Racial and Ethnic Survival Disparities in Pediatric Oncology Over Time: An Analysis of the SEER Registry.

BACKGROUND/PURPOSE: Studies have demonstrated existing racial and ethnic disparities in multiple aspects of pediatric oncology. The purpose of this study was to examine how racial and ethnic disparities in mortality among pediatric oncology patients have changed over time. We examined mortality by race and ethnicity over time within the Surveillance, Epidemiology, and End Results (SEER) registry. METHODS: Patients <20 years-old from 1975 to 2016 (n = 49,861) were selected for the analysis. Demographic characteristics, cancer diagnosis, and mortality data were extracted. Patients were divided by race and ethnicity: 1) non-Latino White, 2) Black, 3) Latino, and 4) Other Race. The interaction between race/ethnicity and decade was evaluated to better understand how disparities in mortality have changed over time. RESULTS: Unadjusted mortality among all cancers improved significantly, with 5-year mortality decreasing from the 1970s to the 2010s (log-rank: p < 0.001) for all race/ethnicity groups. However, improvements in mortality were not equal, with 5-year overall survival (OS) improving from 62.7 % in the 1970s to 87.5 % (Δ = 24.8 %) in the 2010s for White patients but only improving from 59.9 % to 80.8 % (Δ = 20.9 %) for Black patients (p < 0.01). The interaction between Race/Ethnicity and decade demonstrated that the Hazard Ratio (HR) for mortality worsened for Black [HR (95 % Confidence Interval): 1.10 (1.05-1.15) and Latino [1.11 (1.07-1.17)] patients compared to White, non-Latino patients. CONCLUSION: There has been a dramatic improvement in survival across pediatric oncology patients since 1975. However, the improvement has not been shared equally across racial/ethnic categories, with overall survival worsening over time for racial/ethnic minorities compared to White patients. LEVEL OF EVIDENCE: III.

Surgical management of liver tumors.

Two percent of pediatric malignancies arise primarily in the liver; roughly 60% of these cancers are hepatoblastoma (HB). Despite the rarity of these cases, international collaborative efforts have led to the consistent histological classification and staging systems, which facilitate ongoing clinical trials. Other primary liver malignancies seen in children include hepatocellular carcinoma (HCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), undifferentiated embryonal sarcoma of the liver (UESL), and hepatocellular neoplasm not otherwise specified (HCN-NOS). This review describes principles of surgical management of malignant pediatric primary liver tumors, within the context of comprehensive multidisciplinary care.

Cholestasis alters polarization and suppressor function of hepatic regulatory T cells.

Fibrosing cholangiopathies, including biliary atresia and primary sclerosing cholangitis, involve immune-mediated bile duct epithelial injury and hepatic bile acid (BA) retention (cholestasis). Regulatory T-cells (Tregs) can prevent auto-reactive lymphocyte activation, yet the effects of BA on this CD4 lymphocyte subset are unknown. Gene regulatory networks for hepatic CD4 lymphocytes in a murine cholestasis model revealed Tregs are polarized to Th17 during cholestasis. Following bile duct ligation, Stat3 deletion in CD4 lymphocytes preserved hepatic Treg responses. While pharmacological reduction of hepatic BA in MDR2-/- mice prompted Treg expansion and diminished liver injury, this improvement subsided with Treg depletion. A cluster of patients diagnosed with biliary atresia showed both increased hepatic Treg responses and improved 2-year native liver survival, supporting that Tregs might protect against neonatal bile duct obstruction. Together, these findings suggest liver BA determine Treg function and should be considered as a therapeutic target to restore protective hepatic immune responses.

Cellular origin and molecular mechanisms of lung metastases in patients with aggressive hepatoblastoma.

BACKGROUND AND AIMS: Lung metastases are the most threatening signs for patients with aggressive hepatoblastoma (HBL). Despite intensive studies, the cellular origin and molecular mechanisms of lung metastases in patients with aggressive HBL are not known. The aims of these studies were to identify metastasis-initiating cells in primary liver tumors and to determine if these cells are secreted in the blood, reach the lung, and form lung metastases. APPROACH: We have examined mechanisms of activation of key oncogenes in primary liver tumors and lung metastases and the role of these mechanisms in the appearance of metastasis-initiating cells in patients with aggressive HBL by RNA-Seq, immunostaining, chromatin immunoprecipitation, Real-Time Quantitative Reverse Transcription PCR and western blot approaches. Using a protocol that mimics the exit of metastasis-initiating cells from tumors, we generated 16 cell lines from liver tumors and 2 lines from lung metastases of patients with HBL. RESULTS: We found that primary HBL liver tumors have a dramatic elevation of neuron-like cells and cancer-associated fibroblasts and that these cells are released into the bloodstream of patients with HBL and found in lung metastases. In the primary liver tumors, the ph-S675-ß-catenin pathway activates the expression of markers of cancer-associated fibroblasts; while the ZBTB3-SRCAP pathway activates the expression of markers of neurons via cancer-enhancing genomic regions/aggressive liver cancer domains leading to a dramatic increase of cancer-associated fibroblasts and neuron-like cells. Studies of generated metastasis-initiating cells showed that these cells proliferate rapidly, engage in intense cell-cell interactions, and form tumor clusters. The inhibition of ß-catenin in HBL/lung metastases-released cells suppresses the formation of tumor clusters. CONCLUSIONS: The inhibition of the ß-catenin-cancer-enhancing genomic regions/aggressive liver cancer domains axis could be considered as a therapeutic approach to treat/prevent lung metastases in patients with HBL.

Children's Oncology Group's 2023 blueprint for research: Surgery.

Surgery plays a crucial role in the treatment of children with solid malignancies. A well-conducted operation is often essential for cure. Collaboration with the primary care team is important for determining if and when surgery should be performed, and if performed, an operation must be done in accordance with well-established standards. The long-term consequences of surgery also need to be considered. Indications and objectives for a procedure vary. Providing education and developing and analyzing new research protocols that include aims relevant to surgery are key objectives of the Surgery Discipline of the Children's Oncology Group. The critical evaluation of emerging technologies to ensure safe, effective procedures is another key objective. Through research, education, and advancing technologies, the role of the pediatric surgeon in the multidisciplinary care of children with solid malignancies will continue to evolve.

EZH2 is a key component of hepatoblastoma tumor cell growth.

BACKGROUND: Enhancer of zeste homolog 2 (EZH2) catalyzes the trimethylation of histone H3 at lysine 27 via the polycomb recessive complex 2 (PRC2) and plays a time-specific role in normal fetal liver development. EZH2 is overexpressed in hepatoblastoma (HB), an embryonal tumor. EZH2 can also promote tumorigenesis via a noncanonical, PRC2-independent mechanism via proto-oncogenic, direct protein interaction, including ß-catenin. We hypothesize that the pathological activation of EZH2 contributes to HB propagation in a PRC2-independent manner. METHODS AND RESULTS: We demonstrate that EZH2 promotes proliferation in HB tumor-derived cell lines through interaction with ß-catenin. Although aberrant EZH2 expression occurs, we determine that both canonical and noncanonical EZH2 signaling occurs based on specific gene-expression patterns and interaction with SUZ12, a PRC2 component, and ß-catenin. Silencing and inhibition of EZH2 reduce primary HB cell proliferation. CONCLUSIONS: EZH2 overexpression promotes HB cell proliferation, with both canonical and noncanonical function detected. However, because EZH2 directly interacts with ß-catenin in human tumors and EZH2 overexpression is not equal to SUZ12, it seems that a noncanonical mechanism is contributing to HB pathogenesis. Further mechanistic studies are necessary to elucidate potential pathogenic downstream mechanisms and translational potential of EZH2 inhibitors for the treatment of HB.

Intrahepatic Cholangiolitis in Cystic Fibrosis (ICCF): An Under-Appreciated Cause of Persistent Cholestasis in Infancy.

Liver histology in infants with cystic fibrosis (CF) and persistent cholestasis is seldom reported in detail. We extend previous observation of a distinctive intrahepatic cholangiopathy (ICCF) to 3 additional infants homozygous for CFTR pathological variants and a fourth infant with a heterozygous CFTR variant, summarizing our experience in 10 infants with CFTR variants and persistent cholestasis. Cholangiograms demonstrate abnormal extrahepatic ducts in 2 infants with CF, 1 with uniform dilatation interpreted as a choledochal cyst and the other with narrow patent ducts. Liver histology in 3 CF homozygotes had prominent ductular reaction with a focally destructive cholangiolitis (inflammation of small bile ducts). The CFTR heterozygote had generalized portal edema with ductular reaction and paucity but no cholangitis. Cholestasis slowly subsided in all infants. ICCF is characterized by severe ductular reaction, prominent cholangiocyte injury, and multifocal necrotizing cholangiolitis. Local aggregates of portal ceroid might suggest previous bile leakage from damaged ducts. ICCF in liver biopsies from infants with cystic fibrosis and persistent cholestasis is unrelated to the specific CFTR genotype. Liver biopsy findings and intraoperative cholangiogram help rule out biliary atresia. ICCF is an early manifestation of CF, a likely prototype for pathogenesis of cystic fibrosis liver disease later in life.

Quality of Life Outcomes for Patients Who Underwent Conventional Resection and Liver Transplantation for Locally Advanced Hepatoblastoma.

Hepatoblastoma is the most common malignant liver tumor of childhood, with liver transplant and extended resection used as surgical treatments for locally advanced tumors. Although each approach has well-described post-operative complications, quality-of-life outcomes have not been described following the two interventions. Long-term pediatric survivors of hepatoblastoma who underwent conventional liver resection or liver transplantation at a single institution from January 2000-December 2013 were recruited to complete quality-of-life surveys. Survey responses for the Pediatric Quality of Life Generic Core 4.0 (PedsQL, n = 30 patient and n = 31 parent surveys) and Pediatric Quality of Life Cancer Module 3.0 (PedsQL-Cancer, n = 29 patient and n = 31 parent surveys) were collected from patients and parents. The mean total patient-reported PedsQL score was 73.7, and the parent-reported score was 73.9. There were no significant differences in scores on the PedsQL between patients who underwent resection compared to those who underwent transplantation (p > 0.05 for all comparisons). On the PedsQL-Cancer module, procedural anxiety scores were significantly lower for patients who underwent resection as compared to transplant (M = 33.47 points less, CI [-60.41, -6.53], p-value 0.017). This cross-sectional study demonstrates that quality of life outcomes are overall similar among patients receiving transplants and resections. Patients who received a resection reported worse procedural anxiety.

Vincristine/irinotecan/temsirolimus upfront window treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 Study Committee.

BACKGROUND: Survival for children with metastatic hepatoblastoma (HB) remains suboptimal. We report the response rate and outcome of two courses of vincristine/irinotecan/temsirolimus (VIT) in children with high-risk (HR)/metastatic HB. PROCEDURES: Patients with newly diagnosed HB received HR window chemotherapy if they had metastatic disease or a serum alpha-fetoprotein (AFP) level less than 100 ng/mL. Patients received vincristine (days 1 and 8), irinotecan (days 1-5), and temsirolimus (days 1 and 8). Cycles were repeated every 21 days. Responders had either a 30% decrease using RECIST (Response Evaluation Criteria in Solid Tumors) criteria OR a 90% (>1 log10 decline) AFP decline after two cycles. Responders received two additional cycles of VIT intermixed with six cycles of cisplatin/doxorubicin/5-fluorouracil/vincristine (C5VD). Nonresponders received six cycles of C5VD alone. RESULTS: Thirty-six eligible patients enrolled on study. The median age at enrollment was 27 months (range: 7-170). Seventeen of 36 patients were responders (RECIST and AFP = 3, RECIST only = 4, AFP only = 10). The median AFP at diagnosis was 222,648 ng/mL and the median AFP following two VIT cycles was 19,262 ng/mL. Three-year event-free survival was 47% (95% confidence interval [CI]: 30%-62%), while overall survival was 67% (95% CI: 49%-80%). CONCLUSION: VIT did not achieve the study efficacy endpoint. Temsirolimus does not improve the response rate seen in patients treated with vincristine and irinotecan (VI) alone as part of the initial treatment regimen explored in this study. Additionally, AFP response may be a more sensitive predictor of disease response than RECIST in HB.

10 Year Analysis of Pediatric Surgery Fellowship Match and Operative Experience: Concerning Trends?

OBJECTIVE: This paper aims to evaluate the pediatric surgery training pipeline vis-à-vis the pediatric surgery match and operative experience of pediatric surgery fellows. SUMMARY OF BACKGROUND DATA: Pediatric surgery remains a competitive surgical subspecialty. However, there is concern that operative experience for pediatric surgery fellows is changing. This paper examines the selectivity of the pediatric surgery match, along with the operative experience of pediatric surgery fellows to characterize the state of pediatric surgery training. METHODS: The pediatric surgery fellowship match was analyzed from the National Resident Matching Program data from 2010 to 2019. Selectivity among fellowships was compared using analysis of variance with Dunnett test. Operative log data for pediatric fellows was analyzed using the Accreditation Council for Graduate Medical Education case logs from 2009 to 2019. Linear regression analysis was used to evaluate trends in operative volume over time. RESULTS: Pediatric surgery had the highest proportion of unmatched applicants (47.2% ± 5.3%) and lowest proportion of unfilled positions (1.4% ± 1.6%) when compared to other National Resident Matching Program surgical fellowships. Accreditation Council for Graduate Medical Education case log analysis revealed a statistically significant decrease in cases for graduating fellows (-5.3 cases/year, P < 0.05). Total index cases decreased (-4.7 cases/year, P < 0.01, R 2 = 0.83) such that graduates in 2019 completed 59 fewer index operations than graduates in 2009. CONCLUSION: Although pediatric surgery fellowship remains highly selective there has been a decline in the operative experience for graduating fellows. This highlights the need for evaluation of training paradigms and operative exposure in pediatric surgery to ensure the training of competent pediatric surgeons.

Phosphorylation-Mediated Activation of ß-Catenin-TCF4-CEGRs/ALCDs Pathway Is an Essential Event in Development of Aggressive Hepatoblastoma.

BACKGROUND AND AIMS: Hepatoblastoma (HBL), a deadly malignancy in children, is the most common type of pediatric liver cancer. We recently demonstrated that ß-catenin, phosphorylated at S675 (ph-S675-ß-catenin), causes pathological alterations in fibrolamellar hepatocellular carcinoma (FLC), by activating oncogenes and fibrotic genes via human genomic regions, known as cancer-enhancing genomic regions or aggressive liver cancer domains (CEGRs/ALCDs). The aim of this study was to determine the role of the ph-S675-ß-catenin-TCF4-CEGRs/ALCDs pathway in HBL. METHODS: The ph-S675-ß-catenin-TCF4-CEGRs/ALCDs pathway was examined in a large cohort of HBL specimens, in HBL cell lines HepG2 and Huh6, and in patient-derived xenografts (PDXs). RESULTS: ß-catenin is phosphorylated at S675 in a large portion of tested HBL patients. In these patients, ph-S675-ß-catenin forms complexes with TCF4 and opens CEGRs/ALCDs-dependent oncogenes for transcription, leading to a massive overexpression of the oncogenes. The inhibition of the ß-catenin-TCF4-CEGRs/ALCDs axis inhibits the proliferation of cancer cells and tumor growth in HBL cell lines and HBL-PDXs. The ph-S675-ß-catenin is abundant in mitotic cells. We found that markers of HBL Glypican 3 (GPC3) and Alpha Fetoprotein (AFP) are increased in HBL patients by ß-catenin-TCF4-p300 complexes. CONCLUSIONS: The phosphorylation-mediated activation of the ß-catenin-TCF4-p300-CEGRs/ALCDs pathway increases oncogene expression in patients with aggressive liver cancer and promotes the development of hepatoblastoma.

ß-catenin cancer-enhancing genomic regions axis is involved in the development of fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLC) is a disease that occurs in children and young adults. The development of FLC is associated with creation of a fusion oncoprotein DNAJB1-PKAc kinase, which activates multiple cancer-associated pathways. The aim of this study was to examine the role of human genomic regions, called cancer-enhancing genomic regions or aggressive liver cancer domains (CEGRs/ALCDs), in the development of FLC. Previous studies revealed that CEGRs/ALCDs are located in multiple oncogenes and cancer-associated genes, regularly silenced in normal tissues. Using the regulatory element locus intersection (RELI) algorithm, we searched a large compendium of chromatin immunoprecipitation-sequencing (ChIP) data sets and found that CEGRs/ALCDs contain regulatory elements in several human cancers outside of pediatric hepatic neoplasms. The RELI algorithm further identified components of the ß-catenin-TCF7L2/TCF4 pathway, which interacts with CEGRs/ALCDs in several human cancers. Particularly, the RELI algorithm found interactions of transcription factors and chromatin remodelers with many genes that are activated in patients with FLC. We found that these FLC-specific genes contain CEGRs/ALCDs, and that the driver of FLC, fusion oncoprotein DNAJB1-PKAc, phosphorylates ß-catenin at Ser675, resulting in an increase of ß-catenin-TCF7L2/TCF4 complexes. These complexes increase a large family of CEGR/ALCD-dependent collagens and oncogenes. The DNAJB1-PKAc-ß-catenin-CEGR/ALCD pathway is preserved in lung metastasis. The inhibition of ß-catenin in FLC organoids inhibited the expression of CEGRs/ALCDs-dependent collagens and oncogenes, preventing the formation of the organoid's structure. Conclusion: This study provides a rationale for the development of ß-catenin-based therapy for patients with FLC.

The Outcome of Patients With Cystic Biliary Atresia With Intact Proximal Hepatic Ducts Following Hepatic-Cyst-Jejunostomy.

OBJECTIVES: To determine the outcomes of patients with cystic biliary atresia by correlating the anatomy of the hepatic ducts with the choice of biliary reconstruction surgery. BACKGROUND: The Kasai hepatoportoenterostomy (Kasai) is the initial surgical procedure offered to most patients with biliary atresia. In contrast, a hepatic-cyst-jejunostomy has been reported to be effective in patients with the cystic form of biliary atresia. METHODS AND RESULTS: We performed an international multicenter retrospective review. Two hundred eighty-seven patients were included, and 33 cases of cystic biliary atresia were identified. Outcomes were the serum total bilirubin level 3 months post-surgery and native liver survival at 2 years of age and were compared between cases who received the Kasai versus hepatic-cyst-jejunostomy in correlation to the anatomy of proximal hepatic ducts. The patients were categorized into 3 anatomical groups: patent intact hepatic ducts (n = 10), patent hypoplastic hepatic ducts (n = 13), and obliterated hepatic ducts (n = 10). All 10 patients with patent intact hepatic duct group underwent hepatic-cyst-jejunostomy, and 9 experienced bile drainage and native liver survival. Among the 13 patients with hypoplastic hepatic ducts, 11 underwent the Kasai procedure, and 9 had bile drainage, whereas 2 underwent hepatic-cyst-jejunostomy, and one survived with the native liver. All of the patients with obliterated hepatic ducts underwent the Kasai procedure; 5 established biliary drainage and survived with the native liver. Of 5 who did not drain, 3 underwent liver transplantation. CONCLUSIONS: In patients with cystic biliary atresia, the subset with a connection between cyst and intrahepatic bile ducts via intact proximal hepatic ducts had favorable clinical outcomes following hepatic-cyst-jejunostomy.

Planned Preterm Delivery and Treatment of Severe Infantile FEVR With Osteoporosis-Pseudoglioma Syndrome.

Familial exudative vitreoretinopathy (FEVR) is a rare hereditary vitreoretinopathy resulting from mutations in the wnt signaling pathway leading to abnormalities in fetal retinal vasculogenesis, angiogenesis, and retinal vascular maintenance. Severe FEVR may result in congenital retinal detachment resembling Norrie disease. The authors report the first case of planned preterm delivery and treatment of a patient with severe FEVR from biallelic LRP5 mutations whose siblings had congenital tractional retinal detachments with light perception vision outcomes after conventional care. Early intervention allowed laser ablation of avascular retina and functional visual outcome despite a successfully repaired unilateral tractional retinal detachment. [Ophthalmic Surg Lasers Imaging Retina. 2022;53(4):228-232.].

Predictors of survival following liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma: Experience from the Society of Pediatric Liver Transplantation (SPLIT).

Management of unresectable pediatric hepatoblastoma (HB) and hepatocellular carcinoma (HCC) remains challenging. The Society of Pediatric Liver Transplantation (SPLIT) database was used to study survival predictors in pediatric liver transplantation (LT) for HB and HCC. Event-free survival (EFS), associated risk factors, and postoperative complications were studied in children requiring LT for HB/HCC at 16 SPLIT centers. Three-year EFS was 81% for HB (n = 157) and 62% for HCC (n = 18) transplants. Of HB transplants, 6.9% were PRETEXT II and 15.3% were POST-TEXT I/II. Tumor extent did not impact survival (p = NS). Salvage (n = 13) and primary HB transplants had similar 3-year EFS (62% versus 78%, p = NS). Among HCC transplants, 3-year EFS was poorer in older patients (38% in ≥8-year-olds vs 86% <8-year-olds) and those with larger tumors (48% for those beyond versus 83% within Milan criteria, p = NS). Risk of infection (HR 1.5, 95% CI 1.1-2.2, p = .02) and renal injury (HR 2.4, 95% CI 1.7-3.3, p < .001) were higher in malignant versus nonmalignant LT. Survival is favorable for pediatric HB and HCC LT, including outcomes after salvage transplant. Unexpected numbers of LTs occurred in PRE/POST-TEXT I/II tumors. Judicious patient selection is critical to distinguish tumors that are potentially resectable; simultaneously, we must advocate for patients with unresectable malignancies to receive organs.

Doxorubicin in combination with cisplatin, 5-flourouracil, and vincristine is feasible and effective in unresectable hepatoblastoma: A Children's Oncology Group study.

BACKGROUND: The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. METHODS: In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. RESULTS: One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. CONCLUSIONS: The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials.

Relation of Liver Volume to Adverse Cardiovascular Events in Adolescents and Adults With Fontan Circulation.

Elevated central venous pressure in those with Fontan circulation causes liver congestion and hepatomegaly. We assessed if liver volume by magnetic resonance imaging (MRI) is associated with adverse cardiovascular outcomes. Retrospective study of 122 patients with Fontan circulation who were >10 years old and had a liver MRI with magnetic resonance elastography. Liver volume (ml) was measured by manual segmentation from axial T2-weighted images and was indexed to body surface area. The composite outcome included death, heart transplant, ventricular assist device placement, or nonelective cardiovascular hospitalization. The median age at the time of MRI was 18.9 (interquartile range 15.8 to 25.9) years, and 47% of the patients were women. The mean indexed liver volume was 1,133 ± 180 ml/m2. Indexed liver volume was not significantly associated with age, years since Fontan, or with liver stiffness (r = 0.15, p = 0.10), but was positively correlated with Fontan pressure (r = 0.32, p = 0.002). Over a median follow-up of 2.1 (0.8 to 4.2) years, 32 patients (26%) experienced the composite outcome. Higher indexed liver volume was associated with a greater hazard for the composite outcome (hazard ratio per 1 SD increase = 1.74, 95% confidence interval 1.27 to 2.35, p = 0.0004) but increased liver stiffness was not significantly associated with the composite outcome (hazard ratio per 1 SD increase 1.44, 95% confidence interval 0.90 to 2.21, p = 0.11). In conclusion, greater liver volume indexed to body surface area is associated with unfavorable hemodynamics and adverse outcomes in patients with Fontan circulation. Liver volume may be a useful, simple imaging biomarker in adolescents and adults with Fontan circulation.

Urinary 11-dehydrothromboxane B2 aspirin efficacy testing is sensitive to perioperative inflammation in pediatric solid-organ transplant patients.

BACKGROUND: Evidence for aspirin efficacy testing in pediatrics is limited, especially outside of cardiology, yet thrombotic events have high morbidity in other areas such as pediatric transplant surgery. Debates about whether thromboembolic events while on aspirin represent "aspirin resistance" or "high on-treatment platelet reactivity" persist, given the poor intertest agreement between testing platforms. PROCEDURE: This prospective observational study involved measuring aspirin efficacy using ex vivo testing of platelet aggregation (VerifyNow-Aspirin, VN) and urine 11-dehydrothromboxane B2 (AsprinWorks, UTxB2) contemporaneously at up to three time points after major noncardiac organ transplant surgery. The collection days (CD) were the second and seventh days after stable aspirin dosing and then a convalescent time point 2-9 months later. RESULTS: Fifty-five participants (age range, 0-21 years) were enrolled, having undergone total pancreatectomy with islet autotransplantation (N = 36), orthotopic liver transplantation (N = 18), and combined liver-kidney transplantation (N = 1). Platelet reactivity measured by VN remained unchanged, whereas UTxB2, which was elevated postoperatively, decreased significantly from CD1 to CD2 and CD3. Discordance in therapeutic efficacy was noted per manufacturer cutoffs, with therapeutic VN results in 86% of tests, whereas 12% of UTxB2 were therapeutic. Age-based stratification of UTxB2 results using previously published pediatric median levels increased overall UTxB2 therapeutic rates (80%) and intertest concordance (67% vs 27% if using adult range). No thrombotic events were observed. CONCLUSIONS: Our data suggest that urine thromboxane production may be an underappreciated reflection of postoperative inflammation. Validation of pediatric normal ranges for UTxB2 is a critical next step.