stay and increased hospitalization costs.

Adolescent↗
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

Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review.

Propionic acidemia is a rare metabolic disorder that often results in episodic hyperammonemia, basal ganglia infarction, mental retardation, and cardiomyopathy. OLT has been used as a treatment for propionic acidemia, but its benefit in patients with this disease is unclear. The current study was undertaken to clarify the role of OLT in the management of this disease. The medical literature, a national registry of US OLT recipients, and a single institution liver transplant experience were reviewed for cases of OLT for propionic acidemia. Accumulated cases demonstrate that OLT has resulted in clear evidence of clinical improvement in several patients, often obviating the need for dietary restriction or other forms of medical management. OLT appears to halt the decline in neurocognitive function often associated with propionic acidemia. In total, 12 patients with propionic acidemia have undergone a total of 14 OLTs. A quantitative analysis of outcomes shows an overall patient survival rate of 72.2% at one year after OLT. In conclusion, OLT should be considered a treatment option for patients with propionic acidemia who continue to experience episodes of hyperammonemia in spite of maximal medical therapy. Early OLT may limit the development of mental retardation and/or cardiomyopathy.

Adult↗
PubMed2005

Combined lung and liver transplantation: the United States experience.

BACKGROUND: Combined transplantation of the lungs and liver is indicated for patients who would not be expected to survive transplantation of either organ alone. No single center has accumulated a significant experience, and as a result the expectations for this operation in the current era are unknown. METHODS: Patients that have undergone combined lung-liver transplantation in the United States were enrolled through the United Network for Organ Sharing Organ Procurement and Transplantation Network database. In addition, the English-language literature was searched for additional cases of combined lung-liver transplantation. RESULTS: Eleven patients have undergone combined lung and liver transplantation in the United States at different centers. The 1- and 5-year patient survival rates are of 79% and 63%, respectively, and no patient has required retransplantation. These patient survival rates are equivalent to similar a combined lung-liver case series from the United Kingdom (P=0.37, log-rank test) and isolated orthotopic liver transplantation in the United States (P=0.59, log-rank test), and are comparable to patient survival rates following isolated lung transplantation in the United States. CONCLUSIONS: Patient survival of combined lung-liver transplantation is comparable to that of isolated liver and isolated bilateral lung transplantation. This option should be considered for patients with end-stage lung disease and liver disease when transplantation of a single organ transplantation is precluded by severe disease in the other organ system.

Adolescent↗
PubMed2005

Health-related quality of life after pancreatic islet transplantation: a longitudinal study.

BACKGROUND: Pancreatic islet transplantation (PIT) has proven effective in achieving insulin independence, but to date, the impact of PIT on health-related quality of life (HRQL) has not been studied. METHODS: Ten patients who have undergone PIT at our institution were administered three HRQL questionnaires: the Hypoglycemia Fear Survey, the 36-Item Short Form Health Survey (SF-36), and a fatigue questionnaire. HRQL was assessed before PIT, then 3, 6, and 12 months after PIT. Responses were compared by analysis of variance and paired Student's t tests. RESULTS: Hypoglycemia Fear Survey responses demonstrated that hypoglycemia-related anxiety and hypoglycemia-related behavior modification occurred less frequently after PIT (P=0.003 and 0.0001, respectively). The total scores of the hypoglycemia questionnaire were also significantly improved after PIT, from a median score of 156 points before transplantation to 55 points 3 months after PIT (P=0.004), 38 points 6 months after PIT (P=0.001), and 69 points 12 months after PIT (P=0.04). The median scores of all SF-36 components also improved after PIT. No significant changes were seen in the fatigue symptoms as assessed by the fatigue questionnaire. CONCLUSION: PIT recipients have less anxiety about the symptoms and consequences of hypoglycemia. PIT recipients also indicate that their behavior requires significantly less modification to prevent or treat hypoglycemia after PIT compared with before PIT. Further investigation is needed to determine whether PIT improves generic measures of HRQL.

Anxiety↗
PubMed2005

Inflammation-mediated dysfunction and apoptosis in pancreatic islet transplantation: implications for intrahepatic grafts.

Recent advances in clinical protocols have improved the outcomes of pancreatic islet transplantation (PIT), yet PIT recipients typically require pancreatic islet grafts derived from multiple donors to achieve insulin independence. This along with experimental models of syngeneic PIT, showing that up to 60% of pancreatic islet tissue undergoes apoptosis within the first several days post-transplantation, strongly suggest the involvement of nonalloantigen-specific, inflammatory events in partial destruction of the graft following PIT. Interleukin-1beta appears to be among the most important inflammatory mediators, causing pancreatic islet dysfunction and apoptosis through the up-regulation of inducible nitric oxide (NO) synthase and cyclooxygenase-2. Kupffer cells secrete many molecules, including cytokines, NO, and free radicals, which are known to be directly toxic to the pancreatic islets, and depletion or inhibition of Kupffer cells improves outcomes following experimental PIT. Immediately after transplantation, the pancreatic islets are perfused only by portal vein blood until the process of angiogenesis restores arterial blood flow some 7-10 days later. This delayed vascularization may have implications for the expression of leukocyte adhesion molecules, the effects of free radicals, and the role of ischemia-reperfusion injury. Finally, in the immediate post-transplant period, hepatocytes may contribute to pancreatic islet injury through the production of NO. This paper reviews literature regarding the inflammatory events that follow PIT as well as the pathogenesis of diabetes and the pathophysiology of hepatic ischemia-reperfusion and their relation to the survival and function of intrahepatic pancreatic islet grafts.

Animals↗
PubMed2005

Liver transplantation for severe hepatic graft-versus-host disease: an analysis of aggregate survival data.

Graft-versus-host disease (GVHD) often occurs after bone marrow transplantation (BMT). GVHD may lead to cirrhosis or complete destruction of the bile ducts, and few effective treatment options exist for such cases. Orthotopic liver transplantation (OLT) has been described as an option, but to date the patient survival, graft survival, and GVHD recurrence rates after OLT have been unknown. Cases of OLT for GVHD were accumulated from several sources: (1) cases of OLT performed at a single institution, (2) the English-language medical literature, and (3) the United Network for Organ Sharing (UNOS) liver transplant registry. Descriptive data were derived from pre- and post-OLT information; survival analysis was performed using the Kaplan-Meier method. One case of OLT for GVHD after BMT was found at our institution, and another 6 cases were previously reported in the literature. Extrahepatic GVHD recurred in 2 cases, but no recurrence of hepatic GVHD was reported. The UNOS registry contained an additional 73 patients who underwent OLT for hepatic GVHD. The 1- and 5-year actuarial patient survival rates were 72.4% and 62.9%, respectively. Although 4 patients required retransplantation, no deaths or retransplants were attributed to the recurrence of hepatic GVHD. OLT is an effective treatment for hepatic GVHD after BMT or non-liver organ transplant. Long-term disease-free survival is obtainable in these cases, and recurrence of hepatic GVHD has not been reported. These findings suggest that OLT should be considered as an effective treatment option for cases of hepatic GVHD recalcitrant to medical treatment.

Adolescent↗
PubMed2005

Ischemia-reperfusion of rat liver modulates hepcidin in vivo expression.

The recently identified acute-phase response antimicrobial peptide hepcidin has been postulated to maintain iron homeostasis by modulating iron absorption at both the intestinal and macrophage levels. Hepcidin has also been reported to be responsible for anemia associated with chronic inflammatory diseases, and in anemia in patients with hepatic adenomas. Since Kupffer cells are known to be the primary contributor to early-phase ischemia-reperfusion injury in the liver and iron is known to modulate Kupffer cell production of proinflammatory cytokine and reactive oxygen species, we investigated hepcidin in vivo expression in the well-established rat partial-liver ischemia-reperfusion model. We found that both liver ischemia alone and liver ischemia-reperfusion significantly induced serum and liver hepcidin levels. Furthermore, currently proposed mediators of in vivo hepcidin expression, such as interleukin-6, signal transducers and activators of transcription-family transducers, and CCAAT/enhancing binding protein-alpha do not appear to modulate hepcidin expression in the liver ischemia-reperfusion acute inflammatory model. In this study we report the first in vivo evidence of liver ischemia and liver ischemia-reperfusion modulation of hepcidin expression. In conclusion, in the well-characterized liver ischemia-reperfusion model of acute inflammation, mechanism(s) other than interleukin-6 signal transduction via signal transducers and activators of transcription-3 may be responsible for hepcidin induction.

Animals↗