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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↗
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↗
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↗
PubMed2005

Orthotopic liver transplantation for biliary atresia: the U.S. experience.

Biliary atresia is the most common indication for orthotopic liver transplantation (OLT) in the pediatric population. The outcomes of liver transplantation for biliary atresia, however, have not been formally examined on a national scale. The objective of this study was to identify pretransplant variables that predict patient survival after primary liver transplantation for biliary atresia. A cohort of 1,976 pediatric patients undergoing primary liver transplantation for biliary atresia between 1/1988 to 12/2003 was enrolled from the United Network for Organ Sharing database after excluding patients with a history of multiorgan transplant or previous liver transplant. Follow-up data up to 16 years post-OLT was available. The 5- and 10-year actuarial survival rates of patients that underwent liver transplantation for biliary atresia in the United States are 87.2% and 85.8%, respectively, and the 5- and 10-year graft actuarial survival rates are 76.2% and 72.7%, respectively. Early deaths (< or =90 days post-OLT) were more often caused by graft failure (P = 0.01), whereas late deaths (>90 days post-OLT) were more often due to malignancy (P < 0.01). An analysis of outcomes over time demonstrated a decrease in post-OLT survival and an increase in the number of OLTs done for biliary atresia at an increasing number of centers. A multivariate analysis revealed that cadaveric partial/reduced liver grafts, a history of life support at the time of OLT, and decreased age were independent predictors of increased post-OLT mortality. In conclusion, OLT is an effective treatment for biliary atresia. Certain pretransplant variables may help predict patient survival following liver transplantation for biliary atresia.

Age Distribution↗
PubMed2005

Transaminitis after pancreatic islet transplantation.

BACKGROUND: An asymptomatic, self-limited transaminitis uniformly follows pancreatic islet transplantation (PIT) performed through portal vein (PV) infusion. The underlying cause and significance of this transaminitis is unclear. STUDY DESIGN: Records of all patients with insulin-dependent diabetes mellitus who had undergone PIT at our institution were reviewed. All PITs were performed in conjunction with a remote pancreatic islet isolation center and done through percutaneous transhepatic PV infusion. Alanine aminotransferase (ALT) levels, serum glucose concentrations, insulin requirements, and color-flow Doppler ultrasonography examinations of the right upper quadrant were assessed before and after PIT. RESULTS: Eleven patients have undergone a total of 26 PITs. An elevated ALT level occurred in all 11 patients (100%) after the first PIT, with the median post-PIT peak ALT level reaching 187 IU/L. Transaminitis was less frequent and less marked after the second PIT. A negative correlation between viability of the pancreatic islets transplanted (r = -0.44, p = 0.03) and a positive correlation between the ratio of maximum to initial PV pressure (r = 0.41, p = 0.04) were seen with the subsequent ALT peak. Color-flow Doppler ultrasonography examinations showed no occurrences of PV thrombosis or intrahepatic hematoma. Finally, the degree of transaminitis did not correlate with post-PIT insulin requirements, indicating that post-PIT transaminitis cannot be used to measure allograft rejection or function. CONCLUSIONS: Transaminitis after PIT is common and self-limited. Post-PIT transaminitis does not signal acute rejection or serious procedure-related complications such as PV thrombosis or intrahepatic hematoma.

Adult↗
PubMed2005

Treatment of acute tacrolimus whole-blood elevation with phenobarbital in the pediatric liver transplant recipient.

The toxicities associated with the chronic use of tacrolimus are well described in the literature; however, little is known about the management during an acute overdose. Phenobarbital is a long-acting barbiturate metabolized in the liver by the cytochrome p450 3a4 system. It is known to enhance the rate of metabolism of itself and the clearance of drugs metabolized by p450 3a4. Because tacrolimus is a substrate of this particular isoenzyme, phenobarbital can be considered a potential option when rapid decreases in tacrolimus whole-blood levels are desired. We hereby report our experience using intravenous phenobarbital in the management of two infants with acute elevations in their tacrolimus whole-blood concentration following liver transplantation. Phenobarbital, through its up-regulation of hepatic cytochrome p450 system increases the elimination of whole-blood tacrolimus concentration in acute overdose situations.

Biliary Atresia↗
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

Rescue purification maximizes the use of human islet preparations for transplantation.

The relative inefficiency of the islet purification process may hamper obtaining enough islets for transplantation even with adequate pre-purification counts. In this study, we determined the effect of an additional purification step on total islet yields and pancreas utilization at our center. Twenty-five pancreata were processed using the automated method followed by continuous gradient purification (CGP), and the less pure islet fractions were subjected to additional rescue gradient purification (RGP). CGP and RGP islets were combined and transplanted into patients with type 1 diabetes. CGP and RGP islets showed no significant differences in cell viability, insulin secretion in vitro and function when transplanted into chemically diabetic mice. Mean RGP contribution to the final preparation was 27.9 +/- 19.9%. In 12 of 25 preparations, CGP yielded <5000 IEQ/kg of recipient body weight, and inclusion of RGP islets to the final preparation allowed to obtain the minimal islet number required for transplantation. Transplanted islets resulted in sustained C-peptide production, HbA1(C) normalization and insulin-independence or reduced insulin requirements. Taken together, our data suggest that RGP islets are comparable in terms of viability and potency to CGP islets. RGP may be of assistance in maximizing the number of islet preparations successfully used in transplant protocols.

Animals↗
PubMed2005

Split-liver transplantation using the left lateral segment: a collaborative sharing experience between two distant centers.

Split-liver transplantation (SLT) increases the pool of organs for pediatric orthotopic liver transplantation (pOLT). With increased collaboration and organ sharing, transplant centers can fully maximize the use of all split donor allografts. Herein, we report the collaborative results between two distant centers involved in a sharing alliance. The current study consists of a retrospective review of 56 pediatric LLS transplants performed at two collaborating centers between 9/1997 and 10/2003. Fifty-three patients (41% Status 1) were transplanted using 56 left lateral segment (LLS) grafts. Sixteen percent of LLS grafts were shared between the two institutions. Overall patient survival at both 1 and 3 years was 90% and 90%, respectively. Overall graft survival at both 1 and 3 years was 82% and 82%, respectively. Shared patient and graft survival was 89% and 89%, respectively. There was an 11% biliary complication and 18% vascular complication rate. Five patients required retransplantation. In conclusion, SLT increases the number of available allografts for pOLT. While SLT is technically demanding, with a significant learning curve, patient and graft survival rates compare favorably with United Network Organ Sharing (UNOS) averages. Sharing of grafts between centers is a safe and effective way to maximize organ usage and should be actively pursued through collaborative networks.

Adolescent↗
PubMed2005

Split-liver transplantation: results of statewide usage of the right trisegmental graft.

Split-liver transplantation (SLT) effectively expands the cadaveric donor pool for children. The remaining right trisegmental (RTS) graft can be transplanted into adults. Limited information exists regarding the outcomes of RTS allografts. Sixty-five RTS graft recipients from five adult transplant programs in Texas were identified. Donor and recipient information were analyzed retrospectively. Most livers (75%) were originally allocated to pediatric recipients. Liver splitting occurred via the in situ (72%) and ex situ (28%) techniques. Arterial reconstruction of RTS grafts was common (52%). Patient and graft survival at 3 months were comparable for the in situ and ex situ techniques (p = 0.2). Cox regression showed only in situ splitting to be a predictor of outcome longer than 3 months posttransplant. Sharing of grafts between centers was frequent (37% of total). One-year patient and allograft survival (87.1% and 85.4%) were excellent with no cases of primary nonfunction. SLT consistently generates two functional liver allografts with excellent recipient survival. In situ splitting of the liver is the preferred technique. Decreased survival is observed with RTS graft use in higher risk recipients. Broader application of SLT with increased sharing is feasible and safely expands the number of liver allografts that can be transplanted.

Adult↗
PubMed2005

Adult liver transplant candidate attitudes toward graft sharing are not obstacles to split liver transplantation.

Split liver transplantation (SLT) benefits society by increasing the total number of transplants that can be performed, but it is yet unknown if a decreased post-transplant survival (in comparison to whole liver transplantation) would make participation in SLT less appealing to adult liver transplant candidates. A 20-item questionnaire was administered to 50 adult candidates to assess attitudes toward SLT and organ sharing. The overall attitudes of 60% of participants were classified as utilitarian (maximizing benefit to greatest number of candidates), while 26% were classified as self-preserving (maximizing individual benefit) and 14% were undecided. Ninety percent of participants would be willing to share even if expected survival was less than that of whole liver transplantation, and 69% felt that pediatric candidates should have priority over adult candidates. In conclusion, attitudes toward graft sharing and the possibility of compromised survival benefit are not barriers to SLT for most adult liver transplant candidates.

Adult↗