Publications by authors named "Sanjeev A Vasudevan"

83 Publications

Hepatoblastomas with carcinoma features represent a biological spectrum of aggressive neoplasms in children and young adults.

J Hepatol 2022 May 13. Epub 2022 May 13.

Departments of Pediatrics; Departments of Pathology & Immunology. Electronic address:

Background & Aims: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant types of liver cancers in children. HB and HCC outcomes and treatment options differ dramatically and most HBs have favorable outcomes following treatment by a combination of chemotherapy and resection. Risk-stratification using a combination of clinical, histological, and molecular parameters can improve therapy selection for these patients, but it is particularly challenging for tumors with mixed HB and HCC histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to produce the first molecular characterization of clinically annotated HCN NOSs.

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 NOSs, 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 NOSs 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) and outlined histological and molecular characteristics for their classification.

Conclusions: Our single-institution study suggested that histological features seen in HBCs are associated with combined HB and HCC molecular features, that HBCs have poor outcomes irrespective of patient age, and that transplanted HBCs are more likely to have good outcomes than HBCs that are 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 hepatoblastomas and hepatocellular carcinomas.
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http://dx.doi.org/10.1016/j.jhep.2022.04.035DOI Listing
May 2022

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.

Cancer 2022 May 13. Epub 2022 May 13.

Division of Pediatric Surgery, Children's Hospital, London Health Sciences Center, London, Ontario, Canada.

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.
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http://dx.doi.org/10.1002/cncr.34256DOI Listing
May 2022

HepT1-derived murine models of high-risk hepatoblastoma display vascular invasion, metastasis, and circulating tumor cells.

Biol Open 2022 Apr 22. Epub 2022 Apr 22.

Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.

Hepatoblastoma (HB) is the most common pediatric primary liver malignancy, and survival for high-risk disease approaches 50%. Mouse models of HB fail to recapitulate hallmarks of high-risk disease. The aim of this work was to generate murine models that show high-risk features including multifocal tumors, vascular invasion, metastasis, and circulating tumor cells (CTCs). HepT1 cells were injected into the livers or tail veins of mice, and tumor growth was monitored with magnetic resonance and bioluminescent imaging. Blood was analyzed with fluorescence activated cell sorting to identify CTCs. Intra- and extra-hepatic tumor samples were harvested for immunohistochemistry and RNA and DNA sequencing. Cell lines were grown from tumor samples and profiled with RNA sequencing. With intrahepatic injection of HepT1 cells, 100% of animals grew liver tumors and showed vascular invasion, metastasis, and CTCs. Mutation profiling revealed genetic alterations in seven cancer-related genes, while transcriptomic analyses showed changes in gene expression with cells that invade vessels. Tail vein injection of HepT1 cells resulted in multifocal, metastatic disease. These unique models will facilitate further meaningful studies of high-risk HB.
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http://dx.doi.org/10.1242/bio.058973DOI Listing
April 2022

Thoracoscopic Resection of Thoracic Inlet Neuroblastic Tumors in Young Children.

J Laparoendosc Adv Surg Tech A 2021 Dec 16;31(12):1475-1479. Epub 2021 Nov 16.

Michael E. Debakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.

Thoracic inlet (TI) tumors are rare, and can be particularly challenging to resect due to proximity to mediastinal vessels and nerves. Traditional resection is typically performed through "trapdoor" or sternoclavicular incisions. The purpose of our study was to evaluate the feasibility and effectiveness of thoracoscopic resection of this group of tumors. We performed a single-center retrospective chart review for children who presented with TI neuroblastic tumors between 2011 and 2020. Demographics, tumor characteristics, treatment, operative complications, and outcomes were collected and analyzed. Eight patients were identified. The median age at diagnosis was 13 months (interquartile range [IQR] 6-32) with median tumor size at diagnosis of 4.1 cm (IQR 3.6-4.4). Neoadjuvant chemotherapy was given in 50% (4/8) with 38% (3/8) undergoing upfront surgery; 1 patient was observed without chemotherapy or surgery. Ultimately, 6 patients had thoracoscopic resection. For thoracoscopic resections, median intraoperative estimated blood loss was 15 mL (IQR 10-28), median operative room time was 199 minutes (IQR 152-259), and median hospital length of stay was 2 days (IQR 2-3). There were two complications: one recurrent laryngeal nerve injury and one new-onset Horner's syndrome. Complete gross total resection was achieved for all children and there were no recurrences or mortalities with a median follow-up of 3 years. Thoracoscopic resection for TI neuroblastic tumors is feasible with minimal morbidity and can lead to adequate oncological resection.
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http://dx.doi.org/10.1089/lap.2021.0332DOI Listing
December 2021

Author Correction: MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma.

Sci Rep 2021 Oct 1;11(1):19916. Epub 2021 Oct 1.

Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Texas Children's Hospital, 1102 Bates Ave., Suite 460G, Houston, TX, 77030-2399, USA.

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http://dx.doi.org/10.1038/s41598-021-98174-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486835PMC
October 2021

Integration of a dedicated management protocol in the care of pediatric liver cancer: From specialized providers to complication reduction.

J Pediatr Surg 2021 Jul 24. Epub 2021 Jul 24.

Division of Pediatric Surgery, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, 6701 Fannin, Suite 1210, Houston, TX, United States. Electronic address:

Introduction: Up to a third of children undergoing partial hepatectomy for primary hepatic malignancies experience at least one perioperative complication, with a presumed deleterious effect on both short- and long-term outcomes. We implemented a multidisciplinary treatment protocol in the management of these patients in order to improve complication rates following partial hepatectomy.

Methods: A retrospective chart review was completed for all patients < 18 years of age who underwent liver resection at our institution between 2002 and 2019 for primary hepatic cancer. Demographic, intraoperative, postoperative, pathologic, and outcome data were analyzed for perioperative complications using the CLASSIC and Clavien-Dindo (CD) scales, event-free survival (EFS) and overall survival (OS).

Results: A total of 73 patients were included in the analysis with 33 prior-to and 40 after dedicated provider protocol implementation. Perioperative complication rates decreased from 52% to 20% (p = 0.005) with major complications going from 18% to 10% (p = 0.31). On multivariable logistic regression, protocol implementation was associated with a reduction in any (OR 0.29 [95% CI 0.09 - 0.89]) but not major complications. On multivariate cox models, post protocol implementation was associated with improved event free survival (EFS) (HR 0.19 (0.036 - 0.195). Among patients with a diagnosis of hepatoblastoma (n = 62), the occurrence of a major perioperative complication was associated with a worse EFS (HR=5.45, p = 0.03) on multivariate analysis, however this did not translate into an impact on overall survival.

Conclusions: Our results demonstrate that, for children with primary liver malignancies, a dedication of patients to high-volume surgeons can improve rates of complications of liver resections and may improve the oncological outcome of hepatoblastoma.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.07.012DOI Listing
July 2021

CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming.

Adv Sci (Weinh) 2021 10 8;8(19):e2005047. Epub 2021 Aug 8.

Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, 77030, USA.

Neuroblastoma (NB) arises from oncogenic disruption of neural crest (NC) differentiation. Treatment with retinoic acid (RA) to induce differentiation has improved survival in some NB patients, but not all patients respond, and most NBs eventually develop resistance to RA. Loss of the chromatin modifier chromatin assembly factor 1 subunit p150 (CHAF1A) promotes NB cell differentiation; however, the mechanism by which CHAF1A drives NB oncogenesis has remained unexplored. This study shows that CHAF1A gain-of-function supports cell malignancy, blocks neuronal differentiation in three models (zebrafish NC, human NC, and human NB), and promotes NB oncogenesis. Mechanistically, CHAF1A upregulates polyamine metabolism, which blocks neuronal differentiation and promotes cell cycle progression. Targeting polyamine synthesis promotes NB differentiation and enhances the anti-tumor activity of RA. The authors' results provide insight into the mechanisms that drive NB oncogenesis and suggest a rapidly translatable therapeutic approach (DFMO plus RA) to enhance the clinical efficacy of differentiation therapy in NB patients.
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http://dx.doi.org/10.1002/advs.202005047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498874PMC
October 2021

Characteristics of benign neuroblastic tumors: Is surgery always necessary?

J Pediatr Surg 2021 Jul 7. Epub 2021 Jul 7.

Division of Pediatric Surgery, Texas Children's Surgical Oncology Program, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, BCM 185, One Baylor Plaza, Houston, TX 77030, USA; Department of Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA. Electronic address:

Purpose: Ganglioneuroma (GN) and ganglioneuroblastoma-intermixed (GNB-I) represent benign variants of neuroblastic tumors in children; however, differentiating from more aggressive histological variants of GNB including the nodular subtype (GNB-N) prior to resection can be challenging, even with biopsy. Currently, no standard treatment guidelines exist. The purpose of this study was to identify pre-operative characteristics of benign neuroblastic tumors and evaluate outcomes for patients who underwent surgical resection or observation.

Methods: Retrospective chart review of children treated at a single institution between 2009 and 2019 for non-metastatic tumor with a tissue diagnosis of GN, GNB-N or GNB-I. Demographics, imaging, labs, operative details and outcomes were recorded and analyzed.

Results: Of 53 patients, 45% were male. The most common tumor location was abdomen (49%), followed by thorax (34%). Forty-five percent had at least one image defined risk factor. Biopsy was performed in 32% (17/53) and upfront surgery in 68% (36/53). Three patients (3/53, 5.6%) with biopsy demonstrating GN tumors were observed due to high surgical risk. Pathology of resected specimens demonstrated GN in 52% (26/50) and GNB-I or GNB-N in 48% (24/50). The majority of GNB tumors (75% (18/24) were GNB-I and 25% (6/24) were GNB-N. Therefore, 88% of the resected tumors were benign spectrum neuroblastic tumors (GN & GNB-I). Seven (7/50, 14%) patients experienced perioperative complication (temporary paralysis, Horner's syndrome, chylothorax, vocal cord paralysis). Recurrence was noted in 1 patient with GN (1/50, 2%) and 3 with GNB-N (3/50, 6%). There were no tumor-related deaths. Patients with GN were older than those with GNB (8.8 years (IQR 6-11.25) vs 5.6 years for GN (IQR 3-7); p = 0.01). GNB tumors were also more likely to have calcifications on imaging (63% vs. 38%, p = .01) and more commonly had MIBG avidity (88% vs 66%, p = .04). There were no significant differences in tumor size or symptoms at presentation.

Conclusions: In children with neuroblastic tumors, older age, CT without tumor calcifications, lack of MIBG avidity, and/or normal urine catecholamines may indicate benign GN. Close observation could be considered for asymptomatic patients meeting these criteria with biopsy-proven GN, with resection reserved for progressive growth or symptom development. However, larger, multicenter studies are needed for further validation.

Level Of Evidence: IV.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.07.002DOI Listing
July 2021

Angiosarcoma of the Pancreas in a Pediatric Patient With an Activating KDR-Internal Tandem Duplication: A Case Report and Review of the Literature.

J Pediatr Hematol Oncol 2022 Apr;44(3):e751-e755

Michael E. DeBakey Department of Surgery, Division of Pediatric Surgery, Texas Children's Surgical Oncology Program.

Pancreatic angiosarcoma is an exceedingly rare malignancy accounting for <1% of pancreatic neoplasms. A very limited number of pancreatic angiosarcomas have been reported in the literature without any cases described in children. We present the case of a 17-year-old female diagnosed with angiosarcoma of the pancreas following pancreaticoduodenectomy for a pancreatic mass, initially presumed to be a solid pseudopapillary neoplasm of the pancreas. The angiosarcoma was found to have a novel activating internal tandem duplication in the KDR gene (KDR-internal tandem duplication). We discuss the current literature on this disease process. This is the first reported case of pancreatic angiosarcoma in a pediatric patient and the first with an activating KDR-internal tandem duplication.
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http://dx.doi.org/10.1097/MPH.0000000000002248DOI Listing
April 2022

Restoration of the molecular clock is tumor suppressive in neuroblastoma.

Nat Commun 2021 06 28;12(1):4006. Epub 2021 Jun 28.

Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, USA.

MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of the main regulators of the molecular clock loops is profoundly disrupted in MYCN-amplified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORα via its genetic overexpression and its stimulation through the agonist SR1078, restores BMAL1 expression and oscillation, effectively blocks MYCN-mediated tumor growth and de novo lipogenesis, and sensitizes NB tumors to conventional chemotherapy. In conclusion, reactivation of RORα could serve as a therapeutic strategy for MYCN-amplified NBs by blocking the dysregulation of molecular clock and cell metabolism mediated by MYCN.
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http://dx.doi.org/10.1038/s41467-021-24196-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238982PMC
June 2021

Pathologic correlation with near infrared-indocyanine green guided surgery for pediatric liver cancer.

J Pediatr Surg 2022 Apr 25;57(4):700-710. Epub 2021 Apr 25.

Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX USA. Electronic address:

Purpose: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the most common primary malignant tumors of childhood. Intraoperative indocyanine green (ICG) administration with near-infrared imaging (NIR) has emerged as a surgical technology that can be used to assist with localization of pulmonary metastases secondary to HB; however, there has been limited application as an adjunct for resection of the primary liver tumor and assessment of extrahepatic disease.

Methods: We present 14 patients treated for HB, HCC, and malignant rhabdoid tumor at our institution with the use of intraoperative NIR-ICG guidance. All patients were treated with 0.2-0.75 mg/kg IV ICG, 48-96 h prior to surgery. Intraoperative NIR-ICG guided imaging was performed with several commercial devices.

Results: Intraoperative NIR-ICG guidance allowed pulmonary metastasectomy in five patients using thoracoscopy or thoracotomy allowing for visualization of multiple nodules not seen on preoperative imaging most of which were positive for malignancy. NIR-ICG guidance allowed for assessment of extrahepatic extension in three patients; an HCC patient with extrahepatic lymph node extension of disease, an HB patient with extrapulmonary thoracic recurrence in the diaphragm and chest wall, and a patient with tumor rupture at diagnosis with peritoneal nodules at the time of surgery. This technique was used to guide partial hepatectomy in 11 patients for which the technique enabled successful identification of tumor and tumor margins. Three patients had nonspecific staining of the liver secondary to decreased timing from ICG injection to surgery or biliary obstruction. NIR-ICG enabled resection of satellite HB lesions in three multifocal patients and confirmed a benign satellite lesion in two additional patients.

Conclusions: Intraoperative use of NIR-ICG imaging during partial hepatectomy enabled enhanced identification and guidance for surgical resection of extrahepatic disease and multifocal liver tumors for the treatment of children with primary liver cancer.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.04.019DOI Listing
April 2022

Transarterial Radioembolization Treatment as a Bridge to Surgical Resection in Pediatric Hepatocellular Carcinoma.

J Pediatr Hematol Oncol 2021 Nov;43(8):e1181-e1185

Singleton Department of Pediatric Radiology, Division of Interventional Radiology, Texas Children's Hospital Liver Tumor Program, Baylor College of Medicine, Houston.

Background: Children with unresectable hepatocellular carcinoma (HCC) have a poor prognosis and limited treatment options. Transarterial radioembolization (TARE) using Yttrium-90 (Y90) has emerged as a potential bridge therapy to hepatic resection or transplantation for HCC with very limited studies in children.

Observations: Here we present the clinical course of 2 children successfully treated with TARE Y90 for initially unresectable fibrolamellar HCC (FL-HCC) and bridged to partial hemihepatectomy with >1-year overall survival post-TARE.

Conclusion: Although there have been prior published reports of pediatric patients with HCC being treated with TARE Y90 and some being able to undergo subsequent orthotopic liver transplantation, this is the first report of pediatric HCC patients treated with TARE Y90 as a bridge to nontransplant resections and going on to have >1-year overall survival.
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http://dx.doi.org/10.1097/MPH.0000000000002089DOI Listing
November 2021

Pediatric Gastrointestinal Stromal Tumors and Neuroendocrine Tumors: Advances in Surgical Management.

Surg Oncol Clin N Am 2021 04;30(2):219-233

Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, 7200 Cambridge Street, 7th Floor, Houston, TX 77030, USA. Electronic address:

Gastrointestinal stromal tumors and neuroendocrine tumors in adult and pediatric populations differ immensely. Despite these established differences, the extreme rarity of gastrointestinal stromal tumors and neuroendocrine tumors in the pediatric population has resulted in the lack of consensus management guidelines, making optimal surgical approaches unclear. Comprehensive management principles to guide surgical approaches in adult literature are extensive. However, these are still lacking for pediatric patients. International cooperation to develop standardized pediatric-specific guidelines is urgently warranted in the future. This article highlights the vast differences between adult and pediatric parameters and provides recommendations on optimal and novel surgical approaches in children.
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http://dx.doi.org/10.1016/j.soc.2020.11.001DOI Listing
April 2021

MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma.

Sci Rep 2021 02 3;11(1):2967. Epub 2021 Feb 3.

Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Texas Children's Hospital, 1102 Bates Ave., Suite 460G, Houston, TX, 77030-2399, USA.

Hepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient quality of life. Most HB cases are TP53 wild-type; therefore, we hypothesized that targeting the p53 regulator Murine double minute 4 (MDM4) to reactivate p53 signaling may show efficacy. MDM4 expression was elevated in HB patient samples, and increased expression was strongly correlated with decreased expression of p53 target genes. Treatment with NSC207895 (XI-006), which inhibits MDM4 expression, or ATSP-7041, a stapled peptide dual inhibitor of MDM2 and MDM4, showed significant cytotoxic and antiproliferative effects in HB cells. Similar phenotypes were seen with short hairpin RNA (shRNA)-mediated inhibition of MDM4. Both NSC207895 and ATSP-7041 caused significant upregulation of p53 targets in HB cells. Knocking-down TP53 with shRNA or overexpressing MDM4 led to resistance to NSC207895-mediated cytotoxicity, suggesting that this phenotype is dependent on the MDM4-p53 axis. MDM4 inhibition also showed efficacy in a murine model of HB with significantly decreased tumor weight and increased apoptosis observed in the treatment group. This study demonstrates that inhibition of MDM4 is efficacious in HB by upregulating p53 tumor suppressor signaling.
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http://dx.doi.org/10.1038/s41598-021-82542-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859402PMC
February 2021

Subcutaneous analgesic system versus epidural for post-operative pain control in surgical pediatric oncology patients.

J Pediatr Surg 2021 Jan 6;56(1):104-109. Epub 2020 Oct 6.

Department of Surgery, Division of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, TX. Electronic address:

Background/purpose: Pediatric oncology patients often undergo open operations for tumor resection, and epidural catheters are commonly utilized for pain control. Our purpose was to evaluate whether a subcutaneous analgesic system (SAS) provides equivalent post-operative pain control.

Methods: An IRB approved, retrospective chart review of children age <18 undergoing open abdominal, pelvic or thoracic surgery for tumor resection between 2017 and 2019 who received either epidural or SAS for post-operative pain control was performed. Comparisons of morphine milligram equivalents (MME), pain scores, and post-operative course were made using parametric and non-parametric analyses.

Results: Of 101 patients, median age was 7 years (2 months-17.9 years). There were 65 epidural and 36 SAS patients. Transverse laparotomy was the most common incision (41%), followed by thoracotomy (29%). Pain scores, MME, urinary catheter days, and post-operative length of stay (LOS) were similar between the two groups. Urinary catheter use was more common in epidural patients (70% vs 30%, p = <0.001). SAS patients had faster time to ambulation and time to regular diet by 1 day (p = 0.02). Epidural patients more commonly had a complication with the pain device (20% vs 3%, p = 0.02) and were more likely to be discharged with narcotics (60% vs. 40%, p = 0.04). Charges associated with the hospital stay were similar between the two groups.

Conclusion: In pediatric oncology patients undergoing open abdominal, pelvic, and thoracic surgery, SAS may provide similar pain control to epidural, but with faster post-operative recovery, fewer complications, and less discharge narcotic use. A prospective study is needed to validate these results.

Type Of Study: Retrospective Comparative LEVEL OF EVIDENCE: Level III.
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http://dx.doi.org/10.1016/j.jpedsurg.2020.09.041DOI Listing
January 2021

Thoracoscopy vs thoracotomy for the management of metastatic osteosarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

Int J Cancer 2021 03 31;148(5):1164-1171. Epub 2020 Aug 31.

Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.

Complete surgical resection of pulmonary metastatic disease in patients with osteosarcoma is crucial to long-term survival. Open thoracotomy allows palpation of nodules not identified on imaging but the impact on survival is unknown. The objective of this study was to compare overall survival (OS) and pulmonary disease-free survival (DFS) in children who underwent thoracotomy vs thoracoscopic surgery for pulmonary metastasectomy. A multi-institutional collaborative group retrospectively reviewed 202 pediatric patients with osteosarcoma who underwent pulmonary metastasectomy by thoracotomy (n = 154) or thoracoscopy (n = 48). Results were analyzed by Kaplan-Meier survival estimates and multivariate Cox proportional hazard regression models. With median follow-up of 45 months, 135 (67.5%) patients had a pulmonary relapse and 95 (47%) patients were deceased. Kaplan-Meier analysis showed no significant difference in 5-year pulmonary DFS (25% vs 38%; P = .18) or OS (49% vs 42%, P = .37) between the surgical approaches of thoracotomy and thoracoscopy. In Cox regression analysis controlling for other factors impacting outcome, there was a significantly increased risk of mortality (HR 2.11; P = .027; 95% CI 1.09-4.09) but not pulmonary recurrence (HR 0.96; P = .90; 95% CI 0.52-1.79) with a thoracoscopic approach. However, in the subset analysis limited to patients with oligometastatic disease, thoracoscopy had no increased risk of mortality (HR 1.16; P = .62; 0.64-2.11). In conclusion, patients with metastatic osteosarcoma and limited pulmonary disease burden demonstrate comparable outcomes after thoracotomy and thoracoscopy for metastasectomy. While significant selection bias in these surgical cohorts limits the generalizability of the conclusions, clinical equipoise for a randomized clinical trial in patients with oligometastatic disease is supported.
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http://dx.doi.org/10.1002/ijc.33264DOI Listing
March 2021

Sclerosing Encapsulating Peritonitis in a Pediatric Patient Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

J Pediatr Hematol Oncol 2021 07;43(5):e685-e688

Michael E. DeBakey Department of Surgery, Divisions of Pediatric Surgery and Surgical Research, Texas Children's Hospital Surgical Oncology Program, Dan L. Duncan Cancer Center.

Background: Sclerosing encapsulating peritonitis (SEP) is a rare chronic inflammatory condition characterized by small bowel encapsulation by a thick fibrocollagenous membrane. Patients with SEP often present with nonspecific symptoms, such as abdominal pain and distension, however some patients may present with symptoms suggestive of intestinal obstruction. Secondary SEP has been reported in patients undergoing peritoneal dialysis and has been recently described in adults following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

Observations: We report a clinical case of a 13-year-old female who presented with worsening abdominal pain and distension and persistent emesis who was found to have SEP 13 months following CRS and HIPEC for management of desmoplastic small round cell tumor and subsequently required operative intervention.

Conclusion: Although there have been published reports of adult patients experiencing cases of SEP following CRS/HIPEC, this is the first published case of secondary SEP occurring in a pediatric oncology patient.
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http://dx.doi.org/10.1097/MPH.0000000000001899DOI Listing
July 2021

Pancreaticoduodenectomy for the treatment of pancreatic neoplasms in children: A Pediatric Surgical Oncology Research Collaborative study.

Pediatr Blood Cancer 2020 09 13;67(9):e28425. Epub 2020 Jul 13.

Division of Pediatric Surgery, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada.

Background: To better characterize short-term and long-term outcomes in children with pancreatic tumors treated with pancreaticoduodenectomy (PD).

Methods: Patients 21 years of age or younger who underwent PD at Pediatric Surgical Oncology Collaborative (PSORC) hospitals between 1990 and 2017 were identified. Demographic, clinical information, and outcomes (operative complications, long-term pancreatic function, recurrence, and survival) were collected.

Results: Sixty-five patients from 18 institutions with a median age of 13 years (4 months-22 years) and a median (IQR) follow-up of 2.8 (4.3) years were analyzed. Solid pseudopapillary tumor of the pancreas (SPN) was the most common histology. Postoperative complications included pancreatic leak in 14% (n = 9), delayed gastric emptying in 9% (n = 6), marginal ulcer in one patient, and perioperative (30-day) death due to hepatic failure in one patient. Pancreatic insufficiency was observed in 32% (n = 21) of patients, with 23%, 3%, and 6% with exocrine, or endocrine insufficiencies, or both, respectively. Children with SPN and benign neoplasms all survived. Overall, there were 14 (22%) recurrences and 11 deaths (17%). Univariate analysis revealed non-SPN malignant tumor diagnosis, preoperative vascular involvement, intraoperative transfusion requirement, pathologic vascular invasion, positive margins, and need for neoadjuvant chemotherapy as risk factors for recurrence and poor survival. Multivariate analysis only revealed pathologic vascular invasion as a risk factor for recurrence and poor survival.

Conclusion: This is the largest series of pediatric PD patients. PD is curative for SPN and benign neoplasms. Pancreatic insufficiency is the most common postoperative complication. Outcome is primarily associated with histology.
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http://dx.doi.org/10.1002/pbc.28425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674210PMC
September 2020

Endoscopic Ultrasound in an Adolescent With Rectal Adenocarcinoma and Lynch Syndrome.

J Pediatr Gastroenterol Nutr 2020 06;70(6):e136

Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine.

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http://dx.doi.org/10.1097/MPG.0000000000002533DOI Listing
June 2020

Pneumonectomy for Pediatric Tumors-a Pediatric Surgical Oncology Research Collaborative Study.

Ann Surg 2021 12;274(6):e605-e609

Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Objective: To describe utilization and long-term outcomes of pneumonectomy in children and adolescents with cancer.

Summary Background Data: Pneumonectomy in adults is associated with significant morbidity and mortality. Little is known about the indications and outcomes of pneumonectomy for pediatric tumors.

Methods: The Pediatric Surgical Oncology Research Collaborative (PSORC) identified pediatric patients <21 years of age who underwent pneumonectomy from 1990 to 2017 for primary or metastatic tumors at 12 institutions. Clinical information was collected; outcomes included operative complications, long-term function, recurrence, and survival. Univariate log rank, and multivariable Cox analyses determined factors associated with survival.

Results: Thirty-eight patients (mean 12 ± 6 yrs) were identified; median (IQR) follow-up was 19 (5-38) months. Twenty-six patients (68%) underwent pneumonectomy for primary tumors and 12 (32%) for metastases. The most frequent histologies were osteosarcoma (n = 6), inflammatory myofibroblastic tumors (IMT; n = 6), and pleuropulmonary blastoma (n = 5). Median postoperative ventilator days were 0 (0-1), intensive care 2 (1-3), and hospital 8 (5-16). Early postoperative complications occurred in 10 patients including 1 death. Of 25 (66%) patients alive at 1 year, 15 reported return to preoperative pulmonary status. All IMT patients survived while all osteosarcoma patients died during follow-up. On multivariable analysis, metastatic indications were associated with nonsurvival (HR = 3.37, P = 0.045).

Conclusion: This is the largest review of children who underwent pneumonectomy for cancer. There is decreased procedure-related morbidity and mortality than reported for adults. Survival is worse with preoperative metastatic disease, especially osteosarcoma.
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http://dx.doi.org/10.1097/SLA.0000000000003795DOI Listing
December 2021

Optimization of percutaneous biopsy for diagnosis and pretreatment risk assessment of neuroblastoma.

Pediatr Blood Cancer 2020 05 19;67(5):e28153. Epub 2020 Feb 19.

Division of Pediatric Surgery, Department of Surgery, C. S. Mott Children's Hospital, The University of Michigan, Ann Arbor, Michigan.

Background: Image-guided percutaneous core needle biopsy (PCNB) is increasingly utilized to diagnose solid tumors. The objective of this study is to determine whether PCNB is adequate for modern biologic characterization of neuroblastoma.

Procedure: A multi-institutional retrospective study was performed by the Pediatric Surgical Oncology Research Collaborative on children with neuroblastoma at 12 institutions over a 3-year period. Data collected included demographics, clinical details, biopsy technique, complications, and adequacy of biopsies for cytogenetic markers utilized by the Children's Oncology Group for risk stratification.

Results: A total of 243 children were identified with a diagnosis of neuroblastoma: 79 (32.5%) tumor excision at diagnosis, 94 (38.7%) open incisional biopsy (IB), and 70 (28.8%) PCNB. Compared to IB, there was no significant difference in ability to accurately obtain a primary diagnosis by PCNB (95.7% vs 98.9%, P = .314) or determine MYCN copy number (92.4% vs 97.8%, P = .111). The yield for loss of heterozygosity and tumor ploidy was lower with PCNB versus IB (56.1% vs 90.9%, P < .05; and 58.0% vs. 88.5%, P < .05). Complications did not differ between groups (2.9 % vs 3.3%, P = 1.000), though the PCNB group had fewer blood transfusions and lower opioid usage. Efficacy of PCNB was improved for loss of heterozygosity when a pediatric pathologist evaluated the fresh specimen for adequacy.

Conclusions: PCNB is a less invasive alternative to open biopsy for primary diagnosis and MYCN oncogene status in patients with neuroblastoma. Our data suggest that PCNB could be optimized for complete genetic analysis by standardized protocols and real-time pathology assessment of specimen quality.
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http://dx.doi.org/10.1002/pbc.28153DOI Listing
May 2020

Animal Modeling of Pediatric Liver Cancer.

Cancers (Basel) 2020 Jan 22;12(2). Epub 2020 Jan 22.

Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.

Hepatoblastoma (HB) is the most common pediatric liver malignancy. Management of HB requires multidisciplinary efforts. The 5-year overall survival of this disease is about 80% in developed countries. Despite advances in the care of these patients, survival in recurrent or treatment-refractory disease is lower than 50%. This is due to more complex tumor biology, including hepatocellular carcinoma (HCC)-like mutations and expression of aggressive gene signatures leading to chemoresistance, vascular invasion, and metastatic spread. The current treatment protocols for pediatric liver cancer do not incorporate targeted therapies, and the ability to test these therapies is limited due to the inaccessibility of cell lines and mouse models. In this review, we discuss the current status of preclinical animal modeling in pediatric liver cancer, primarily HB. Although HB is a rare cancer, the research community has worked together to develop a range of interesting and relevant mouse models for diverse preclinical studies.
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http://dx.doi.org/10.3390/cancers12020273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072332PMC
January 2020

Surgical Management of Hepatoblastoma and Recent Advances.

Cancers (Basel) 2019 Dec 4;11(12). Epub 2019 Dec 4.

Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.

Hepatoblastoma is the most common childhood liver malignancy. The management of hepatoblastoma requires multidisciplinary efforts. The five-year overall survival is approximately 80% in developed countries. Surgery remains the mainstay of treatment for hepatoblastoma, and meticulous techniques must be employed to ensure safe and effective local control surgeries. Additionally, there have been several advances from both pediatric and adult literature in the way liver tumor surgery is performed. In this review, we highlight important aspects of liver surgery for hepatoblastoma, the management of metastatic disease, and the most current technical advances in performing these procedures in a safe and effective manner.
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http://dx.doi.org/10.3390/cancers11121944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966548PMC
December 2019

Salvage sacrococcygeal resection for yolk sac tumors after chemotherapy: report of 2 cases.

J Neurosurg Pediatr 2019 Oct 4:1-8. Epub 2019 Oct 4.

1Division of Pediatric Neurosurgery, Department of Surgery, Texas Children's Hospital, Baylor College of Medicine.

Pediatric germ cell tumors (GCTs) are neoplasms that originate from primordial germ cells and, according to their site of presentation, are classified as gonadal or extragonadal. The most common site of extragonadal GCTs in children is the sacrococcygeal region, and the standard management is multimodal with a focus on chemotherapy. In selected instances, sacrococcygeal resection is performed. Herein, the authors report on 2 patients who presented with presacral yolk sac tumors managed with multimodal treatment. Both patients underwent salvage sacrococcygeal resection for oncological control and surgical removal of the sacral vertebral elements: a 27-month-old girl with a recurrent sacrococcygeal yolk sac tumor following chemotherapy and initial resection and a 24-month-old boy in whom a primary sacrococcygeal yolk sac tumor was resected following chemotherapy. These 2 cases illustrate the complexity in the management of these unusual tumors and will help neurosurgeons with the understanding of yolk sac tumors in the sacrococcygeal region.
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http://dx.doi.org/10.3171/2019.7.PEDS19321DOI Listing
October 2019

Congenital spindle cell rhabdomyosarcoma.

Pediatr Blood Cancer 2019 11 24;66(11):e27935. Epub 2019 Jul 24.

Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Houston, Texas.

Spindle cell and sclerosing rhabdomyosarcoma (ssRMS) is a rare variant of rhabdomyosarcoma, which includes three distinct subtypes. In infants, these tumors are commonly associated with recurring fusions involving VGLL2 or NCOA2 and have a favorable prognosis. We present four cases of ssRMS and 16 additional cases from the literature, which show that these patients present with localized disease and have an excellent prognosis regardless of surgical margin or lack of radiation therapy. Molecularly defined spindle cell rhabdomyosarcoma in infants is likely a biologically distinct entity which may not require the aggressive multimodal treatment used for other subtypes of rhabdomyosarcoma.
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http://dx.doi.org/10.1002/pbc.27935DOI Listing
November 2019

Small molecule inhibitor agerafenib effectively suppresses neuroblastoma tumor growth in mouse models via inhibiting ERK MAPK signaling.

Cancer Lett 2019 08 14;457:129-141. Epub 2019 May 14.

Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address:

Neuroblastoma (NB) is the most common extracranial solid tumor in early childhood. Despite intensive multimodal therapy, nearly half of children with high-risk disease will relapse with therapy-resistant tumors. Dysregulation of MAPK pathway has been implicated in the pathogenesis of relapsed and refractory NB patients, which underscores the possibility of targeting MAPK signaling cascade as a novel therapeutic strategy. In this study, we found that high expressions of RAF family kinases correlated with advanced tumor stage, high-risk disease, tumor progression, and poor overall survival. Targeted inhibition of RAF family kinases with the novel small molecule inhibitor agerafenib abrogated the activation of ERK MAPK pathway in NB cells. Agerafenib significantly inhibited the cell proliferation and colony formation ability of NB cells in vitro, and its combination with traditional chemotherapy showed a synergistic pro-apoptotic effect. More importantly, agerafenib exhibited a favorable toxicity profile, potently suppressed tumor growth, and prolonged survival in NB mouse models. In conclusion, our preclinical data suggest that agerafenib might be an effective therapeutic agent for NB treatment, both as a single-agent and in combination with chemotherapy.
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http://dx.doi.org/10.1016/j.canlet.2019.05.011DOI Listing
August 2019

Characterization of pediatric hepatocellular carcinoma reveals genomic heterogeneity and diverse signaling pathway activation.

Pediatr Blood Cancer 2019 07 11;66(7):e27745. Epub 2019 Apr 11.

Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.

Background: Pediatric hepatocellular carcinoma (HCC) is a rare liver tumor in children with a poor prognosis. Comprehensive molecular profiling to understand the underlying genomic drivers of this tumor has not been completed, and it is unclear whether nonfibrolamellar pediatric HCC is more genomically similar to hepatoblastoma or adult HCC.

Procedure: To characterize the molecular landscape of these tumors, we analyzed a cohort of 15 pediatric non-FL-HCCs by sequencing a panel of cancer-associated genes and conducting copy-number and gene-expression analyses.

Results: We detected multiple types of molecular alterations in Wnt signaling genes, including APC inversion, AMER1 somatic mutation, and most commonly CTNNB1 intragenic deletions. There were multiple alterations to the telomerase pathway via TERT activation or ATRX mutation. Therapeutically targetable activating mutations in MAPK/ERK signaling pathway genes, including MAPK1 and BRAF, were detected in 20% of tumors. TP53 mutations occurred far less frequently in our pediatric HCC cohort than reported in adult cohorts. Tumors arising in children with underlying liver disease were found to be molecularly distinct from the remainder and lacking detectable oncogenic drivers, as compared with those arising in patients without a history of underlying liver disease; the majority of both types were positive for glypican-3, another potential therapeutic target.

Conclusion: Our study revealed pediatric HCC to be a molecularly heterogeneous group of tumors. Those non-FL-HCC tumors arising in the absence of underlying liver disease harbor genetic alterations affecting multiple cancer pathways, most notably Wnt signaling, and share some characteristics with adult HCC.
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http://dx.doi.org/10.1002/pbc.27745DOI Listing
July 2019

Inhibition of Ubiquitin-Specific Protease 14 Suppresses Cell Proliferation and Synergizes with Chemotherapeutic Agents in Neuroblastoma.

Mol Cancer Ther 2019 06 8;18(6):1045-1056. Epub 2019 Apr 8.

Division of Pediatric Surgery, Texas Children's Hospital Department of Surgery, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.

Neuroblastoma is the most common extracranial malignant solid tumor in children, and drug resistance is a major reason for poor outcomes. Elevated proteasome activity plays an important role in neuroblastoma tumor development and resistance to conventional chemotherapy. Ubiquitin-specific protease 14 (USP14), one of three deubiquitinases associated with the regulatory subunit of the proteasome, is emerging as a potential therapeutic target in multiple tumor types. However, the role of USP14 in neuroblastoma is yet to be elucidated. We found that USP14 inhibition in neuroblastoma via knockdown or a specific inhibitor such as b-AP15 suppressed cell proliferation by inducing cell apoptosis. Furthermore, b-AP15 significantly inhibited neuroblastoma tumor growth in NGP and SH-SY5Y xenograft mouse models. For combination treatment, b-AP15 plus conventional chemotherapeutic agents such as doxorubicin or VP-16 resulted in synergistic antitumor effects on neuroblastoma. Our study demonstrates that USP14 is required for cell viability and is a novel therapeutic target in neuroblastoma. Moreover, USP14 inhibition may add value in combination therapy due to its powerful synergistic effects in treating neuroblastoma.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565366PMC
June 2019

Pancreatic islet cell tumors in adolescents and young adults.

J Pediatr Surg 2019 Oct 27;54(10):2103-2106. Epub 2019 Mar 27.

Department of Surgery, University of Alabama at Birmingham, Children's of Alabama, Birmingham, AL. Electronic address:

Background: Pancreatic islet cell tumors are rare in adolescents, and most studies published to date focus on older patients. We utilized a national database to describe the histology and clinical pattern of pancreatic islet cell tumors in adolescent and young adult (AYA) patients, and to compare AYAs to older adults. We hypothesized that AYAs with pancreatic islet cell tumors would have better overall survival.

Methods: The National Cancer Data Base (NCDB, 1998-2012) was queried for AYA patients (15-39 years) with a pancreatic islet cell tumor diagnosis. Demographics, tumor characteristics, treatment modalities, and outcomes were abstracted and compared to adults (≥40 years).

Results: 383 patients (56.4% female, 65% non-Hispanic Whites) were identified, with a median age of 27 (IQR 16-34) years. Islet cell carcinoma was the most common histology. Of patients with known stage of disease, 49% presented with early stage (I or II). Seventy percent of patients underwent surgical resection, including local excision 44%, Whipple procedure 37.5%, or total pancreatectomy 19%. Chemotherapy was utilized in 27% and radiotherapy in 7%. All-cause mortality was 36%. AYA patients underwent more extensive resections (p = 0.001) and had lower mortality rates (p < 0.001), with no differences in tumor stage or use of adjuvant therapies, when compared to adults.

Conclusions: AYA patients with pancreatic islet cell tumors had comparable utilization of adjuvant therapies but underwent more extensive resections and demonstrated a higher overall survival rate than adult counterparts. Further investigation into approaches to earlier diagnosis and tailoring of multimodality therapy of these neoplasms in the AYA population is needed.

Levels Of Evidence: Prognostic Study, Level II - retrospective study.
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http://dx.doi.org/10.1016/j.jpedsurg.2019.01.060DOI Listing
October 2019

Targeting LRH‑1 in hepatoblastoma cell lines causes decreased proliferation.

Oncol Rep 2019 Jan 15;41(1):143-153. Epub 2018 Oct 15.

Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey, Department of Surgery, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.

Hepatoblastoma is the most common malignant liver tumor in children. Since it is often unresectable and exhibits drug resistance, the treatment of advanced hepatoblastoma is challenging. The orphan nuclear receptor liver receptor homolog‑1 (LRH‑1) serves prominent roles in malignancy; however, to the best of our knowledge, the role of LRH‑1 in hepatoblastoma remains unknown. In the present study, human hepatoblastoma cell lines were analyzed; the mRNA and protein expression levels of LRH‑1 were significantly higher in HepG2 and HuH6 cells compared with those in HepT1 cells and control THLE‑2 cells. Knockdown of LRH‑1 resulted in decreased HepG2 and HuH6 cell proliferation via downregulation of cyclin D1 (CCND1) and c‑Myc. Furthermore, treatment with an LRH‑1 antagonist (LRA) inhibited the proliferation and colony formation of cell lines in a dose‑dependent manner, and induced cell cycle arrest at G1 phase through inhibition of CCND1 expression. Finally, LRA treatment enhanced the cytotoxic effects of doxorubicin on hepatoblastoma cells. Collectively, these findings suggested that LRH‑1 may have an important role in the progression of hepatoblastoma and implicated LRA as a novel, potential therapeutic agent for the treatment of hepatoblastoma.
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http://dx.doi.org/10.3892/or.2018.6793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278492PMC
January 2019
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