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Greg Tiao
Department of Pediatric and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America

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Original article
Published: 08 February 2021 in Hepatology
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Biliary atresia (BA) is a devastating cholangiopathy of infancy. Upon diagnosis, surgical reconstruction by Kasai portoenterostomy (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 danger‐associated molecular patterns capable of mediating inflammation during infection‐associated responses. In this study, we investigated the role of HMGB1 in BA pathogenesis. In cholangiocytes, RRV induced the expression and release of HMGB1 through the p38 MAPK 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. In conclusion 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 BA patients with high HMGB1.

ACS Style

Sujit K. Mohanty; Bryan Donnelly; Haley Temple; Ana Ortiz‐Perez; Sarah Mowery; Inna Lobeck; Phylicia Dupree; Holly M. Poling; Monica McNeal; Reena Mourya; Todd Jenkins; Ruchi Bansal; Jorge Bezerra; Greg Tiao. High Mobility Group Box 1 Release by Cholangiocytes Governs Biliary Atresia Pathogenesis and Correlates With Increases in Afflicted Infants. Hepatology 2021, 74, 864 -878.

AMA Style

Sujit K. Mohanty, Bryan Donnelly, Haley Temple, Ana Ortiz‐Perez, Sarah Mowery, Inna Lobeck, Phylicia Dupree, Holly M. Poling, Monica McNeal, Reena Mourya, Todd Jenkins, Ruchi Bansal, Jorge Bezerra, Greg Tiao. High Mobility Group Box 1 Release by Cholangiocytes Governs Biliary Atresia Pathogenesis and Correlates With Increases in Afflicted Infants. Hepatology. 2021; 74 (2):864-878.

Chicago/Turabian Style

Sujit K. Mohanty; Bryan Donnelly; Haley Temple; Ana Ortiz‐Perez; Sarah Mowery; Inna Lobeck; Phylicia Dupree; Holly M. Poling; Monica McNeal; Reena Mourya; Todd Jenkins; Ruchi Bansal; Jorge Bezerra; Greg Tiao. 2021. "High Mobility Group Box 1 Release by Cholangiocytes Governs Biliary Atresia Pathogenesis and Correlates With Increases in Afflicted Infants." Hepatology 74, no. 2: 864-878.

Case report
Published: 18 July 2020 in Journal of Pediatric Surgery Case Reports
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We present the case of a 39 week-gestational age female infant who, following an uncomplicated pregnancy developed progressively worsening respiratory distress. She was diagnosed with a mediastinal bronchogenic cyst which was intermittently occluding the left mainstem bronchus, leading to overinflation of the left lung, mediastinal shift with the heart in the right chest and a hypoplastic right lung. Despite luminal stenting, the left lung remained enlarged with the right lung hypoinflated. Interestingly, there was no physiologic consequences to the significant mediastinal shift. We hypothesize that the process began in utero where the bronchogenic cyst caused unilateral bronchial occlusion triggering left lung hyperplasia. The cyst was resected without complication and the patient suffered no further respiratory issues.

ACS Style

Monica L. Wagner; Catherine K. Hart; Dan Benscoter; Robert J. Fleck; Gregory M. Tiao. Congenital lung overinflation secondary to a unilateral obstructing mediastinal bronchogenic cyst. Journal of Pediatric Surgery Case Reports 2020, 60, 101570 .

AMA Style

Monica L. Wagner, Catherine K. Hart, Dan Benscoter, Robert J. Fleck, Gregory M. Tiao. Congenital lung overinflation secondary to a unilateral obstructing mediastinal bronchogenic cyst. Journal of Pediatric Surgery Case Reports. 2020; 60 ():101570.

Chicago/Turabian Style

Monica L. Wagner; Catherine K. Hart; Dan Benscoter; Robert J. Fleck; Gregory M. Tiao. 2020. "Congenital lung overinflation secondary to a unilateral obstructing mediastinal bronchogenic cyst." Journal of Pediatric Surgery Case Reports 60, no. : 101570.

Original article
Published: 23 September 2019 in Digestive Diseases and Sciences
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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. 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. 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. 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.

ACS Style

Frank DiPaola; Andrew T. Trout; Ashley E. Walther; Anita Gupta; Rachel Sheridan; Kathleen M. Campbell; Greg Tiao; Jorge A. Bezerra; Kevin E. Bove; Manish Patel; Jaimie D. Nathan. Congenital Portosystemic Shunts in Children: Associations, Complications, and Outcomes. Digestive Diseases and Sciences 2019, 65, 1239 -1251.

AMA Style

Frank DiPaola, Andrew T. Trout, Ashley E. Walther, Anita Gupta, Rachel Sheridan, Kathleen M. Campbell, Greg Tiao, Jorge A. Bezerra, Kevin E. Bove, Manish Patel, Jaimie D. Nathan. Congenital Portosystemic Shunts in Children: Associations, Complications, and Outcomes. Digestive Diseases and Sciences. 2019; 65 (4):1239-1251.

Chicago/Turabian Style

Frank DiPaola; Andrew T. Trout; Ashley E. Walther; Anita Gupta; Rachel Sheridan; Kathleen M. Campbell; Greg Tiao; Jorge A. Bezerra; Kevin E. Bove; Manish Patel; Jaimie D. Nathan. 2019. "Congenital Portosystemic Shunts in Children: Associations, Complications, and Outcomes." Digestive Diseases and Sciences 65, no. 4: 1239-1251.

Protocol
Published: 24 April 2019 in Methods in Molecular Biology
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Biliary atresia is a devastating neonatal cholangiopathy that affects both extra- and intrahepatic bile ducts progressing to fibrosis and end-stage liver disease by 2 years of age. Despite re-establishment of biliary drainage following a Kasai portoenterostomy (surgical procedure), many infants develop fibrosis requiring liver transplant. In the murine model of biliary atresia, rhesus rotavirus infection of newborn pups results in a cholangiopathy paralleling human biliary atresia and is used to study mechanistic aspects of the disease. The infected mice displayed histopathological signs similar to human biliary atresia, with bile duct obstruction, bile duct proliferation, and liver inflammation with fibrosis.

ACS Style

Sujit K. Mohanty; Bryan Donnelly; Haley Temple; Gregory M. Tiao. A Rotavirus-Induced Mouse Model to Study Biliary Atresia and Neonatal Cholestasis. Methods in Molecular Biology 2019, 1981, 259 -271.

AMA Style

Sujit K. Mohanty, Bryan Donnelly, Haley Temple, Gregory M. Tiao. A Rotavirus-Induced Mouse Model to Study Biliary Atresia and Neonatal Cholestasis. Methods in Molecular Biology. 2019; 1981 ():259-271.

Chicago/Turabian Style

Sujit K. Mohanty; Bryan Donnelly; Haley Temple; Gregory M. Tiao. 2019. "A Rotavirus-Induced Mouse Model to Study Biliary Atresia and Neonatal Cholestasis." Methods in Molecular Biology 1981, no. : 259-271.

Review
Published: 21 December 2018 in Children
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The most common primary malignant liver tumor of childhood, hepatoblastoma has increased in incidence over the last 30 years, but little is still known about its pathogenesis. Discoveries in molecular biology provide clues but have yet to define targeted therapies. Disease-free survival varies according to stage, but is greater than 90% in favorable risk populations, in part due to improvements in chemotherapeutic regimens, surgical resection, and earlier referral to liver transplant centers. This article aims to highlight the principles of disease that guide current treatment algorithms. Surgical treatment, especially orthotopic liver transplantation, will also be emphasized in the context of the current Children’s Oncology Group international study of pediatric liver cancer (AHEP-1531).

ACS Style

Irene Lim; Alexander Bondoc; James Geller; Gregory Tiao. Hepatoblastoma—The Evolution of Biology, Surgery, and Transplantation. Children 2018, 6, 1 .

AMA Style

Irene Lim, Alexander Bondoc, James Geller, Gregory Tiao. Hepatoblastoma—The Evolution of Biology, Surgery, and Transplantation. Children. 2018; 6 (1):1.

Chicago/Turabian Style

Irene Lim; Alexander Bondoc; James Geller; Gregory Tiao. 2018. "Hepatoblastoma—The Evolution of Biology, Surgery, and Transplantation." Children 6, no. 1: 1.

Review
Published: 01 November 2018 in ASAIO Journal
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Biliary atresia is a newborn cholangiopathy that may lead to portopulmonary hypertension and cirrhosis-induced cardiomyopathy while awaiting liver transplantation. Extracorporeal life support and hepatic toxin filtration are life-saving interventions that provide cardiopulmonary support and hepatic dialysis to allow resolution of a child’s illness. We utilized a combination of these extreme measures to bridge an infant with biliary atresia to transplantation. We reviewed cases of extracorporeal life support utilization in transplantation recipients in the Extracorporeal Life Support Organization database and determined that ours was the only use of pretransplant extracorporeal life support in biliary atresia.

ACS Style

Inna N. Lobeck; Alexander Bondoc; Heather Nolan; Jason S. Frischer; Kathleen M. Campbell; Thomas D. Ryan; Stuart L. Goldstein; Jaimie D. Nathan; Maria H. Alonso; Greg M. Tiao. Extracorporeal Membrane Oxygenation in a Patient with Biliary Atresia: Case and Review of Extracorporeal Life Support Organization Data. ASAIO Journal 2018, 64, e191 -e195.

AMA Style

Inna N. Lobeck, Alexander Bondoc, Heather Nolan, Jason S. Frischer, Kathleen M. Campbell, Thomas D. Ryan, Stuart L. Goldstein, Jaimie D. Nathan, Maria H. Alonso, Greg M. Tiao. Extracorporeal Membrane Oxygenation in a Patient with Biliary Atresia: Case and Review of Extracorporeal Life Support Organization Data. ASAIO Journal. 2018; 64 (6):e191-e195.

Chicago/Turabian Style

Inna N. Lobeck; Alexander Bondoc; Heather Nolan; Jason S. Frischer; Kathleen M. Campbell; Thomas D. Ryan; Stuart L. Goldstein; Jaimie D. Nathan; Maria H. Alonso; Greg M. Tiao. 2018. "Extracorporeal Membrane Oxygenation in a Patient with Biliary Atresia: Case and Review of Extracorporeal Life Support Organization Data." ASAIO Journal 64, no. 6: e191-e195.

Research article
Published: 03 July 2018 in Pediatric Blood & Cancer
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1 Background Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm that is often chemoresistant. Complete surgical resection remains the mainstay of therapy. The role of liver transplantation (LT) in pediatric HCC is in evolution, as is the role of adjuvant chemotherapy for stage I disease. 2 Methods A retrospective review of patients < 18 years of age with completely resected HCC treated with surgical intervention alone at our institution from 2004 to 2015 was conducted. 3 Results Twelve patients with a median age of 12 years (range = 1–17; number of females = 7) with upfront resected HCC (Evans stage I) were identified. Four patients had HCC without identifiable risk factors (fibrolamellar‐HCC = 2; early HCC arising in focal nodular hyperplasia = 1, well‐differentiated [wd] HCC = 1). Four patients had early or wd‐HCC in the context of portosystemic shunts (Abernethy = 2; mesocaval shunt and portal vein thrombosis = 2). Four patients had moderate to wd‐HCC in the context of pre‐existing liver disease with cirrhosis (progressive familial intrahepatic cholestasis type‐2 = 2, alpha‐1 antitrypsin deficiency = 1, Alagille syndrome = 1). Seven patients underwent LT (multifocal = 5; solitary = 2); five exceeded Milan criteria (MC) by imaging. Five patients underwent complete resection (segmentectomy = 2; hemihepatectomy = 3). Ten patients received no adjuvant chemotherapy. All patients are alive without evidence of disease with a median follow‐up of 54.1 months (range = 28.1–157.7 months). 4 Conclusions Pediatric and adolescent patients with upfront, completely resected HCC can be effectively treated without chemotherapy. LT should be considered for nonmetastatic HCC, especially in the context of pre‐existing chronic liver disease, even when the tumor exceeds MC. Distinct pediatric selection criteria are needed to identify patients most suitable for LT.

ACS Style

Amber M. D'souza; Rachana Shah; Anita Gupta; Alexander Towbin; Maria Alonso; Jaimie D. Nathan; Alex Bondoc; Greg Tiao; James I. Geller. Surgical management of children and adolescents with upfront completely resected hepatocellular carcinoma. Pediatric Blood & Cancer 2018, 65, e27293 .

AMA Style

Amber M. D'souza, Rachana Shah, Anita Gupta, Alexander Towbin, Maria Alonso, Jaimie D. Nathan, Alex Bondoc, Greg Tiao, James I. Geller. Surgical management of children and adolescents with upfront completely resected hepatocellular carcinoma. Pediatric Blood & Cancer. 2018; 65 (11):e27293.

Chicago/Turabian Style

Amber M. D'souza; Rachana Shah; Anita Gupta; Alexander Towbin; Maria Alonso; Jaimie D. Nathan; Alex Bondoc; Greg Tiao; James I. Geller. 2018. "Surgical management of children and adolescents with upfront completely resected hepatocellular carcinoma." Pediatric Blood & Cancer 65, no. 11: e27293.

Pediatric oncology
Published: 20 May 2018 in Journal of Clinical Oncology
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E22505 Background: Hepatocellular carcinoma (HCC) is an often chemoresistant neoplasm with a poor prognosis. Pediatric HCC may reflect unique biological and clinical heterogeneity. Methods: An IRB approved retrospective institutional review of HCC patients treated between 2004-2015 was undertaken. Results: 32 patients with HCC, median age 11.5 years (range 1-20) were identified. Pre-existing conditions included PFIC2 (2), Alagille (3), alpha-1 antitrypsin (1), Wilson’s disease (1), Fanconi anemia (2), cryptogenic cirrhosis (2), fatty liver disease (1), Fontan (1), Abernethy malformation (2), and portal venous thrombosis (2). Histology was conventional HCC (25; 9 with cirrhosis) and fibrolamellar HCC (7; 1 with cirrhosis). Evan’s staging was 1 (12); 2 (1); 3 (10); 4 (9). Evan’s stage in those with vs without a predisposition were 1 (8 vs 4), 2 (0 vs 1), 3 (6 vs 4) and 4 (3 vs 6). 16 patients underwent upfront surgical resection and 5 after neoadjuvant chemotherapy. Surgery included liver transplantation (LT, 11), hemihepatectomy (9), and segmentectomy (1). Other local control included Yttrium-90 radioembolization (4), radiofrequency ablation (RFA) (3), and abdominal radiation (1). 18 patients had medical therapy. Most common initial medical therapy included sorafenib alone (7) and cisplatin/doxorubicin based regimen (8; 3 with concurrent sorafenib). Overall, 14 (43.8%) survived with a median follow-up of 58.8 months (range 26.5-157.6). Cause of death was linked to lack of primary tumor surgery (11), Fanconi BMT complication (1), dialysis complication (1), progressive disease (subtotal resection) (1), and relapse (4). Of the survivors, Evan’s stage was 1 (11), 2 (1), and 3 (2, both treated with LT). 4/18 patients (22%) who received medical therapy survived. 9/17 with a predisposition are alive (53%). 8/11 (82%) who underwent LT remain alive. Conclusions: Various genetic and anatomic predisposing conditions were seen in over half of this pediatric HCC cohort and correlated with lower stage, adequate local control, and possibly survival. LT also associated with survival. Use of known chemotherapy agents may benefit a smaller group of pediatric HCC and warrants formal prospective study through cooperative group trials.

ACS Style

Amber M D'souza; Alexander Towbin; Alexander Bondoc; Anita Gupta; Jaimie Nathan; Maria Alonso; Greg Tiao; James I. Geller. Heterogeneity of pediatric hepatocellular carcinoma. Journal of Clinical Oncology 2018, 36, e22505 -e22505.

AMA Style

Amber M D'souza, Alexander Towbin, Alexander Bondoc, Anita Gupta, Jaimie Nathan, Maria Alonso, Greg Tiao, James I. Geller. Heterogeneity of pediatric hepatocellular carcinoma. Journal of Clinical Oncology. 2018; 36 (15_suppl):e22505-e22505.

Chicago/Turabian Style

Amber M D'souza; Alexander Towbin; Alexander Bondoc; Anita Gupta; Jaimie Nathan; Maria Alonso; Greg Tiao; James I. Geller. 2018. "Heterogeneity of pediatric hepatocellular carcinoma." Journal of Clinical Oncology 36, no. 15_suppl: e22505-e22505.

Article
Published: 18 December 2017 in Pediatric Blood & Cancer
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Conflicting reports on the frequency of germline adenomatous polyposis coli (APC) gene mutations in patients with hepatoblastoma (HB) have called into question the clinical value of APC mutation testing on apparently sporadic HB. An Institutional Review Board approved retrospective review of clinical data collected from patients with HB who received APC testing at our institution was conducted. All HB patients seen at Cincinnati Children's Hospital Medical Center were eligible for testing. Potential genotype/phenotype correlations were assessed. As of July 2015, 29 patients with HB had received constitutional APC testing. Four (14%) were found to have APC pathogenic truncations of the APC protein and in addition two (7%) had APC missense variants of unknown clinical significance. Two patients (7%) had family histories indicative of familial adenomatous polyposis (FAP). Response to chemotherapy tracked differently in APC pathogenic cases, with a slower imaging response despite an equivalent or slightly faster α-fetoprotein (AFP) response. The prevalence of pathogenic APC variants in apparently sporadic HB may be higher than previously detected. Differences in time to imaging response, despite similar AFP response, may impact surgical planning. All patients with HB warrant germline APC mutation testing for underlying FAP.

ACS Style

Adeline Yang; Rebecca Sisson; Anita Gupta; Greg Tiao; James I. Geller. Germline APC mutations in hepatoblastoma. Pediatric Blood & Cancer 2017, 65, e26892 .

AMA Style

Adeline Yang, Rebecca Sisson, Anita Gupta, Greg Tiao, James I. Geller. Germline APC mutations in hepatoblastoma. Pediatric Blood & Cancer. 2017; 65 (4):e26892.

Chicago/Turabian Style

Adeline Yang; Rebecca Sisson; Anita Gupta; Greg Tiao; James I. Geller. 2017. "Germline APC mutations in hepatoblastoma." Pediatric Blood & Cancer 65, no. 4: e26892.

Original article
Published: 08 December 2017 in Pediatric Radiology
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Hepatoblastoma is the most common primary hepatic malignancy in children. We have recently noticed an increased incidence of unsuspected fractures in children with newly diagnosed hepatoblastoma. This association has been suggested in the past, but the incidence and pathophysiology remain uncertain. To define the incidence and imaging features of fractures in children with newly diagnosed hepatoblastoma. We searched the oncology database and the radiology picture archiving and communication system of our large tertiary care children's hospital between January 2000 and August 2013 for all patients who presented to our institution with newly diagnosed hepatoblastoma. We reviewed all available imaging exams (radiographs, CT scans, MRIs, and nuclear medicine studies) to identify children who had radiologically apparent fractures on exams during the 50 days prior to diagnosis or up to 2 weeks after the date of hepatoblastoma diagnosis. Forty-five children were included in this retrospective study. Eight children (17.8%) had fractures within 50 days prior to diagnosis or up to 2 weeks after the date of diagnosis, with a mean number of 4.9 fractures per patient (range 1-13). Only 21 of the 39 fractures (54%) were diagnosed during the initial image interpretation. Fractures most commonly occurred in the ribs (n=21) and vertebral bodies (n=10). The presence of a fracture was not associated with an identified demographic, tumor or laboratory finding. Unsuspected fractures are relatively common in children with newly diagnosed hepatoblastoma.

ACS Style

Alexander J. Towbin; Fernanda D. C. Braojos Braga; Bin Zhang; James I. Geller; Greg M. Tiao; Daniel J. Podberesky. Fractures in children with newly diagnosed hepatoblastoma. Pediatric Radiology 2017, 48, 581 -585.

AMA Style

Alexander J. Towbin, Fernanda D. C. Braojos Braga, Bin Zhang, James I. Geller, Greg M. Tiao, Daniel J. Podberesky. Fractures in children with newly diagnosed hepatoblastoma. Pediatric Radiology. 2017; 48 (4):581-585.

Chicago/Turabian Style

Alexander J. Towbin; Fernanda D. C. Braojos Braga; Bin Zhang; James I. Geller; Greg M. Tiao; Daniel J. Podberesky. 2017. "Fractures in children with newly diagnosed hepatoblastoma." Pediatric Radiology 48, no. 4: 581-585.

Article
Published: 01 August 2017 in Journal of Virology
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Rotavirus infection is one of the most common causes of diarrheal illness in humans. In neonatal mice, rhesus rotavirus (RRV) can induce biliary atresia (BA), a disease resulting in inflammatory obstruction of the extrahepatic biliary tract and intrahepatic bile ducts. We previously showed that the amino acid arginine (R) within the sequence SRL (amino acids 445 to 447) in the RRV VP4 protein is required for viral binding and entry into biliary epithelial cells. To determine if this single amino acid (R) influences the pathogenicity of the virus, we generated a recombinant virus with a single amino acid mutation at this site through a reverse genetics system. We demonstrated that the RRV mutant (RRV VP4-R446G ) produced less symptomatology and replicated to lower titers both in vivo and in vitro than those seen with wild-type RRV, with reduced binding in cholangiocytes. Our results demonstrate that a single amino acid change in the RRV VP4 gene influences cholangiocyte tropism and reduces pathogenicity in mice. IMPORTANCE Rotavirus is the leading cause of diarrhea in humans. Rhesus rotavirus (RRV) can also lead to biliary atresia (a neonatal human disease) in mice. We developed a reverse genetics system to create a mutant of RRV (RRV VP4-R446G ) with a single amino acid change in the VP4 protein compared to that of wild-type RRV. In vitro , the mutant virus had reduced binding and infectivity in cholangiocytes. In vivo , it produced fewer symptoms and lower mortality in neonatal mice, resulting in an attenuated form of biliary atresia.

ACS Style

Sujit K. Mohanty; Bryan Donnelly; Phylicia Dupree; Inna Lobeck; Sarah Mowery; Jaroslaw Meller; Monica McNeal; Greg Tiao. A Point Mutation in the Rhesus Rotavirus VP4 Protein Generated through a Rotavirus Reverse Genetics System Attenuates Biliary Atresia in the Murine Model. Journal of Virology 2017, 91, e00510-17 .

AMA Style

Sujit K. Mohanty, Bryan Donnelly, Phylicia Dupree, Inna Lobeck, Sarah Mowery, Jaroslaw Meller, Monica McNeal, Greg Tiao. A Point Mutation in the Rhesus Rotavirus VP4 Protein Generated through a Rotavirus Reverse Genetics System Attenuates Biliary Atresia in the Murine Model. Journal of Virology. 2017; 91 (15):e00510-17.

Chicago/Turabian Style

Sujit K. Mohanty; Bryan Donnelly; Phylicia Dupree; Inna Lobeck; Sarah Mowery; Jaroslaw Meller; Monica McNeal; Greg Tiao. 2017. "A Point Mutation in the Rhesus Rotavirus VP4 Protein Generated through a Rotavirus Reverse Genetics System Attenuates Biliary Atresia in the Murine Model." Journal of Virology 91, no. 15: e00510-17.

Review
Published: 01 April 2017 in Journal of Pediatric Surgery
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Choledochoceles may cause biliary obstruction and harbor malignancy. We conducted a 40-year systematic review of the literature for this rare anomaly. PubMed and Cochrane databases were accessed 1975-2015 using terms "choledochocele" or "choledochal cyst". Studies reviewed that met the following criteria: English language, published 1975-2015 with human subjects. 325 patients with a choledochocele were identified, including 71 case reports and 254 cases within institutional reviews. 13 pediatric case reports of choledochocele exist, with abdominal pain being the most common symptom (n=11). The most frequent diagnostic and treatment modalities were ultrasound (n=10), and endoscopic sphincterotomy (n=5). No malignancies were reported. 58 adult case reports exist, with the most common presenting symptom being abdominal pain (n=54). Ultrasound was the frequently employed diagnostic modality (n=32). Open procedures were performed more often (n=30). Malignant lesions were identified in 5. In 42 institutional reviews, the frequency of choledochocele was 0.7%. Of those for whom treatment was reported, 69% underwent endoscopic sphincterotomy. Choledochocele is a rare malformation. Similarities exist between pediatric and adult patients, but malignancy has only been reported in adults. An algorithm based on patient age, cyst size, lining and amenability to endoscopic resection may be considered as a treatment strategy for this uncommon condition.

ACS Style

Inna N. Lobeck; Phylicia Dupree; Richard A. Falcone; Tom K. Lin; Andrew Trout; Jaimie D. Nathan; Greg M. Tiao. The presentation and management of choledochocele (type III choledochal cyst): A 40-year systematic review of the literature. Journal of Pediatric Surgery 2017, 52, 644 -649.

AMA Style

Inna N. Lobeck, Phylicia Dupree, Richard A. Falcone, Tom K. Lin, Andrew Trout, Jaimie D. Nathan, Greg M. Tiao. The presentation and management of choledochocele (type III choledochal cyst): A 40-year systematic review of the literature. Journal of Pediatric Surgery. 2017; 52 (4):644-649.

Chicago/Turabian Style

Inna N. Lobeck; Phylicia Dupree; Richard A. Falcone; Tom K. Lin; Andrew Trout; Jaimie D. Nathan; Greg M. Tiao. 2017. "The presentation and management of choledochocele (type III choledochal cyst): A 40-year systematic review of the literature." Journal of Pediatric Surgery 52, no. 4: 644-649.

Journal article
Published: 01 March 2017 in American Journal of Surgical Pathology
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Cystic biliary atresia (CBA), a rare cystic expansion of atretic extrahepatic bile ducts in young infants, overlaps in age at presentation and imaging features with early choledochal cysts (CC). Treatment and prognosis differ; histologic differences are unsettled. We compared 10 patients with CBA, 1975 to 2015, to an age-similar cohort of 13 infants, and to older patients who had surgery for CC. Operative details, imaging, and clinical courses were correlated to pathologic specimens. Immunostains for smooth muscle actin and myosin heavy chain were used to evaluate cyst walls and atretic segments. CBA cysts typically lacked epithelium and inflammation; cyst walls had an inner, dense cicatricial layer associated with myofibroblastic (MF) hyperplasia that often delaminated producing a grossly visible inner cyst wall. Seven proximal biliary remnants in CBA featured circumferential peribiliary MF hyperplasia/fibrosis with little or no inflammation, similar to isolated BA. Extrahepatic atresia was usually both proximal and distal to the cyst. Features in 10/13 CC from infants and 8/8 CC in older patients had mostly preserved uninjured epithelium and no subepithelial cicatrix. Mural smooth muscle (absent in CBA) was present to some extent in CC at all ages. Unexpectedly, focal MF hyperplasia and laminar sclerosis was present in a few CC in infants, resembling CBA. CBA and infant CC are distinct histologic entities that occasionally overlap. CBA bile duct injury mimics non-CBA. Cystification is an aberrant manifestation of stromal proliferation in BA. The current management approach assuming CBA and CC in infants are 2 separate disease processes is supported but caution is advised.

ACS Style

Inna N. Lobeck; Rachel Sheridan; Mark Lovell; Phylicia Dupree; Greg M. Tiao; Kevin E. Bove. Cystic Biliary Atresia and Choledochal Cysts Are Distinct Histopathologic Entities. American Journal of Surgical Pathology 2017, 41, 354 -364.

AMA Style

Inna N. Lobeck, Rachel Sheridan, Mark Lovell, Phylicia Dupree, Greg M. Tiao, Kevin E. Bove. Cystic Biliary Atresia and Choledochal Cysts Are Distinct Histopathologic Entities. American Journal of Surgical Pathology. 2017; 41 (3):354-364.

Chicago/Turabian Style

Inna N. Lobeck; Rachel Sheridan; Mark Lovell; Phylicia Dupree; Greg M. Tiao; Kevin E. Bove. 2017. "Cystic Biliary Atresia and Choledochal Cysts Are Distinct Histopathologic Entities." American Journal of Surgical Pathology 41, no. 3: 354-364.

Journal article
Published: 17 November 2016 in Hepatology
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Biliary atresia (BA) is a neonatal obstructive cholangiopathy that progresses to end‐stage liver disease, often requiring transplantation. The murine model of BA, employing rhesus rotavirus (RRV), parallels human disease and has been used to elucidate mechanistic aspects of a virus induced biliary cholangiopathy. We previously reported that the RRV VP4 gene plays an integral role in activating the immune system and induction of BA. Using rotavirus binding and blocking assays, this study elucidated how RRV VP4 protein governs cholangiocyte susceptibility to infection both in vitro and in vivo in the murine model of BA. We identified the amino acid sequence on VP4 and its cholangiocyte binding protein, finding that the sequence is specific to those rotavirus strains that cause obstructive cholangiopathy. Pretreatment of murine and human cholangiocytes with this VP4‐derived peptide (TRTRVSRLY) significantly reduced the ability of RRV to bind and infect cells. However, the peptide did not block cholangiocyte binding of TUCH and Ro1845, strains that do not induce murine BA. The SRL sequence within TRTRVSRLY is required for cholangiocyte binding and viral replication. The cholangiocyte membrane protein bound by SRL was found to be Hsc70. Inhibition of Hsc70 by small interfering RNAs reduced RRV's ability to infect cholangiocytes. This virus‐cholangiocyte interaction is also seen in vivo in the murine model of BA, where inoculation of mice with TRTRVSRLY peptide significantly reduced symptoms and mortality in RRV‐injected mice. Conclusion : The tripeptide SRL on RRV VP4 binds to the cholangiocyte membrane protein Hsc70, defining a novel binding site governing VP4 attachment. Investigations are underway to determine the cellular response to this interaction to understand how it contributes to the pathogenesis of BA. (Hepatology 2017;65:1278‐1292)

ACS Style

Sujit K. Mohanty; Bryan Donnelly; Inna Lobeck; Ashley Walther; Phylicia DuPree; Abigail Coots; Jaroslaw Meller; Monica McNeal; Karol Sestak; Greg Tiao. The SRL peptide of rhesus rotavirus VP4 protein governs cholangiocyte infection and the murine model of biliary atresia. Hepatology 2016, 65, 1278 -1292.

AMA Style

Sujit K. Mohanty, Bryan Donnelly, Inna Lobeck, Ashley Walther, Phylicia DuPree, Abigail Coots, Jaroslaw Meller, Monica McNeal, Karol Sestak, Greg Tiao. The SRL peptide of rhesus rotavirus VP4 protein governs cholangiocyte infection and the murine model of biliary atresia. Hepatology. 2016; 65 (4):1278-1292.

Chicago/Turabian Style

Sujit K. Mohanty; Bryan Donnelly; Inna Lobeck; Ashley Walther; Phylicia DuPree; Abigail Coots; Jaroslaw Meller; Monica McNeal; Karol Sestak; Greg Tiao. 2016. "The SRL peptide of rhesus rotavirus VP4 protein governs cholangiocyte infection and the murine model of biliary atresia." Hepatology 65, no. 4: 1278-1292.

Book chapter
Published: 02 October 2016 in Fundamentals of Pediatric Surgery
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Choledochal cyst is a rare congenital anomaly that left untreated can progress to cholangitis and biliary cirrhosis. Most commonly grouped by the Todani classification, five types of choledochal cysts have been described with types I and IV being the most common. Signs at presentation may include jaundice, fever, abdominal pain, and a right upper quadrant mass. Because of the widespread use of perinatal ultrasound, these biliary anomalies may also be diagnosed antenatally. Surgical management of a choledochal cyst should proceed in a timely fashion to avoid cholangitis, pancreatitis, and the small risk of cirrhosis. The goal of surgical intervention is complete cyst excision and biliary bypass. Cyst excision with roux-en-Y hepaticojejunostomy is generally effective for types I, II, and IV choledochal cysts. Type III cysts (choledochocele) may be treated using endoscopic sphincterotomy. Patients with type V cysts (Caroli’s disease) require partial hepatectomy or transplantation depending on the extent of biliary abnormalities.

ACS Style

Inna N. Lobeck; Gregory M. Tiao. Choledochal Cysts. Fundamentals of Pediatric Surgery 2016, 647 -652.

AMA Style

Inna N. Lobeck, Gregory M. Tiao. Choledochal Cysts. Fundamentals of Pediatric Surgery. 2016; ():647-652.

Chicago/Turabian Style

Inna N. Lobeck; Gregory M. Tiao. 2016. "Choledochal Cysts." Fundamentals of Pediatric Surgery , no. : 647-652.

Journal article
Published: 23 September 2016 in Virology
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The Rhesus rotavirus (RRV) induced murine model of biliary atresia (BA) is a useful tool in studying the pathogenesis of this neonatal biliary obstructive disease. In this model, the mitogen associated protein kinase pathway is involved in RRV infection of biliary epithelial cells (cholangiocytes). We hypothesized that extracellular signal-related kinase (ERK) phosphorylation is integral to calcium influx, allowing for viral replication within the cholangiocyte. Utilizing ERK and calcium inhibitors in immortalized cholangiocytes and BALB/c pups, we determined that ERK inhibition resulted in reduced viral yield and subsequent decreased symptomatology in mice. In vitro, the RRV VP6 protein induced ERK phosphorylation, leading to cellular calcium influx. Pre-treatment with an ERK inhibitor or Verapamil resulted in lower viral yields. We conclude that the pathogenesis of RRV-induced murine BA is dependent on the VP6 protein causing ERK phosphorylation and triggering calcium influx allowing replication in cholangiocytes.

ACS Style

Inna Lobeck; Bryan Donnelly; Phylicia DuPree; Maxime Mahe; Monica McNeal; Sujit K. Mohanty; Greg Tiao. Rhesus rotavirus VP6 regulates ERK-dependent calcium influx in cholangiocytes. Virology 2016, 499, 185 -195.

AMA Style

Inna Lobeck, Bryan Donnelly, Phylicia DuPree, Maxime Mahe, Monica McNeal, Sujit K. Mohanty, Greg Tiao. Rhesus rotavirus VP6 regulates ERK-dependent calcium influx in cholangiocytes. Virology. 2016; 499 ():185-195.

Chicago/Turabian Style

Inna Lobeck; Bryan Donnelly; Phylicia DuPree; Maxime Mahe; Monica McNeal; Sujit K. Mohanty; Greg Tiao. 2016. "Rhesus rotavirus VP6 regulates ERK-dependent calcium influx in cholangiocytes." Virology 499, no. : 185-195.

Journal article
Published: 01 June 2016 in Journal of Pediatric Surgery Case Reports
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ACS Style

Inna N. Lobeck; Phylicia DuPree; Richard A. Falcone; Tom K. Lin; Andrew T. Trout; Jaimie D. Nathan; Greg M. Tiao. Transduodenal resection of a choledochocele (type III choledochal cyst) with sphincteroplasty: A case report. Journal of Pediatric Surgery Case Reports 2016, 9, 26 -30.

AMA Style

Inna N. Lobeck, Phylicia DuPree, Richard A. Falcone, Tom K. Lin, Andrew T. Trout, Jaimie D. Nathan, Greg M. Tiao. Transduodenal resection of a choledochocele (type III choledochal cyst) with sphincteroplasty: A case report. Journal of Pediatric Surgery Case Reports. 2016; 9 ():26-30.

Chicago/Turabian Style

Inna N. Lobeck; Phylicia DuPree; Richard A. Falcone; Tom K. Lin; Andrew T. Trout; Jaimie D. Nathan; Greg M. Tiao. 2016. "Transduodenal resection of a choledochocele (type III choledochal cyst) with sphincteroplasty: A case report." Journal of Pediatric Surgery Case Reports 9, no. : 26-30.

Pediatric oncology
Published: 20 May 2016 in Journal of Clinical Oncology
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10516 Background: The identification of new therapies for high-risk (HR) hepatoblastoma (HB) is challenging. Children’s Oncology Group Study AHEP0731 included a HR stratum to explore novel agents. We report the response rate to vincristine/irinotecan and the outcome of high-risk HB patients. Methods: Patients with newly diagnosed metastatic HB or those with a serum alpha-fetoprotein (AFP) < 100 ng/ml were eligible. Patients received 2 cycles of vincristine (V) 1.5 mg/m2/day intravenously, on days 1 and 8 and irinotecan (I) 50 mg/m2/day, intravenously, on days 1-5. Patients were defined as responders if they had either a 30% decrease in tumor burden according to RECIST criteria or a 90% (> 1 log10 ) decline in the AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of cisplatin/doxorubicin/5-fluorouracil/vincristine (C5VD). Non-responders were to receive 6 cycles of C5VD alone. Results: Thirty-two patients (median age at diagnosis, 26 months, range: 11-159) were enrolled on study between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP = 6, RECIST only = 3, AFP only = 5). The median AFP decline following 2 cycles of VI was 345,565 ng/ml or 85% of the initial AFP. Three-year event-free and overall survival was 49% (95% confidence interval-CI: 30-65%) and 62% (CI: 42-77%) respectively. VI was well tolerated with the most common grade 3 and 4 toxicities during the first two cycles being diarrhea (n=8 patients, 26%); anorexia and febrile neutropenia (n=7 patients, 23%); nausea (n=6 patients, 19%); and a documented infection (n=4, 13%). Neuropathy was only reported in one patient (3%). Conclusions: The combination of vincristine and irinotecan has substantial activity against HR hepatoblastoma. AFP response may be a more sensitive predictor of activity than RECIST. The ultimate impact of this regimen in improving outcomes of children with HR hepatoblastoma remains to be determined. Clinical trial information: NCT00980460.

ACS Style

Howard M. Katzenstein; Wayne Lee Furman; Marcio Malogolowkin; Mark D. Krailo; M Beth McCarville; Alexander Towbin; Greg Tiao; Milton Finegold; Sarangarajan Ranganathan; Stephen Dunn; Max Langham; Eugene McGahren; Carlos Rodriguez-Galindo; Rebecka Meyers. Vincristine/irinotecan upfront window treatment of high-risk hepatoblastoma: A report from the Children’s Oncology Group (COG) AHEP0731 study committee. Journal of Clinical Oncology 2016, 34, 10516 -10516.

AMA Style

Howard M. Katzenstein, Wayne Lee Furman, Marcio Malogolowkin, Mark D. Krailo, M Beth McCarville, Alexander Towbin, Greg Tiao, Milton Finegold, Sarangarajan Ranganathan, Stephen Dunn, Max Langham, Eugene McGahren, Carlos Rodriguez-Galindo, Rebecka Meyers. Vincristine/irinotecan upfront window treatment of high-risk hepatoblastoma: A report from the Children’s Oncology Group (COG) AHEP0731 study committee. Journal of Clinical Oncology. 2016; 34 (15_suppl):10516-10516.

Chicago/Turabian Style

Howard M. Katzenstein; Wayne Lee Furman; Marcio Malogolowkin; Mark D. Krailo; M Beth McCarville; Alexander Towbin; Greg Tiao; Milton Finegold; Sarangarajan Ranganathan; Stephen Dunn; Max Langham; Eugene McGahren; Carlos Rodriguez-Galindo; Rebecka Meyers. 2016. "Vincristine/irinotecan upfront window treatment of high-risk hepatoblastoma: A report from the Children’s Oncology Group (COG) AHEP0731 study committee." Journal of Clinical Oncology 34, no. 15_suppl: 10516-10516.

Journal article
Published: 15 September 2015 in American Journal of Physiology-Gastrointestinal and Liver Physiology
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Biliary atresia (BA), a neonatal obstructive cholangiopathy, remains the most common indication for pediatric liver transplantation in the United States. In the murine model of BA, Rhesus rotavirus (RRV) VP4 surface protein determines biliary duct tropism. In this study, we investigated how VP4 governs induction of murine BA. Newborn mice were injected with 16 strains of rotavirus and observed for clinical symptoms of BA and mortality. Cholangiograms were performed to confirm bile duct obstruction. Livers and bile ducts were harvested 7 days postinfection for virus titers and histology. Flow cytometry assessed mononuclear cell activation in harvested cell populations from the liver. Cytotoxic NK cell activity was determined by the ability of NK cells to kill noninfected cholangiocytes. Of the 16 strains investigated, the 6 with the highest homology to the RRV VP4 (>87%) were capable of infecting bile ducts in vivo. Although the strain Ro1845 replicated to a titer similar to RRV in vivo, it caused no symptoms or mortality. A Ro1845 reassortant containing the RRV VP4 induced all BA symptoms, with a mortality rate of 89%. Flow cytometry revealed that NK cell activation was significantly increased in the disease-inducing strains and these NK cells demonstrated a significantly higher percentage of cytotoxicity against noninfected cholangiocytes. Rotavirus strains with >87% homology to RRV's VP4 were capable of infecting murine bile ducts in vivo. Development of murine BA was mediated by RRV VP4-specific activation of mononuclear cells, independent of viral titers.

ACS Style

Ashley Walther; Sujit K. Mohanty; Bryan Donnelly; Abigail Coots; Celine S. Lages; Inna Lobeck; Phylicia Dupree; Jarek Meller; Monica McNeal; Karol Sestak; Greg Tiao. Rhesus rotavirus VP4 sequence-specific activation of mononuclear cells is associated with cholangiopathy in murine biliary atresia. American Journal of Physiology-Gastrointestinal and Liver Physiology 2015, 309, G466 -G474.

AMA Style

Ashley Walther, Sujit K. Mohanty, Bryan Donnelly, Abigail Coots, Celine S. Lages, Inna Lobeck, Phylicia Dupree, Jarek Meller, Monica McNeal, Karol Sestak, Greg Tiao. Rhesus rotavirus VP4 sequence-specific activation of mononuclear cells is associated with cholangiopathy in murine biliary atresia. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2015; 309 (6):G466-G474.

Chicago/Turabian Style

Ashley Walther; Sujit K. Mohanty; Bryan Donnelly; Abigail Coots; Celine S. Lages; Inna Lobeck; Phylicia Dupree; Jarek Meller; Monica McNeal; Karol Sestak; Greg Tiao. 2015. "Rhesus rotavirus VP4 sequence-specific activation of mononuclear cells is associated with cholangiopathy in murine biliary atresia." American Journal of Physiology-Gastrointestinal and Liver Physiology 309, no. 6: G466-G474.

Journal article
Published: 29 August 2015 in Pediatric Transplantation
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Kidney transplantation is the optimal treatment of ESRD in children. Some studies have reported inferior outcomes in recipients of LDN allografts who are ≤5 yr of age. We performed a retrospective review of pediatric recipient outcomes of 110 LDN allografts at our institution and examined predictors of adverse outcomes. Subgroup analysis was performed by dividing recipients into three age categories: 0–5 yr, 6–17 yr, and ≥18 yr. There was no significant difference between incidences of DGF or ARE between groups. Kaplan–Meier analysis demonstrated 100% allograft survival in 0‐ to 5‐yr‐old recipients, nearly reaching statistical significance (p = 0.07) for outcome superior to that of the two older age groups. Pretransplant HD was associated with increased risk of DGF (p = 0.05). Significant risk factors for ARE were recipient weight >15 kg (p = 0.033) and multiple renal arteries (p = 0.047). Previous ARE was associated with an increased risk of allograft failure (p = 0.02). LDN is not associated with increased risk of DGF, ARE, or allograft failure in the youngest recipients. These findings support an aggressive pursuit of preemptive transplantation even in the youngest pediatric allograft recipients.

ACS Style

Ashley E. Walther; Abigail C. Coots; Jens W. Goebel; Maria H. Alonso; Frederick C. Ryckman; Greg M. Tiao; Jaimie D. Nathan. Laparoscopic donor nephrectomy for the pediatric recipient population: Risk factors for adverse outcomes. Pediatric Transplantation 2015, 19, 836 -843.

AMA Style

Ashley E. Walther, Abigail C. Coots, Jens W. Goebel, Maria H. Alonso, Frederick C. Ryckman, Greg M. Tiao, Jaimie D. Nathan. Laparoscopic donor nephrectomy for the pediatric recipient population: Risk factors for adverse outcomes. Pediatric Transplantation. 2015; 19 (8):836-843.

Chicago/Turabian Style

Ashley E. Walther; Abigail C. Coots; Jens W. Goebel; Maria H. Alonso; Frederick C. Ryckman; Greg M. Tiao; Jaimie D. Nathan. 2015. "Laparoscopic donor nephrectomy for the pediatric recipient population: Risk factors for adverse outcomes." Pediatric Transplantation 19, no. 8: 836-843.