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Imaging analysis of hepatoblastoma resectability across neoadjuvant chemotherapy.
Murphy AJ, Ayers GD, Hilmes MA, Mukherjee K, Wilson KJ, Allen WM, Fernandez-Pineda I, Shinall MC, Zhao Z, Furman WL, McCarville MB, Davidoff AM, Lovvorn HN
(2013) J Pediatr Surg 48: 1239-48
MeSH Terms: Algorithms, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Chemotherapy, Adjuvant, Cisplatin, Clinical Protocols, Doxorubicin, Female, Fluorouracil, Hepatectomy, Hepatoblastoma, Humans, Image Interpretation, Computer-Assisted, Liver Neoplasms, Magnetic Resonance Imaging, Male, Models, Statistical, Neoadjuvant Therapy, Retrospective Studies, Tomography, X-Ray Computed, Treatment Outcome, Tumor Burden, Vincristine
Show Abstract · Added December 26, 2013
PURPOSE - Hepatoblastomas often require neoadjuvant chemotherapy to facilitate partial hepatectomy, which necessitates freedom of tumor borders from the confluence of hepatic veins (COHV), portal vein bifurcation (PVB), and retrohepatic inferior vena cava (IVC). This study aimed to clarify the effect of incremental neoadjuvant cycles on the AHEP0731 protocol criteria of hepatoblastoma resectability.
METHODS - Hepatoblastoma responses to neoadjuvant chemotherapy were analyzed among patients (n=23) treated at two children's hospitals between 1996 and 2010. Using digital imaging data, ellipsoid and point-based models were created to measure tumor volume regression and respective distances from tumor borders nearest to the COHV, PVB, and IVC.
RESULTS - Hepatoblastoma volumes regressed with incremental neoadjuvant chemotherapy cycles (p<0.001). Although tumor borders regressed away from the COHV (p=0.008), on average only 1.1mm was gained. No change from tumor borders to the PVB was detected (p=0.102). Distances from tumor borders to the IVC remained stable at one hospital (p=0.612), but increased only 0.15 mm every 10 days of therapy at the other (p=0.002). Neoadjuvant chemotherapy induced slightly more tumors to meet the threshold vascular margin of 1cm (baseline to completion): COHV, 11 (47.8%) to 17 (73.9%; p=0.058); PVB, 11 (47.8%) to 15 (65.2%; p=0.157); and IVC, 4 (17.4%) to 10 (43.5%; p=0.034). No differences were detected in demographic or disease-specific characteristics between patients who did or did not achieve this 1-cm margin after conclusion of chemotherapy.
CONCLUSION - Hepatoblastoma volumes regress significantly with increasing neoadjuvant chemotherapy cycles. However, tumors often remain anchored to the major hepatic vasculature, showing marginal improvement in resectability criteria.
Copyright © 2013 Elsevier Inc. All rights reserved.
0 Communities
3 Members
0 Resources
23 MeSH Terms
CITED1 expression in liver development and hepatoblastoma.
Murphy AJ, de Caestecker C, Pierce J, Boyle SC, Ayers GD, Zhao Z, Libes JM, Correa H, Walter T, Huppert SS, Perantoni AO, de Caestecker MP, Lovvorn HN
(2012) Neoplasia 14: 1153-63
MeSH Terms: Animals, Cell Line, Tumor, Cell Proliferation, DNA-Binding Proteins, Embryo, Mammalian, Hepatoblastoma, Humans, Liver, Liver Neoplasms, Liver Regeneration, Membrane Proteins, Mice, Mutation, Nuclear Proteins, RNA, Messenger, Time Factors, Trans-Activators, Transcription Factors, Wnt Signaling Pathway, beta Catenin
Show Abstract · Added January 10, 2014
Hepatoblastoma, the most common pediatric liver cancer, consists of epithelial mixed embryonal/fetal (EMEF) and pure fetal histologic subtypes, with the latter exhibiting a more favorable prognosis. Few embryonal histology markers that yield insight into the biologic basis for this prognostic discrepancy exist. CBP/P-300 interacting transactivator 1 (CITED1), a transcriptional co-activator, is expressed in the self-renewing nephron progenitor population of the developing kidney and broadly in its malignant analog, Wilms tumor (WT). In this current study, CITED1 expression is detected in mouse embryonic liver initially on post-coitum day 10.5 (e10.5), begins to taper by e14.5, and is undetectable in e18.5 and adult livers. CITED1 expression is detected in regenerating murine hepatocytes following liver injury by partial hepatectomy and 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Importantly, while CITED1 is undetectable in normal human adult livers, 36 of 41 (87.8%) hepatoblastoma specimens express CITED1, where it is enriched in EMEF specimens compared to specimens of pure fetal histology. CITED1 overexpression in Hep293TT human hepatoblastoma cells induces cellular proliferation and upregulates the Wnt inhibitors Kringle containing transmembrane protein 1 (KREMEN1) and CXXC finger protein 4 (CXXC4). CITED1 mRNA expression correlates with expression of CXXC4 and KREMEN1 in clinical hepatoblastoma specimens. These data show that CITED1 is expressed during a defined time course of liver development and is no longer expressed in the adult liver but is upregulated in regenerating hepatocytes following liver injury. Moreover, as in WT, this embryonic marker is reexpressed in hepatoblastoma and correlates with embryonal histology. These findings identify CITED1 as a novel marker of hepatic progenitor cells that is re-expressed following liver injury and in embryonic liver tumors.
2 Communities
5 Members
0 Resources
20 MeSH Terms
Chronic biloma after right hepatectomy for stage IV hepatoblastoma managed with Roux-en-Y biliary cystenterostomy.
Murphy AJ, Rauth TP, Lovvorn HN
(2012) J Pediatr Surg 47: e5-9
MeSH Terms: Anastomosis, Roux-en-Y, Biliary Fistula, Chronic Disease, Cutaneous Fistula, Female, Hepatectomy, Hepatic Duct, Common, Hepatoblastoma, Humans, Infant, Intestine, Small, Liver Neoplasms, Neoplasm Staging, Postoperative Complications
Show Abstract · Added December 26, 2013
We report the complex case of a 12-month-old girl with stage IV hepatoblastoma accompanied by thrombosis and cavernous transformation of the portal vein. After neoadjuvant chemotherapy, she underwent right hepatectomy, which was complicated by iatrogenic injury of her left hepatic duct, and subsequently developed a postoperative biloma and chronic biliocutaneous fistula. Concomitant with multiple percutaneous interventions to manage the biloma nonoperatively while the child completed her adjuvant chemotherapy, she progressed to develop chronic malnutrition, jaundice, and failure to thrive. Once therapy was completed and the child was deemed free of disease, she underwent exploratory laparotomy with Roux-en-Y biliary cystenterostomy for definitive management, resulting in resolution of her biliary fistula, jaundice, and marked improvement in her nutritional status. Roux-en-Y biliary cystenterostomy is a unique and efficacious management option in the highly selected patient population with chronic biliary leak refractory to minimally invasive management.
Copyright © 2012 Elsevier Inc. All rights reserved.
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1 Members
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14 MeSH Terms
Defining hepatoblastoma responsiveness to induction therapy as measured by tumor volume and serum alpha-fetoprotein kinetics.
Lovvorn HN, Ayers D, Zhao Z, Hilmes M, Prasad P, Shinall MC, Berch B, Neblett WW, O'Neill JA
(2010) J Pediatr Surg 45: 121-8; discussion 129
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Child, Preschool, Female, Follow-Up Studies, Functional Laterality, Hepatoblastoma, Humans, Infant, Kinetics, Liver, Liver Neoplasms, Male, Neoadjuvant Therapy, Preoperative Care, Remission Induction, Survival Analysis, Treatment Outcome, Tumor Burden, alpha-Fetoproteins
Show Abstract · Added December 26, 2013
PURPOSE - Hepatoblastoma is commonly unresectable at presentation, necessitating induction chemotherapy before definitive resection. To refine the paradigm for timing of resection, we questioned whether a plateau in hepatoblastoma responsiveness to neoadjuvant therapy could be detected by calculating tumor volume (TV) and serum alpha-fetoprotein (sAFP) kinetics.
METHODS - To calculate TV and sAFP as measures of treatment responsiveness over time, infants having initially unresectable epithelial-type hepatoblastomas were identified at a single institution (1996-2008). Effects of therapy type, therapy duration, and lobe of liver involvement on TV, sAFP, margin status, and toxicity were analyzed.
RESULTS - Of 24 infants treated for epithelial-type hepatoblastoma during this interval, 5 were resected primarily, and 15 had complete digital films for kinetics analysis. Both TV and sAFP decreased dramatically over time (P < .0001). No statistically significant difference in mean TV or sAFP was detected after chemotherapy cycle 2. Left lobe tumors had greater presenting levels of and significantly slower decay in sAFP compared with right lobe tumors (P = .005), although no statistically significant differences in TV existed between liver lobes. Resection margins did not change with therapy duration.
CONCLUSIONS - Measuring TV and sAFP kinetics accurately reflects hepatoblastoma responsiveness to induction therapy. Treatment toxicities may be reduced by earlier resection and tailoring of chemotherapeutic regimens.
Copyright 2010 Elsevier Inc. All rights reserved.
0 Communities
1 Members
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19 MeSH Terms
Protocol for the examination of specimens from pediatric patients with hepatoblastoma.
Finegold MJ, Lopez-Terrada DH, Bowen J, Washington MK, Qualman SJ, College of American Pathologists
(2007) Arch Pathol Lab Med 131: 520-9
MeSH Terms: Biopsy, Child, Hepatoblastoma, Histological Techniques, Humans, Liver Neoplasms
Added March 5, 2014
0 Communities
1 Members
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6 MeSH Terms
Liver transplantation for childhood hepatic malignancy: a review of the United Network for Organ Sharing (UNOS) database.
Austin MT, Leys CM, Feurer ID, Lovvorn HN, O'Neill JA, Pinson CW, Pietsch JB
(2006) J Pediatr Surg 41: 182-6
MeSH Terms: Adolescent, Carcinoma, Hepatocellular, Child, Child, Preschool, Databases, Factual, Female, Hepatoblastoma, Humans, Infant, Liver Neoplasms, Liver Transplantation, Male, Multivariate Analysis, Retrospective Studies, Survival Analysis, Tissue and Organ Procurement, Treatment Outcome
Show Abstract · Added December 26, 2013
BACKGROUND - Orthotopic liver transplantation (OLT) is the only treatment option for unresectable hepatoblastoma (HB) and hepatocellular carcinoma (HCC) in children. Aggregated outcomes of OLT for these hepatic malignancies have not been evaluated in the United Network for Organ Sharing national database.
PURPOSE - The purpose of this study was to evaluate graft and patient survival in pediatric OLT recipients with HB and HCC.
METHODS - Data from the United Network for Organ Sharing Standard Transplant and Research Files were analyzed and included pediatric (<18 years) OLT recipients with HB or HCC from 1987 to 2004. The effects of diagnosis on pretransplant variables were evaluated using analysis of variance methods or chi2 tests, as appropriate. Actuarial survival and effect of diagnosis on survival were determined using Kaplan-Meier methods and log-rank tests.
RESULTS - Since 1987, 152 OLTs have been performed in 135 pediatric patients for HB and 43 OLTs in 41 pediatric patients for HCC. Respective 1-, 5-, and 10-year patient survival after OLT was 79%, 69%, and 66% for HB and 86%, 63%, and 58% for HCC (P = .73). The primary cause of death for both groups was metastatic or recurrent disease, accounting for 54% of deaths in the HB group and 86% in the HCC group (P = .338). Patients with hepatoblastoma were younger (mean age, 2.9 +/- 2.5 vs 10.4 +/- 4.8 years for the HCC group; P < .001) and more likely to receive a living donor organ (16% vs 4%, P = .03). A greater proportion of the patients with HB had previous abdominal surgery than patients with HCC (63% HB vs 37% HCC, P = .04). Pretransplant medical condition and transplant era were associated with graft and patient survival on univariate and multivariate analysis (all P < .05).
CONCLUSIONS - Orthotopic liver transplantation remains a viable option for pediatric patients with unresectable primary hepatic malignancies and results in good long-term survival. Pretransplant medical condition is an important predictor of outcome. Thus, in conjunction with better chemotherapy regimens, earlier evaluation for OLT in patients with unresectable HB and HCC may result in yet further improved long-term survival.
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17 MeSH Terms
Mitochondrial calcium uptake regulates cold preservation-induced Bax translocation and early reperfusion apoptosis.
Anderson CD, Belous A, Pierce J, Nicoud IB, Knox C, Wakata A, Pinson CW, Chari RS
(2004) Am J Transplant 4: 352-62
MeSH Terms: Apoptosis, Calcium, Caspase 3, Caspases, Cryopreservation, Cytochromes c, Hepatoblastoma, Humans, Indicators and Reagents, Mitochondria, Protein Transport, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Reperfusion Injury, Ruthenium Red, Tumor Cells, Cultured, bcl-2-Associated X Protein
Show Abstract · Added January 10, 2014
Mitochondrial calcium (mCa + 2) overload occurs during cold preservation and is an integral part of mitochondrial-dependent apoptotic pathways. We investigated the role of mCa + 2 overload in cell death following hypothermic storage using HepG2 cells stored in normoxic-hypothermic (4 degrees C) or hypoxic (< 0.1% O2)-hypothermic Belzer storage solution. Cells were stored for 6 h, with or without 10 microM ruthenium red (mCa + 2 uniporter inhibitor) followed by rewarming in oxygenated media at 37 degrees C. Cytoplasmic cytochrome c levels were studied by Western analysis and by fluorescent microscopy after transfection of cytochrome c-GFP expression plasmid. Immunofluorescence determined the intracellular, spatio-temporal distribution of Bax, and TUNEL staining was used to evaluate cell death after 180 min of rewarming. Caspase activation was evaluated using Western analysis and a caspase 3 activity assay. Bax translocation, cytochrome c release, and early rewarming cell death occurred following hypothermic storage and were exacerbated by hypoxia. Caspase 3 activation did not occur following hypothermic storage. Blockade of mCa + 2 uptake prevented Bax translocation, cytochrome c release, and early rewarming cell death. These studies demonstrate that mCa + 2 uptake during hypothermic storage, both hypoxic and normoxic, contributes to early rewarming apoptosis by triggering Bax translocation to mitochondria and cytochrome c release.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia.
Clericuzio CL, Chen E, McNeil DE, O'Connor T, Zackai EH, Medne L, Tomlinson G, DeBaun M
(2003) J Pediatr 143: 270-2
MeSH Terms: Beckwith-Wiedemann Syndrome, Female, Hepatoblastoma, Humans, Hypertrophy, Infant, Infant, Newborn, Liver Neoplasms, Male, alpha-Fetoproteins
Show Abstract · Added September 19, 2013
An elevated risk of hepatoblastoma for children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia is well established. We describe five children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia for whom serial serum alpha-fetoprotein screening, usually in combination with abdominal ultrasound, led to early detection of hepatoblastoma.
0 Communities
1 Members
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10 MeSH Terms
Screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndromes: a cost-effective model.
McNeil DE, Brown M, Ching A, DeBaun MR
(2001) Med Pediatr Oncol 37: 349-56
MeSH Terms: Age Distribution, Beckwith-Wiedemann Syndrome, Child, Child, Preschool, Cohort Studies, Comorbidity, Cost-Benefit Analysis, Female, Hepatoblastoma, Humans, Infant, Kidney Neoplasms, Liver Neoplasms, Male, Mass Screening, Registries, Sensitivity and Specificity, Sex Distribution, Survival Analysis, Ultrasonography, United States, Wilms Tumor
Show Abstract · Added November 27, 2013
BACKGROUND - We undertook a cost-benefit analysis of screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndrome (BWS), a known cancer predisposition syndrome. The purpose of this analysis was twofold: first, to assess whether screening in children with BWS has the potential to be cost-effective; second, if screening appears to be cost-effective, to determine which parameters would be most important to assess if a screening trial were initiated.
PROCEDURES - We used data from the BWS registry at the National Cancer Institute, the National Wilms Tumor Study (NWTS), and large published series to model events for two hypothetical cohorts of 1,000 infants born with BWS. One hypothetical cohort was screened for cancer until a predetermined age, representing the base case. The other cohort was unscreened. For our base case, we assumed: (a) sonography examinations three times yearly (triannually) from birth until 7 years of age; (b) screening would result in one stage shift downward at diagnosis for Wilms tumor and hepatoblastoma; (c) 100% sensitivity and 95% specificity for detecting clinical stage I Wilms tumor and hepatoblastoma; (d) a 3% discount rate; (e) a false positive result cost of $402. We estimated mortality rates based on published Wilms tumor and hepatoblastoma stage specific survival.
RESULTS - Using the base case, screening a child with BWS from birth until 4 years of age results in a cost per life year saved of $9,642 while continuing until 7 years of age results in a cost per life-year saved of $14,740. When variables such as cost of screening examination, discount rate, and effectiveness of screening were varied based on high and low estimates, the incremental cost per life-year saved for screening up until age four remained comparable to acceptable population based cancer screening ranges (< $50,000 per life year saved).
CONCLUSIONS - Under our model's assumptions, abdominal sonography examinations in children with BWS represent a reasonable strategy for a cancer screening program. A cancer screening trial is warranted to determine if, when, and how often children with BWS should be screened and to determine cost-effectiveness in clinical practice.
Published 2001 Wiley-Liss, Inc.
1 Communities
1 Members
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22 MeSH Terms
Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry.
DeBaun MR, Tucker MA
(1998) J Pediatr 132: 398-400
MeSH Terms: Beckwith-Wiedemann Syndrome, Child, Preschool, Cohort Studies, Female, Hepatoblastoma, Humans, Incidence, Infant, Male, Neuroblastoma, Registries, Risk, Wilms Tumor
Show Abstract · Added November 27, 2013
To determine the incidence and relative risk (RR) of cancer in children with Beckwith-Wiedemann syndrome (BWS), children with BWS were followed up from birth until death, diagnosis of cancer, fourth birthday, or last day of follow-up. A total of 183 children with BWS were followed up for 482 person-years. The end points were incidence of cancer, RR of cancer, and RR associated with specific BWS phenotypic features. Thirteen children were identified with cancers before the fourth year of life in comparison with fewer than one cancer expected in this group on the basis of general population rates over the same period. The average annual incidence of cancer in the first 4 years of life was 0.027 cancer per person-year. The RR of Wilms tumor (RR = 816; 95% confidence interval [CI], 359-1156), neuroblastoma (RR = 197; 95% CI, 22-711), and hepatoblastoma (RR = 2280; 95% CI, 928-11,656) were statistically significant. Asymmetry of the limbs (hemihypertrophy) was the only clinical feature associated with an increased RR of cancer (RR = 4.6; 95% CI, 1.5-14.2). Given the high incidence of cancer in infancy and early childhood of patients with BWS, a prospective study is warranted to address the utility of screening for cancer.
1 Communities
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13 MeSH Terms