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1.
Cancers (Basel) ; 16(13)2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-39001363

RESUMO

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. METHODS: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. RESULTS: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. CONCLUSIONS: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers.

2.
Pediatr Blood Cancer ; 71(6): e30975, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38556718

RESUMO

BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare tumor for which there are few evidence-based guidelines. The aim of this study was to define current management strategies and outcomes for these patients using a multi-institutional dataset curated by the Pediatric Surgical Oncology Research Collaborative. METHODS: Data were collected retrospectively for patients with UESL treated across 17 children's hospitals in North America from 1989 to 2019. Factors analyzed included patient and tumor characteristics, PRETEXT group, operative details, and neoadjuvant/adjuvant regimens. Event-free and overall survival (EFS, OS) were the primary and secondary outcomes, respectively. RESULTS: Seventy-eight patients were identified with a median age of 9.9 years [interquartile range [IQR): 7-12]. Twenty-seven patients underwent resection at diagnosis, and 47 patients underwent delayed resection, including eight liver transplants. Neoadjuvant chemotherapy led to a median change in maximum tumor diameter of 1.6 cm [IQR: 0.0-4.4] and greater than 90% tumor necrosis in 79% of the patients undergoing delayed resection. R0 resections were accomplished in 63 patients (81%). Univariate analysis found that metastatic disease impacted OS, and completeness of resection impacted both EFS and OS, while multivariate analysis revealed that R0 resection was associated with decreased expected hazards of experiencing an event [hazard ratio (HR): 0.14, 95% confidence interval (CI): 0.04-0.6]. At a median follow-up of 4 years [IQR: 2-8], the EFS was 70.0% [95% CI: 60%-82%] and OS was 83% [95% CI: 75%-93%]. CONCLUSION: Complete resection is associated with improved survival for patients with UESL. Neoadjuvant chemotherapy causes minimal radiographic response, but significant tumor necrosis.

3.
Semin Pediatr Surg ; 32(5): 151340, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38008042

RESUMO

The appropriate management of pediatric liver malignancies, primarily hepatoblastoma and hepatocellular carcinoma, requires an in depth understanding of contemporary preoperative risk stratification, experience with advanced hepatobiliary surgery, and a good relationship with one's local or regional liver transplant center. While chemotherapy regimens have become more effective, operative indications more well-defined, and overall survival improved, the complexity of liver surgery in small children provides ample opportunity for protocol violation, inadequate resection, and iatrogenic morbidity. These guidelines represent the distillation of contemporary literature and expert opinion as a means to provide a framework for preoperative planning and intraoperative decision-making for the pediatric surgeon.


Assuntos
Carcinoma Hepatocelular , Hepatoblastoma , Neoplasias Hepáticas , Transplante de Fígado , Criança , Humanos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Hepatoblastoma/cirurgia , Hepatoblastoma/patologia , Transplante de Fígado/métodos , Resultado do Tratamento
4.
Cancers (Basel) ; 15(15)2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37568737

RESUMO

BACKGROUND: Hepatoblastoma (HB) is the most common liver malignancy in children. There is no standard of care for management of relapsed/refractory HB (rrHB) and reports in the literature are limited. OBJECTIVE: To describe presenting features, biology, treatment strategies, and outcomes for pediatric patients with relapsed/refractory hepatoblastoma. METHODS: An IRB-approved retrospective institutional review of patients with rrHB who presented for consultation and/or care from 2000-2019. Clinical, radiographic, and histologic data were collected from all patients. RESULTS: Thirty subjects were identified with a median age of 19.5 months (range 3-169 months) at initial diagnosis and 32.5 months (range 12-194 months) at time of first relapse. 63% of subjects were male, 70% Caucasian, and 13% were born premature. Three subjects had a known cancer predisposition syndrome. Eight patients had refractory disease while 22 patients had relapsed disease. Average time from initial diagnosis to relapse or progression was 12.5 months. Average alpha-fetoprotein (AFP) at initial diagnosis was 601,203 ng/mL (range 121-2,287,251 ng/mL). Average AFP at relapse was 12,261 ng/mL (range 2.8-201,000 ng/mL). For patients with tumor sequencing (n = 17), the most common mutations were in CTNNB1 (13) and NRF2 (4). First relapse sites were lungs (n = 12), liver (n = 11) and both (n = 6). More than one relapse/progression occurred in 47% of subjects; 6 had ≥3 relapses. Pathology in patients with multiply relapsed disease was less differentiated including descriptions of small cell undifferentiated (n = 3), pleomorphic (n = 1), transitional liver cell tumor (n = 2) and HB with carcinoma features (n = 1). All subjects underwent surgical resection of site of relapsed disease with 7 subjects requiring liver transplantation. Overall survival was 50%. Survival was associated with use of cisplatin at relapse (78.6% with vs. 25% without, p = 0.012). The most common late effect was ototoxicity with at least mild sensorineural hearing loss found in 80% of subjects; 54% required hearing aids. CONCLUSIONS: Retreatment with cisplatin at the time of relapse may provide an advantage for some patients with hepatoblastoma. Multiply relapsed disease was not uncommon and not associated with a worse prognosis. Careful attention should be paid to cumulative therapy-induced toxicity while concurrently aiming to improve cure.

5.
Pediatr Blood Cancer ; 70 Suppl 6: e30576, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37495540

RESUMO

Liver tumors account for approximately 1%-2% of all pediatric malignancies, with the two most common tumors being hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Previous Children's Oncology Group studies have meaningfully contributed to the current understanding of disease pathophysiology and treatment, laying groundwork for the ongoing prospective international study of both HB and HCC. Future work is focused on elucidating the biologic underpinnings of disease to support an evolution in risk categorization, advancements in the multidimensional care required to treat these patients, and the discovery of novel therapies.


Assuntos
Carcinoma Hepatocelular , Hepatoblastoma , Neoplasias Hepáticas , Criança , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Estudos Prospectivos , Hepatoblastoma/terapia , Hepatoblastoma/patologia , Terapia Combinada
6.
Pediatr Transplant ; 27(4): e14509, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36919408

RESUMO

BACKGROUND: Tacrolimus (TAC)-mediated renal disease occurs in up to 70% of pediatric liver transplant (LT) recipients. The safety and efficacy of renal-sparing immunosuppression using anti-thymocyte globulin (ATG) induction and delayed TAC administration has not been studied in children. We evaluated the safety and efficacy of ATG induction on preserving renal function in children within the first year (Y1) post-LT in a single-center retrospective cohort study. METHODS: Children under age 18 years of who received isolated LT from 2008 to 2020 with a GFR < 70 received renal-sparing (RS) protocol consisting of ATG with methylprednisolone (MP), delayed TAC administration, lower initial TAC trough goals, and mycophenolate mofetil (MMF). The RS group was matched 1:2 by age and LT indication with standard immunosuppression (SI) group. Changes in renal function as well as adverse events within Y1 post-LT were compared. RESULTS: Forty-four pediatric patients were included in the analysis, of which 13 received RS. As expected, the RS group had significantly lower mean TAC trough levels at 30 days (10.3 vs. 13.2, p = .001) post-LT. Renal function was significantly preserved at 6 (-0.26 vs. 0.21, p = .004) and 12 months (-0.33 vs. 0.11, p = .003) post-LT in the RS versus SI group as measured by mean change in serum creatinine, with similar trends observed in eGFR and cystatin C. ACR, sepsis, viremia, graft loss and mortality occurred at similar rates in both RS and SI groups. CONCLUSION: Induction immunosuppression with ATG and delayed TAC administration in children with renal impairment is safe and effectively preserves renal function during Y1 post-LT.


Assuntos
Transplante de Fígado , Tacrolimo , Humanos , Criança , Adolescente , Tacrolimo/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Imunossupressores/uso terapêutico , Estudos Retrospectivos , Transplante de Fígado/efeitos adversos , Ácido Micofenólico/uso terapêutico , Rim/fisiologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto
7.
J Pediatr Surg ; 58(8): 1483-1488, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36496264

RESUMO

BACKGROUND: Controversies in management of biliary atresia (BA) after hepatoportoenterostomy (HPE) lead to variable treatment protocols. We implemented standardized medical management after HPE, customizing the use of antibiotics and corticosteroids based on patient-specific factors. METHODS: In this retrospective analysis, 20 consecutive infants underwent HPE for BA and were compared to a historical cohort. Analysis of successful biliary drainage 3 months after HPE (defined as serum total bilirubin <2 mg/dL) was the primary endpoint; survival with native liver at 2 years was the secondary endpoint. RESULTS: Sixteen of 20 (80%) infants had successful bile drainage, compared to 8 of 20 (40%) infants in the historical cohort (P = 0.0225). Sixteen of 20 patients in the new protocol have reached 2 years of age or required liver transplantation. Among the sixteen, 11 (68.8%) are alive with native livers versus 10 of 20 (50%) in the historical cohort (P = 0.0970). CONCLUSION: This preliminary report suggests the potential benefit of tailored use of postoperative antibiotics and corticosteroids in improving biliary drainage after HPE. LEVEL OF EVIDENCE: III.


Assuntos
Atresia Biliar , Lactente , Humanos , Atresia Biliar/complicações , Estudos Retrospectivos , Bile , Portoenterostomia Hepática/métodos , Drenagem , Corticosteroides , Resultado do Tratamento
8.
Hepatology ; 77(2): 530-545, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36069569

RESUMO

BACKGROUND AND AIMS: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis. APPROACH AND RESULTS: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS. CONCLUSIONS: Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important.


Assuntos
Síndrome de Alagille , Colestase , Técnicas de Imagem por Elasticidade , Hepatopatias , Humanos , Criança , Fígado/patologia , Metaloproteinase 7 da Matriz , Endoglina , Interleucina-8 , Colestase/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Hepatopatias/patologia , Biomarcadores , Síndrome de Alagille/patologia
9.
J Pediatr Surg ; 57(10): 251-256, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35810020

RESUMO

BACKGROUND: Hepatoblastoma (HB) requires surgical resection for cure, but only 20-30% of patients have resectable disease at diagnosis. Patients who undergo partial hepatectomy at diagnosis have historically received 4-6 cycles of adjuvant chemotherapy; however, those with 100% well-differentiated fetal histology (WDF) have been observed to have excellent outcomes when treated with surgery alone. PATIENTS AND METHODS: Patients on the Children's Oncology Group non randomized, multicenter phase III study, AHEP0731, were stratified based on Evan's stage, tumor histology, and serum alpha-fetoprotein level at diagnosis. Patients were eligible for the very low risk stratum of surgery and observation if they had a complete resection at diagnosis and rapid central histologic review demonstrated HB with 100% WDF histology. RESULTS: A total of 8 eligible patients were enrolled on study between September 14, 2009 and May 28, 2014. Outcome current to 06/30/2020 was used in this analysis. The median age at enrollment was 22.5 months (range: 8-84 months) and the median AFP at enrollment was 714 ng/ml (range: 18-77,747 ng/mL). With a median follow-up of 6.6 years (range: 3.6-9.8 years), the 5-year event-free (EFS) and overall survival (OS) were both 100%. CONCLUSION: This report supports that HB with 100% WDF histology completely resected at diagnosis is curable with surgery only. The development of evidence-based surgical guidelines utilizing criteria based on PRETEXT group, vascular involvement (annotation factors), tumor-specific histology and corresponding biology will be crucial for optimizing which patients are candidates for resection at diagnosis followed by observation. LEVEL OF EVIDENCE: Prognosis study, Level I evidence.


Assuntos
Hepatoblastoma , Neoplasias Hepáticas , Quimioterapia Adjuvante , Criança , Hepatectomia , Hepatoblastoma/patologia , Humanos , Lactente , Neoplasias Hepáticas/patologia , Prognóstico , Resultado do Tratamento
10.
Cancer ; 128(14): 2786-2795, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35561331

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis. METHODS: A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse. RESULTS: In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival. CONCLUSIONS: This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC. LAY SUMMARY: This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Oncologia Cirúrgica , Carcinoma Hepatocelular/patologia , Criança , Humanos , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos
11.
J Hepatol ; 77(4): 1026-1037, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35577029

RESUMO

BACKGROUND & AIMS: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS. METHODS: We tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8). RESULTS: Molecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes. CONCLUSIONS: Our study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms. LAY SUMMARY: We molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.


Assuntos
Carcinoma Hepatocelular , Hepatoblastoma , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Criança , Aberrações Cromossômicas , Hepatoblastoma/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Mutação , Adulto Jovem
12.
J Clin Oncol ; 40(5): 459-467, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-34874751

RESUMO

PURPOSE: Small cell undifferentiated (SCU) histology in hepatoblastoma (HB) tumors has historically been associated with a poor prognosis. Tumors from patients enrolled on Children's Oncology Group (COG) study AHEP0731 underwent institutional and central pathologic review for identification of SCU histology. PATIENTS AND METHODS: Patients with SCU histology identified at the local treating institution who had otherwise low-risk tumors were upstaged to the intermediate-risk treatment stratum, whereas those only identified by retrospective central review were treated per the local institution as low-risk. Patients with otherwise intermediate- or high-risk tumors remained in that treatment stratum, respectively. Central review was to be performed for all tissue samples obtained at any time point. Treatment was per local review, whereas analysis of outcome was based on central review. RESULTS: Thirty-five patients had some elements (1%-25%) of SCU identified on central review of diagnostic specimens. All but two patient tissue sample retained nuclear INI1 expression. The presence of SCU histology did not correlate with age, alpha-fetoprotein level at diagnosis, or sex. The presence of SCU did not affect event-free survival (EFS). EFS at 5 years for patients with low-risk, intermediate-risk, and high-risk with SCU HB was 86% (95% CI, 33 to 98), 81% (95% CI, 57 to 92), and 29% (95% CI, 4 to 61), respectively, compared with EFS at 5 years for patients without SCU enrolled with low-risk, intermediate-risk, and high-risk of 87% (95% CI, 72 to 95), 88% (95% CI, 79 to 94), and 55% (95% CI, 32 to 74; P = .17), respectively. CONCLUSION: The presence of SCU histology in HB does not appear to adversely affect outcome. Future studies should be able to treat patients with SCU HB according to risk stratification without regard to the presence of SCU histology.


Assuntos
Diferenciação Celular , Hepatoblastoma/patologia , Neoplasias Hepáticas/patologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Progressão da Doença , Feminino , Hepatectomia , Hepatoblastoma/mortalidade , Hepatoblastoma/terapia , Humanos , Lactente , Recém-Nascido , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Transplante de Fígado , Masculino , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo
13.
J Pediatr Surg ; 56(6): 1196-1202, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33838903

RESUMO

BACKGROUND/PURPOSE: The purpose of this study was to assess variability in age at Kasai portoenterostomy (KP) in infants with biliary atresia (BA) across children's hospitals in the United States. STUDY DESIGN: A multi-institutional retrospective study was performed examining infants with BA undergoing KP within 6 months of birth from 2016-2019, utilizing the Pediatric Health Information System (PHIS). Multivariable negative binomial mixed effects regression was performed for age at KP, and inter-hospital variability was examined. RESULTS: Across 46 hospitals, 470 infants with BA underwent KP at a median age of 57 days (IQR 42-72), with 212 (45.1%) undergoing KP at ≥60 days of age. There was significant inter-hospital variability in age at KP ranging from 38 days (95% CI: 31d, 47d) to 76 days (95% CI: 63d, 91d) (p<0.0001). Factors associated with later KP were black or African-American race, urgent/emergent admission, and treatment at a hospital in the Pacific-West region. Predictors of earlier KP included later year, history of neonatal comorbidity, and admission to an intensive care service (all p<0.05). CONCLUSION: There is significant variability in the age at KP in infants with BA across children's hospitals in the United States. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: III.


Assuntos
Atresia Biliar , Transplante de Fígado , Atresia Biliar/epidemiologia , Atresia Biliar/cirurgia , Criança , Hospitais Pediátricos , Humanos , Lactente , Recém-Nascido , Portoenterostomia Hepática , Estudos Retrospectivos , Resultado do Tratamento
14.
Surg Oncol Clin N Am ; 30(2): 253-274, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33706899

RESUMO

The most recent advance in the care of children diagnosed with hepatoblastoma and hepatocellular carcinoma is the Pediatric Hepatic International Tumor Trial, which opened to international enrollment in 2018. It is being conducted as a collaborative effort by the pediatric multicenter trial groups in North America, Europe, and the Far East. This international effort was catalyzed by a new unified global risk stratification system for hepatoblastoma, an international histopathologic consensus classification for pediatric liver tumors, and a revised 2017 collaborative update of the PRE-Treatment EXTent of disease radiographic based staging system.


Assuntos
Carcinoma Hepatocelular , Hepatoblastoma , Neoplasias Hepáticas , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/terapia , Criança , Hepatoblastoma/epidemiologia , Hepatoblastoma/terapia , Humanos , Neoplasias Hepáticas/terapia , Estudos Multicêntricos como Assunto
15.
Hepatology ; 74(2): 864-878, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33559243

RESUMO

BACKGROUND AND AIMS: Biliary atresia (BA) is a devastating cholangiopathy of infancy. Upon diagnosis, surgical reconstruction by Kasai hepatoportoenterostomy (HPE) restores biliary drainage in a subset of patients, but most patients develop fibrosis and progress to end-stage liver disease requiring liver transplantation for survival. In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling that of human BA. High-mobility group box 1 (HMGB1) is an important member of the danger-associated molecular patterns capable of mediating inflammation during infection-associated responses. In this study, we investigated the role of HMGB1 in BA pathogenesis. APPROACH AND RESULTS: In cholangiocytes, RRV induced the expression and release of HMGB1 through the p38 mitogen-activated protein kinase signaling pathway, and inhibition of p38 blocked HMGB1 release. Treatment of cholangiocytes with ethyl pyruvate suppressed the release of HMGB1. Administration of glycyrrhizin in vivo decreased symptoms and increased survival in the murine model of BA. HMGB1 levels were measured in serum obtained from infants with BA enrolled in the PROBE and START studies conducted by the Childhood Liver Disease Research Network. High HMGB1 levels were found in a subset of patients at the time of HPE. These patients had higher bilirubin levels 3 months post-HPE and a lower survival of their native liver at 2 years. CONCLUSIONS: These results suggest that HMGB1 plays a role in virus induced BA pathogenesis and could be a target for therapeutic interventions in a subset of patients with BA and high HMGB1.


Assuntos
Atresia Biliar/patologia , Doença Hepática Terminal/epidemiologia , Proteína HMGB1/sangue , Proteína HMGB1/metabolismo , Infecções por Rotavirus/patologia , Animais , Animais Recém-Nascidos , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Ductos Biliares/cirurgia , Atresia Biliar/sangue , Atresia Biliar/cirurgia , Atresia Biliar/virologia , Bilirrubina/sangue , Biomarcadores/sangue , Linhagem Celular , Pré-Escolar , Chlorocebus aethiops , Modelos Animais de Doenças , Doença Hepática Terminal/patologia , Células Epiteliais , Humanos , Lactente , Recém-Nascido , Camundongos , Portoenterostomia Hepática , Medição de Risco , Fatores de Risco , Rotavirus/metabolismo , Rotavirus/patogenicidade , Infecções por Rotavirus/virologia , Resultado do Tratamento
16.
Pediatr Blood Cancer ; 67(6): e28307, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32307899

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is often a chemoresistant neoplasm with a poor prognosis. Pediatric HCC may reflect unique biological and clinical heterogeneity. PROCEDURE: An IRB-approved retrospective institutional review of patients with HCC treated between 2004 and 2015 was undertaken. Clinical, radiographic, and histologic data were collected from all patients. RESULTS: Thirty-two patients with HCC, median age 11.5 years (range 1-20) were identified. Seventeen patients had a genetic or anatomic predisposition. Histology was conventional HCC (25) and fibrolamellar HCC (7). Evans staging was 1 (12); 2 (1); 3 (10); 4 (9). Sixteen patients underwent resection at diagnosis and five patients after neoadjuvant chemotherapy. Surgical procedures included liver transplantation (LT, 11), hemihepatectomy (9), and segmentectomy (1). Eighteen patients had medical therapy (13 neoadjuvant, 5 adjuvant). Most common initial medical therapy included sorafenib alone (7) and cisplatin/doxorubicin-based therapy (8). Overall, 14 (43.8%) patients survived with a median follow-up of 58.8 months (range 26.5-157.6). Cause of death was most often linked to lack of primary tumor surgery (11). Of the survivors, Evans stage was 1 (11), 2 (1), and 3 (2, both treated with LT). Four of 18 patients (22%) who received medical therapy, 8 of 17 patients with a predisposition (47%), and 14 of 21 patients (66%) who underwent surgery remain alive. CONCLUSIONS: Genetic and anatomic predisposing conditions were seen in over half of this cohort. Evans stage 1 or 2 disease was linked to improved survival. LT trended toward improved survival. Use of known chemotherapy agents may benefit a smaller group of pediatric HCC and warrants formal prospective study through cooperative group trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/patologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Neoplasias Hepáticas/patologia , Transplante de Fígado/mortalidade , Terapia Neoadjuvante/mortalidade , Adolescente , Adulto , Carcinoma Hepatocelular/terapia , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Neoplasias Hepáticas/terapia , Masculino , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
17.
Front Immunol ; 11: 329, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161597

RESUMO

Biliary atresia (BA) is a devastating fibro-inflammatory disease characterized by the obstruction of extrahepatic and intrahepatic bile ducts in infants that can have fatal consequences, when not treated in a timely manner. It is the most common indication of pediatric liver transplantation worldwide and the development of new therapies, to alleviate the need of surgical intervention, has been hindered due to its complexity and lack of understanding of the disease pathogenesis. For that reason, significant efforts have been made toward the development of experimental models and strategies to understand the etiology and disease mechanisms and to identify novel therapeutic targets. The only characterized model of BA, using a Rhesus Rotavirus Type A infection of newborn BALB/c mice, has enabled the identification of key cellular and molecular targets involved in epithelial injury and duct obstruction. However, the establishment of an unleashed chronic inflammation followed by a progressive pathological wound healing process remains poorly understood. Like T cells, macrophages can adopt different functional programs [pro-inflammatory (M1) and resolutive (M2) macrophages] and influence the surrounding cytokine environment and the cell response to injury. In this review, we provide an overview of the immunopathogenesis of BA, discuss the implication of innate immunity in the disease pathogenesis and highlight their suitability as therapeutic targets.


Assuntos
Atresia Biliar/imunologia , Atresia Biliar/patologia , Imunidade Inata/imunologia , Animais , Atresia Biliar/terapia , Atresia Biliar/virologia , Colestase/etiologia , Colestase/metabolismo , Citocinas , Modelos Animais de Doenças , Progressão da Doença , Humanos , Imunidade Humoral , Inflamação , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Rotavirus/patogenicidade , Infecções por Rotavirus
18.
Dig Dis Sci ; 65(4): 1239-1251, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31549332

RESUMO

BACKGROUND: Congenital portosystemic shunt (CPSS) is a rare malformation in which splanchnic venous flow bypasses the liver. CPSS is associated with other congenital anomalies and syndromes and can be associated with life-threatening complications. CPSS and their management remain underreported in the literature. Here, we review the clinical characteristics, management, and outcomes of a cohort of children and young adults with CPSS from two pediatric centers. METHODS: Cases of CPSS from Cincinnati Children's Hospital Medical Center and C.S. Mott Children's Hospital were reviewed to define CPSS anatomy, associated anomalies, complications, interventions, and outcomes. The imaging features and histopathology of liver lesions were characterized in detail. RESULTS: A total of 11 cases were identified. Median age was 10 years (range 0-26); 8 (73%) cases were female. Associated anomalies included six patients with heterotaxy (55%), five patients with congenital heart disease (45%), three patients with Turner syndrome (27%), and two patients with omphalocele, exstrophy, imperforate anus, spinal defects (OEIS) complex (18%). Eight (73%) cases had hyperammonemia ± encephalopathy. A 4-month-old presented with hepatopulmonary syndrome, and 12-year-old presented with pulmonary hypertension. Eight patients (73%) had liver lesions including five with premalignant adenomas and three with well-differentiated hepatocellular carcinoma (HCC). Four children underwent successful CPSS occlusion/ligation. Three children underwent liver transplant (2) or resection (1) for HCC without recurrence at extended follow-up. CONCLUSIONS: CPSS is associated with multiple anomalies (heterotaxy, congenital heart disease) and syndromes (Turner syndrome). CPSS liver lesions should be very carefully evaluated due to risk of premalignant adenomas and HCC. Serious complications of CPSS can occur at a young age but can be managed endovascularly or with open surgery.


Assuntos
Anormalidades Congênitas/diagnóstico por imagem , Fígado/diagnóstico por imagem , Veia Porta/anormalidades , Veia Porta/diagnóstico por imagem , Malformações Vasculares/diagnóstico por imagem , Adolescente , Adulto , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Criança , Anormalidades Congênitas/cirurgia , Feminino , Humanos , Lactente , Recém-Nascido , Fígado/anormalidades , Fígado/cirurgia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Masculino , Veia Porta/cirurgia , Resultado do Tratamento , Malformações Vasculares/complicações , Malformações Vasculares/cirurgia
19.
Surgery ; 166(5): 907-913, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31285046

RESUMO

BACKGROUND: Portal diversion by surgical shunt plays a major role in the treatment of medically refractory portal hypertension. We evaluate our center's experience with surgical shunts for the treatment of pediatric portal hypertension. METHODS: All patients who underwent surgical shunt at a single institution from 2008 to 2017 were reviewed. The primary outcome was intervention-free shunt patency. RESULTS: In this study, 34 pediatric patients underwent portal shunt creation. The median age was 7.7 years (interquartile range 4.3-12.0). Twenty-nine patients (85%) had prehepatic portal hypertension and 5 patients (15%) had intrahepatic portal hypertension. The primary manifestations of portal hypertension were esophageal varices (97%) and gastrointestinal bleeding (77%). Eighteen patients (53%) underwent meso-Rex bypass, 10 patients (29%) underwent splenorenal shunt, and 6 patients (18%) underwent mesocaval shunt. Outcomes were notable for minimal wound complications (9%), rebleeding events (12%), and mortality (3%). In the postoperative setting, 10 patients (29%) experienced a shunt complication (occlusion or stenosis), 4 of which occurred in the early postoperative period and required urgent intervention. The 1-year and 5-year "primary patency" patency rates were 71% and 66%, respectively. CONCLUSION: Children suffer significant morbidity from the sequelae of portal hypertension. Our experience reinforces the feasibility of surgical shunts as an effective treatment option associated with low rates of morbidity and mortality.


Assuntos
Varizes Esofágicas e Gástricas/cirurgia , Hemorragia Gastrointestinal/cirurgia , Hipertensão Portal/cirurgia , Derivação Portossistêmica Cirúrgica/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Adolescente , Criança , Pré-Escolar , Varizes Esofágicas e Gástricas/etiologia , Estudos de Viabilidade , Feminino , Seguimentos , Hemorragia Gastrointestinal/etiologia , Humanos , Hipertensão Portal/complicações , Masculino , Derivação Portossistêmica Cirúrgica/métodos , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Resultado do Tratamento
20.
Pediatr Transplant ; 23(5): e13453, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31066481

RESUMO

INTRODUCTION: Anuria from end-stage renal disease leads to a defunctionalized bladder and may pose technical challenges at the time of renal transplantation. Anuria's effect on bladder function after renal transplantation is considered to be minimal in adults, although a paucity of evidence is available in children. The purpose of this study was to examine the effects of anuria prior to pediatric renal transplantation for ESRD due to medical renal disease on allograft outcome. METHODS: We performed a retrospective review of pediatric patients who underwent renal transplantation for medical renal disease at our institution between 2005 and 2016. Demographics and clinical data were assessed. We also compared GFR at 1 year post-transplant for medical renal patients with history of anuria and those without. RESULTS: Twenty-one patients fulfilled our inclusion criteria with median duration of anuria was 10 months. Preoperative VCUG was available in five patients and their bladder capacity was 29% of expected bladder capacity for age (range 8%-41%). Anticholinergic therapy was prescribed in six patients (28%) for a mean duration of 5 months (range 1-16 months). Comparison of GFR at 1 year post-transplant in anuria group and those without anuria showed no difference (69 vs 75 mL/min, P = 0.37). No correlation was observed between duration of anuria and post-transplant GFR. CONCLUSION: The majority of children in our pretransplant anuria cohort did not develop bladder dysfunction after renal transplantation. No difference was observed between GFR at 1 year when comparing anuric to non-anuric transplant recipients of medical renal disease etiology.


Assuntos
Anuria/complicações , Falência Renal Crônica/cirurgia , Transplante de Rim , Adolescente , Criança , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Estudos Retrospectivos , Transplante Homólogo
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