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Journal of Pediatric Surgery 11/2012; 47(11):2163-5. · 1.45 Impact Factor
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Saif F Hassan,
Shawn Mathur,
Thomas J Magliaro,
Emily L Larimer,
Lauren B Ferrell,
Sanjeev A Vasudevan,
Danielle M Patterson,
Chrystal U Louis,
Heidi V Russell,
Jed G Nuchtern, Eugene S Kim
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ABSTRACT: Open biopsy has been the mainstay for definitive diagnosis of neuroblastoma in pediatric patients. However, needle core biopsy may represent a faster, less invasive, and safer alternative to open biopsy in children. The purpose of this study was to compare safety and efficacy between needle core and open biopsy in the diagnosis of patients with intermediate- and high-risk neuroblastoma at our institution.
We retrospectively reviewed the medical records of children with intermediate- and high-risk neuroblastoma who underwent open or needle core biopsies from 2002 to 2010. Data collected included patient demographics, tumor size, sample adequacy for diagnosis and risk stratification (histology and cytogenetics), length of hospital stay, time to initiate chemotherapy after biopsy, need for repeat biopsy, and both intraoperative and postoperative complications. Mann-Whitney U and Fisher's exact tests were used for statistical analysis.
During the study period, 7 patients underwent needle core primary biopsies (5 intermediate-risk primary tumors and 2 high-risk primary tumors), and 4 patients underwent needle core biopsy for metastatic tumors, whereas 21 patients had open biopsies (10, intermediate risk; 11, high risk). Median age at biopsy and median tumor size were similar in both groups. There was no significant difference in adequacy of biopsy, need for repeat biopsy, time to initiate chemotherapy, length of stay, or minor complications. The rate of major complications differed significantly between the 2 groups with 0% after needle core biopsy vs 48% after open biopsy (P = .027).
In children, needle core biopsy is comparable in efficacy with open biopsy in the diagnosis of intermediate- and high-risk neuroblastoma with significantly lower rates of major postoperative complications. These findings warrant a larger scale evaluation of diagnostic needle core biopsies in pediatric patients with solid tumor.
Journal of Pediatric Surgery 06/2012; 47(6):1261-6. · 1.45 Impact Factor
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ABSTRACT: Congenital long QT syndrome (LQTS) is a rare genetic ion transmembrane disorder that has been associated with multiple various genetic mutations including life-threatening cardiac arrhythmias and sudden death. Left thorascopic sympathectomy is an effective treatment for patients who are refractory to medical therapy or who need frequent epicardial internal cardiodefibrillator intervention. Although there is substantial literature about this therapy in adults, few reports detail the outcomes in children who undergo left thorascopic sympathectomies to treat LQTS. The authors report the successful use of a left thoracic sympathectomy for the treatment of an 11-year-old girl who had persistently symptomatic LQTS, even after implantation of an automatic cardioverter-defibrillator. The patient remained clinically stable without arrhythmias through 6 months' of follow-up. The authors also reviewed the relevant literature and found that it suggests that 77% of patients will have immediate resolution of their symptoms/arrhythmias after the procedure. When the outcome definition was broadened to include patients who had only 1 or 2 cardiac episodes in the follow-up period, 88% of cases were considered successful. The results of this case study and literature review suggest that left thorascopic sympathectomy is a safe and effective approach for treating pediatric patients with LQTS.
Journal of Neurosurgery Pediatrics 11/2011; 8(5):455-9. · 1.53 Impact Factor
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Jason M Shohet,
Rajib Ghosh,
Cristian Coarfa,
Andrew Ludwig,
Ashley L Benham,
Zaowen Chen,
Danielle M Patterson,
Eveline Barbieri,
Pieter Mestdagh,
Denae N Sikorski,
Aleksandar Milosavljevic, Eugene S Kim,
Preethi H Gunaratne
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ABSTRACT: MYCN is a major driver of neuroblastoma tumorigenesis and MYCN amplification is the worst prognostic indicator of aggressive NB. To identify potentially therapeutic tumor suppressor microRNAs for aggressive NB, we utilized a conditional MYCN system to simulate MYCN-amplified and nonamplified tumor types and performed a genome-wide search for MYCN target microRNA promoters differentially repressed under high MYCN conditions. We identified 20 gene promoters hosting 30 microRNAs that were directly bound and differentially regulated by MYCN. Eleven of these genes showed significant clinical correlations for neuroblastoma with 4 genes linked with better survival and 7 genes linked with poor survival. Surprisingly, expression analysis of host genes and microRNAs demonstrated that 8 of 11 pairs were repressed by high levels of MYCN regardless of the clinical correlation of the host gene. We therefore predicted these intronic microRNAs would be tumor suppressors. In fact, detailed gain of function studies for two miRs, miR-591 and miR-558, confirmed potent tumor suppressive effects for miR-591 in orthotopic neuroblastoma xenografts. However, miR-558 markedly increased colony formation, proliferation, and tumor growth in vivo. Our data reveal host-gene independent functions of MYCN-target microRNAs and demonstrate that MYCN represses both tumor suppressive and proproliferative microRNAs.
Cancer Research 06/2011; 71(11):3841-51. · 7.86 Impact Factor
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Danielle M Patterson,
Dongbing Gao,
Denae N Trahan,
Brett A Johnson,
Andrew Ludwig,
Eveline Barbieri,
Zaowen Chen,
Jose Diaz-Miron,
Lyubomir Vassilev,
Jason M Shohet, Eugene S Kim
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ABSTRACT: Neuroblastoma is the most common pediatric abdominal tumor and principally a p53 wild-type, highly vascular, aggressive tumor, with limited response to anti-VEGF therapies alone. MDM2 is a key inhibitor of p53 and a positive activator of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) activity with an important role in neuroblastoma pathogenesis. We hypothesized that concurrent inhibition of both MDM2 and VEGF signaling would have cooperative anti-tumor effects, potentiating anti-angiogenic strategies for neuroblastoma and other p53 wild-type tumors. We orthotopically implanted SH-SY5Y neuroblastoma cells into nude mice (n = 40) and treated as follows: control, bevacizumab, Nutlin-3a, combination of bevacizumab plus Nutlin-3a. Expression of HIF-1α and VEGF were measured by qPCR, Western blot, and ELISA. Tumor apoptosis was measured by immunohistochemistry and caspase assay. Angiogenesis was evaluated by immunohistochemistry for vascular markers (CD-31, type-IV collagen, αSMA). Both angiogenesis and metastatic burden were digitally quantified. In vitro, Nutlin-3a suppresses HIF-1α expression with subsequent downregulation of VEGF. Bevacizumab plus Nutlin-3a leads to significant suppression of tumor growth compared to control (P < 0.01) or either agent alone. Combination treated xenograft tumors display a marked decrease in endothelial cells (P < 0.0001), perivascular basement membrane (P < 0.04), and vascular mural cells (P < 0.004). Nutlin-3a alone and in combination with bevacizumab leads to significant tumor apoptosis (P < 0.0001 for both) and significant decrease in incidence of metastasis (P < 0.05) and metastatic burden (P < 0.03). Bevacizumab plus Nutlin-3a cooperatively inhibits tumor growth and angiogenesis in neuroblastoma in vivo with dramatic effects on tumor vascularity. Concomitantly targeting VEGF and p53 pathways potently suppresses tumor growth, and these results support further clinical development of this approach.
Angiogenesis 04/2011; 14(3):255-66. · 6.06 Impact Factor
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ABSTRACT: Anastomotic leak after tracheoesophageal fistula repair is a well-known complication and can represent a challenging clinical scenario. We present the case of an infant girl with VACTERL syndrome who underwent repair of a type C esophageal atresia and tracheoesophageal fistula repair, which was complicated by an anastomotic leak. Glycopyrrolate (Robinul), an anticholinergic agent, was successfully used to decrease copious salivary secretion and promote spontaneous closure of the leak. This report represents the first description in the medical literature of the use of glycopyrrolate in the treatment of an esophageal anastomotic leak. Glycopyrrolate may be a useful adjunct in the management of anastomotic leak after tracheoesophageal repair.
Journal of Pediatric Surgery 03/2011; 46(3):e29-32. · 1.45 Impact Factor
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ABSTRACT: Neuroblastoma is the most common pediatric abdominal solid tumor. This aggressive embryonal malignancy of neural crest origin has a peak age of onset of 22 months, and accounts for ~11% of all pediatric cancers and 15% of all pediatric cancer deaths. With current treatment protocols, including high-dose chemotherapy with autologous stem cell transplantation, radiation, and surgery, ~80% of high-risk patients go into remission, although the majority relapse and succumb to therapy-resistant tumors. Long-term survival rates (>5 years) are <50%. Mouse models of neuroblastoma provide clinically relevant tools for studying the growth and metastasis of this aggressive malignancy, and for testing the efficacy of potentially novel therapeutics in vivo. This unit describes an orthotopic murine model of neuroblastoma using cultured human cells that closely mimics the clinical condition in terms of the bulky intra-abdominal tumors and other aspects of metastatic disease. Also described are methods for in vivo imaging and monitoring of tumor growth, and procedures for necropsy and tumor preservation for pathological analysis.
Current protocols in pharmacology 03/2011; Chapter 14:Unit 14.17.
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ABSTRACT: Myofibroblastic tumors are soft-tissue neoplasms arising from myofibroblasts, ubiquitous cells sharing ultrastructural features of muscular and fibroblastic cells. Vasudev and Harris described a malignant counterpart of these benign tumors in 1978. Most reported cases of myofibroblastic sarcoma have arisen in the head and neck region and the soft tissues of the extremities. To the best of the authors' knowledge, there have been only 8 previous reports on primary myofibroblastic sarcoma of the bone. The authors report a new case of this rare tumor affecting the sacrum and ilium of a 15-year-old girl and discuss the role of total sacrectomy and lumbopelvic reconstruction for treatment of this disease.
Journal of Neurosurgery Pediatrics 09/2010; 6(3):286-90. · 1.53 Impact Factor
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Sanjeev A Vasudevan,
Xiaoying Shang,
Xiaoyi Shang,
Shirong Chang,
Ningling Ge,
Jose L Diaz-Miron,
Heidi V Russell,
M John Hicks,
Andrew D Ludwig,
Catherine L Wesson,
Susan M Burlingame, Eugene S Kim,
Javed Khan,
Jianhua Yang,
Jed G Nuchtern
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ABSTRACT: Secreted proteins such as growth factors, cytokines, and chemokines play important roles in tumor development. Through expression microarray and bioinformatic analysis, we discovered a novel secreted protein, neuroblastoma-derived secretory protein (NDSP). The NDSP gene is found on chromosome 1q25.2 and encodes a 167 amino acid protein with a putative signal peptide. Using real-time PCR and immunoblotting, we find that NDSP is specifically overexpressed in neuroblastoma at much higher levels than other adult and pediatric malignancies and normal tissues. NDSP is an 18-kDa protein that can be secreted by NDSP-transfected HEK-293T cells, as well as, neuroblastoma cell lines endogenously expressing NDSP. Inhibiting NDSP expression in neuroblastoma cell lines with retrovirally transduced NDSP small hairpin interfering RNA, sh-NDSP, results in decreased cellular proliferation and colony formation. We also find inhibited extracellular signal-regulated kinase (ERK)1/2 phosphorylation in the sh-NDSP cell line. Treating the parental cell line with MAP/ERK kinase 1/2 inhibitors, which diminish ERK1/2 phosphorylation, results in decreased cell proliferation. Culturing these transduced cells with recombinant NDSP, reintroducing NDSP overexpression in the knockdown cell line, or inducing Ras oncogene overexpression for constitutive ERK1/2 activation results in a reversal of the growth-inhibited phenotype and proliferation rates similar to the control cells. In addition, reintroduction of NDSP overexpression in the sh-NDSP cell line results in ERK1/2 phosphorylation similar to control. We conclude that NDSP is specifically overexpressed in neuroblastoma and actively secreted from tumor cells. Furthermore, NDSP serves as a growth factor for neuroblastoma tumor cells through activation of the ERK-mediated proliferation pathway.
Molecular Cancer Therapeutics 09/2009; 8(8):2478-89. · 5.23 Impact Factor
