Characteristics and outcomes in children with undifferentiated embryonal sarcoma of the liver: A report from the National Cancer Database.

OBJECTIVE: To examine patient characteristics and outcomes in children with undifferentiated embryonal sarcoma of the liver (UESL) using a multi-institutional database. SUMMARY BACKGROUND DATA: UESL is a rare disease (incidence is one per million). Therefore, the current literature is mostly limited to small case series. METHODS: The National Cancer Database was queried for primary UESL diagnosed between 1998 and 2012. RESULTS: A total of 103 patients (<18 years) were identified. The 5-year overall survival of the entire group was 86%. The best outcomes were seen in children who had tumors smaller than 15 cm and were able to undergo surgical resection with or without chemotherapy. Margin status did not appear to significantly affect survival. The most common type of resection was hemihepatectomy (37%), followed by sectionectomy (10%) and trisectionectomy (10%). Orthotopic liver transplant was performed in 10 children, all of whom survived to 5 years. CONCLUSION: Surgical resection with or without chemotherapy should be the mainstay of treatment in children with UESL, and is associated with very favorable outcomes. Negative surgical margins were not associated with improved survival. Orthotopic liver transplantation may be a viable method of attaining local control in tumors, which would otherwise be unresectable.

Childhood and adolescent tracheobronchial mucoepidermoid carcinoma (MEC): a case-series and review of the literature.

Tracheobronchial mucoepidermoid carcinomas (MEC) are rare in the pediatric population with literature limited primarily to case reports. Here we present our institutional experience treating MEC in three patients and review the literature of 142 pediatric cases previously published from 1968 to 2013. Although rare, tracheobronchial MEC should be included in the differential diagnosis in a child with recurrent respiratory symptoms. Conservative surgical management is often sufficient to achieve complete resection and good outcomes.

Relapse surveillance in AFP-positive hepatoblastoma: re-evaluating the role of imaging.

BACKGROUND: Children with hepatoblastoma routinely undergo repetitive surveillance imaging, with CT scans for several years after therapy, increasing the risk of radiation-induced cancer. OBJECTIVE: The purpose of this study was to determine the utility of surveillance CT scans compared to serum alpha-fetoprotein (AFP) levels for the detection of hepatoblastoma relapse. MATERIALS AND METHODS: This was a retrospective study of all children diagnosed with AFP-positive hepatoblastoma from 2001 to 2011 at a single institution. RESULTS: Twenty-six children with hepatoblastoma were identified, with a mean age at diagnosis of 2 years 4 months (range 3 months to 11 years). Mean AFP level at diagnosis was 132,732 ng/ml (range 172.8-572,613 ng/ml). Five of the 26 children had hepatoblastoma relapse. A total of 105 imaging exams were performed following completion of therapy; 88 (84%) CT, 8 (8%) MRI, 5 (5%) US and 4 (4%) FDG PET/CT exams. A total of 288 alpha-fetoprotein levels were drawn, with a mean of 11 per child. The AFP level was elevated in all recurrences and no relapses were detected by imaging before AFP elevation. Two false-positive AFP levels and 15 false-positive imaging exams were detected. AFP elevation was found to be significantly more specific than PET/CT and CT imaging at detecting relapse. CONCLUSION: We recommend using serial serum AFP levels as the preferred method of surveillance in children with AFP-positive hepatoblastoma, reserving imaging for the early postoperative period, for children at high risk of relapse, and for determination of the anatomical site of clinically suspected recurrence. Given the small size of this preliminary study, validation in a larger patient population is warranted.

EWS-FLI1 and RNA helicase A interaction inhibitor YK-4-279 inhibits growth of neuroblastoma.

Treatment failure in high risk neuroblastoma (NB) is largely due to the development of chemotherapy resistance. We analyzed the gene expression changes associated with exposure to chemotherapy in six high risk NB tumors with the aid of the Connectivity Map bioinformatics platform. Ten therapeutic agents were predicted to have a high probability of reversing the transcriptome changes associated with neoadjuvant chemotherapy treatment. Among these agents, initial screening showed the EWS-FLI1 and RNA helicase A interaction inhibitor YK-4-279, had obvious cytotoxic effects on NB cell lines. Using a panel of NB cell lines, including MYCN nonamplified (SK-N-AS, SH-SY5Y, and CHLA-255), and MYCN amplified (NB-19, NGP, and IMR-32) cell lines, we found that YK-4-279 had cytotoxic effects on all lines tested. In addition, YK-4-279 also inhibited cell proliferation and anchorage-independent growth and induced cell apoptosis of these cells. YK-4-279 enhanced the cytotoxic effect of doxorubicin (Dox). Moreover, YK-4-279 was able to overcome the established chemoresistance of LA-N-6 NB cells. In an orthotopic xenograft NB mouse model, YK-4-279 inhibited NB tumor growth and induced apoptosis in tumor cells through PARP and Caspase 3 cleavage in vivo. While EWS-FLI1 fusion protein is not frequently found in NB, using the R2 public database of neuroblastoma outcome and gene expression, we found that high expression of EWSR1 was associated with poor patient outcome. Knockdown of EWSR1 inhibited the oncogenic potential of neuroblastoma cell lines. Taken together, our results indicate that YK-4-279 might be a promising agent for treatment of NB that merits further exploration.

The optimal timing of surgical resection in high-risk neuroblastoma.

BACKGROUND: While most high-risk neuroblastoma (HRNB) patients are enrolled in cooperative group or institutional protocols, variability exists within these protocols as to when surgical resection of the primary tumor should be performed after neoadjuvant induction chemotherapy. We sought to determine if the number of chemotherapy cycles prior to surgery affects surgical or survival outcomes in HRNB patients. METHODS: We performed a retrospective review of all HRNB patients <18years of age from 2000 to 2010, at Texas Children's Hospital. Patients were stratified based on the number of neoadjuvant induction chemotherapy cycles prior to surgical resection. Pre and post- chemotherapy tumor size, MYCN status, iodine-131-metaiodobenzylguanidine (MIBG) score at diagnosis, extent of surgical resection, estimated surgical blood loss, post-operative outcomes, and event free (EFS) and overall survival (OS) were evaluated. Data were analyzed using Wilcoxon rank-sum test, Kruskal-Wallis test, Fisher's exact test, Kaplan-Meier analyses, and Cox regression analyses. P-value <0.05 was considered significant. RESULTS: Data from 50 patients with HRNB were analyzed. Patients were stratified by the number of cycles of chemotherapy received prior to surgery. Six patients received 2cycles of chemotherapy (12%), 20 patients received 3cycles (40%), 13 patients received 4cycles (26%), and 11 patients received 5cycles (22%) prior to surgical resection of the primary tumor. The 5-year OS was 33%, 45%, 83% and 36% in patients who received 2, 3, 4 and 5cycles of chemotherapy prior to surgery, respectively (p=0.07). Multivariate analysis revealed that patients who received 4cycles of chemotherapy had a significantly lower mortality (HR: 0.11, 95% CI: 0.01-0.87, p=0.04) compared to those with 2cycles of chemotherapy. Among the different cohorts, there were no differences with respect to MYCN status, MIBG score at diagnosis, incidence of bone marrow metastasis, extent of surgical resection, estimated blood loss, incidence of post-operative complications, or length of stay. CONCLUSION: HRNB patients who receive 4cycles of chemotherapy prior to surgical resection have a superior OS than patients who receive 2. Based on the superior survival of patients who received 4cycles of chemotherapy prior to surgery, further studies are warranted to elucidate these differences.

Assessment of Primary Site Response in Children With High-Risk Neuroblastoma: An International Multicenter Study.

PURPOSE: The International Neuroblastoma Response Criteria (INRC) require serial measurements of primary tumors in three dimensions, whereas the Response Evaluation Criteria in Solid Tumors (RECIST) require measurement in one dimension. This study was conducted to identify the preferred method of primary tumor response assessment for use in revised INRC. PATIENTS AND METHODS: Patients younger than 20 years with high-risk neuroblastoma were eligible if they were diagnosed between 2000 and 2012 and if three primary tumor measurements (antero-posterior, width, cranio-caudal) were recorded at least twice before resection. Responses were defined as ≥ 30% reduction in longest dimension as per RECIST, ≥ 50% reduction in volume as per INRC, or ≥ 65% reduction in volume. RESULTS: Three-year event-free survival for all patients (N = 229) was 44% and overall survival was 58%. The sensitivity of both volume response measures (ability to detect responses in patients who survived) exceeded the sensitivity of the single dimension measure, but the specificity of all response measures (ability to identify lack of response in patients who later died) was low. In multivariable analyses, none of the response measures studied was predictive of outcome, and none was predictive of the extent of resection. CONCLUSION: None of the methods of primary tumor response assessment was predictive of outcome. Measurement of three dimensions followed by calculation of resultant volume is more complex than measurement of a single dimension. Primary tumor response in children with high-risk neuroblastoma should therefore be evaluated in accordance with RECIST criteria, using the single longest dimension.

Primary malignant pulmonary tumors in children: a review of the national cancer data base.

BACKGROUND: The purpose is to delineate the clinical and pathological characteristics of rare primary malignant pulmonary tumors in children. METHODS: Utilizing the National Cancer Data Base (NCDB), we analyzed all children (≤ 18 years) with a primary malignant pulmonary tumor from 1998 to 2011 to identify factors associated with better survival. RESULTS: Of 211 children identified, the most common histology was carcinoid tumor (n=133, 63%) followed by mucoepidermoid carcinoma (MEC) (n=37, 18%), squamous cell carcinoma (SCC) (n=19, 9%), adenocarcinoma (n=16, 8%), bronchoalveolar carcinoma (BAC) (n=4, 2%), and small cell carcinoma (SCLC) (n=2, <1%). Factors that significantly affected survival include histology, race, tumor size, lymph node status, and extent of surgery. Patients with MEC and carcinoid tumors had a better overall survival compared to patients with other histologies (p<0.0001). The 5-year overall survival for MEC and carcinoid tumors was 100% and 95% (95% CI 87-98), respectively, versus 50% (95%CI 1-91) for BAC, 28% (95%CI 9-52) for SCC, and 26% (95%CI 5-55) for adenocarcinoma. CONCLUSION: The majority of pediatric patients with a primary malignant pulmonary tumor present with carcinoid tumor or MEC and have an excellent prognosis. Lung cancers which are common in adults, but rare in children, have a worse prognosis.

Focal nodular hyperplasia in children: an institutional experience with review of the literature.

BACKGROUND: Focal nodular hyperplasia (FNH) is uncommonly diagnosed in pediatric patients and may be difficult to distinguish from a malignancy. We present a review of all children with a tissue diagnosis of FNH at our institution, describe the diagnostic modalities, and provide recommendations for diagnosis and follow-up based on our experience and review of the literature. METHODS: A retrospective review of children <18years of age diagnosed with FNH at a single institution was performed from 2000 to 2013. RESULTS: Twelve patients were identified with a tissue diagnosis of FNH. Two patients required surgical resection of their lesion owing to concern for malignancy. Ten patients were managed expectantly with imaging surveillance after biopsy confirmed a diagnosis of FNH. All patients who underwent MRI had very typical findings including hypointensity on T1 weighted sequences, hyperintensity on T2, and homogenous uptake of contrast on the arterial phase. On follow-up all patients had either a stable lesion or reduction in size. CONCLUSIONS: Focal nodular hyperplasia presents typically in children with liver disease, have undergone chemotherapy, and adolescent females. Young children, particularly <5years of age, without underlying liver disease or history of chemotherapy can pose a diagnostic dilemma. In this unique subgroup of children with FNH, MRI and/or needle biopsy should be adequate diagnostic modalities for these lesions.

Extrarenal Wilms tumor: a case report and review of the literature.

Extrarenal Wilms tumors are extremely rare with only isolated case reports in the pediatric literature. We present the case of a 2-year old boy who presented with a large abdominal mass and constipation. Pathologic diagnosis of the tumor was extrarenal Wilms tumor (ERWT) with favorable histology. We discuss the diagnostic workup, radiologic and operative findings, treatment and review of the literature.

Burns: an update on current pharmacotherapy.

INTRODUCTION: The worldwide occurrence of burn injuries remains high despite efforts to reduce injury incidence through public awareness campaigns and improvements in living conditions. In 2004, almost 11 million people experienced burns severe enough to warrant medical treatment. Advances over the past several decades in aggressive resuscitation, nutrition, excision and grafting have reduced morbidity and mortality. Incorporation of pharmacotherapeutics into treatment regimens may further reduce complications of severe burn injuries. AREAS COVERED: Severe burn injuries, as well as other forms of stress and trauma, trigger a hypermetabolic response that, if left untreated, impedes recovery. In the past two decades, use of anabolic agents, ß-adrenergic receptor antagonists and anti-hyperglycemic agents has successfully counteracted post-burn morbidities including catabolism, the catecholamine-mediated response and insulin resistance. Here, the authors review the most up-to-date information on currently used pharmacotherapies in the treatment of these sequelae of severe burns and the insights that have expanded the understanding of the pathophysiology of severe burns. EXPERT OPINION: Existing drugs offer promising advances in the care of burn injuries. Continued gains in the understanding of the molecular mechanisms driving the hypermetabolic response will enable the application of additional existing drugs to be broadened to further attenuate the hypermetabolic response.

Primary malignant pancreatic neoplasms in children and adolescents: a 20 year experience.

BACKGROUND: Malignant pancreatic neoplasms in children and adolescents are rare. The clinical presentation, pathologic characteristics, management, and outcomes at two institutions are discussed. METHODS: We retrospectively reviewed all pediatric patients (age <= 18 years) treated for malignant pancreatic neoplasms at two institutions between 1991 and 2011. RESULTS: Thirty-one patients were identified with median age of 14.7 years (4-18 years). The most common histology was solid pseudopapillary tumor (SPT) (n=22, 71%) followed by neuroendocrine tumors (n=4, 13%), pancreatoblastoma (n=4, 13%), and one unclassified spindle cell neoplasm (3%). Most patients presented with abdominal pain (n=22, 71%). Complications included pancreatic leak, pseudocyst formation, pancreatitis, pancreatic insufficiency, and small bowel obstruction. The overall 1- and 5-year survival was 96% (95% CI 74%-99%) and 78% (95% CI 43%-93%). Median follow-up among patients alive at the end of follow-up was 20 months (<1 month-16.2 years). Patients with SPT had better overall survival compared to patients with neuroendocrine tumors or pancreatoblastomas (Log-rank; p=0.0143). CONCLUSION: The majority of pediatric and adolescent patients present with SPTs which are usually resectable and associated with an excellent prognosis. Other histologic subtypes more often present with distant metastases and portend a worse prognosis.