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Find video protocols related to scientific articles indexed in Pubmed.
Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B.
N. Engl. J. Med.
PUBLISHED: 11-20-2014
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Background In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. Methods We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×10(12) vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. Results A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. Conclusions In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238 .).
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Clinical Outcomes of Splenectomy in Children: Report of the Splenectomy in Congenital Hemolytic Anemia (SICHA) Registry.
Am. J. Hematol.
PUBLISHED: 10-28-2014
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The outcomes of children with congenital hemolytic anemia (CHA) undergoing total splenectomy (TS) or partial splenectomy (PS) remain unclear. In this study, we collected data from 100 children with CHA who underwent TS or PS from 2005-2013 at 16 sites in the Splenectomy in Congenital Hemolytic Anemia (SICHA) consortium using a patient registry. We analyzed demographics and baseline clinical status, operative details, and outcomes at 4, 24, and 52 weeks after surgery. Results were summarized as hematologic outcomes, short-term adverse events (AEs) (? 30 days after surgery), and long-term AEs (31-365 days after surgery). For children with hereditary spherocytosis, after surgery there was an increase in hemoglobin (baseline 10.1 ± 1.8 gm/dl, 52 week 12.8 ± 1.6 gm/dl; mean ± SD), decrease in reticulocyte and bilirubin as well as control of symptoms. Children with sickle cell disease had control of clinical symptoms after surgery, but had no change in hematologic parameters. There was an 11% rate of short-term AEs and 11% rate of long-term AEs. As we accumulate more subjects and longer follow-up, use of a patient registry should enhance our capacity for clinical trials and engage all stakeholders in the decision-making process.
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MicroRNA-21 promotes glioblastoma tumorigenesis by down-regulating insulin-like growth factor-binding protein-3 (IGFBP3).
J. Biol. Chem.
PUBLISHED: 07-24-2014
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Despite advances in surgery, imaging, chemotherapy, and radiation, patients with glioblastoma multiforme (GBM), the most common histological subtype of glioma, have an especially dismal prognosis; >70% of GBM patients die within 2 years of diagnosis. In many human cancers, the microRNA miR-21 is overexpressed, and accumulating evidence indicates that it functions as an oncogene. Here, we report that miR-21 is overexpressed in human GBM cell lines and tumor tissue. Moreover, miR-21 expression in GBM patient samples is inversely correlated with patient survival. Knockdown of miR-21 in GBM cells inhibited cell proliferation in vitro and markedly inhibited tumor formation in vivo. A number of known miR-21 targets have been identified previously. By microarray analysis, we identified and validated insulin-like growth factor (IGF)-binding protein-3 (IGFBP3) as a novel miR-21 target gene. Overexpression of IGFBP3 in glioma cells inhibited cell proliferation in vitro and inhibited tumor formation of glioma xenografts in vivo. The critical role that IGFBP3 plays in miR-21-mediated actions was demonstrated by a rescue experiment, in which IGFBP3 knockdown in miR-21KD glioblastoma cells restored tumorigenesis. Examination of tumors from GBM patients showed that there was an inverse relationship between IGFBP3 and miR-21 expression and that increased IGFBP3 expression correlated with better patient survival. Our results identify IGFBP3 as a novel miR-21 target gene in glioblastoma and suggest that the oncogenic miRNA miR-21 down-regulates the expression of IGFBP3, which acts as a tumor suppressor in human glioblastoma.
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The role of FDG-PET/CT in the evaluation of residual disease in paediatric non-Hodgkin lymphoma.
Br. J. Haematol.
PUBLISHED: 07-07-2014
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(18) F-labelled-fluorodeoxyglucose positron emission tomography (FDG-PET) findings are challenging to interpret for residual disease versus complete response in paediatric patients with non-Hodgkin lymphoma (NHL). A biopsy is often warranted to confirm the presence or absence of viable tumour if there is clinical or radiographic evidence of residual disease. In this study, we compared conventional imaging and FDG-PET/computerized tomography (CT) findings with biopsy results in 18 children with NHL. Our goal was to provide additional data to establish more reliable criteria for response evaluation. Residual disease was suspected after conventional imaging alone in eight patients, after FDG-PET/CT alone in three and after both modalities in seven patients. Biopsy confirmed the presence of viable tumour in two patients. Two additional patients experienced progressive disease or relapse. The sensitivity and negative predictive value of FDG-PET/CT using the London criteria to indicate residual tumour detectable by biopsy were 100%, but specificity was low (60%), as was the positive predictive value (25%). Thus, in this study, a negative FDG-PET/CT finding was a good indicator of complete remission. However, because false-positive FDG-PET/CT findings are common, biopsy and close monitoring are required for accurate determination of residual disease in individual patients.
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Double small bowel intussusception complicating bilateral partial nephrectomies.
J Pediatr Surg Case Rep
PUBLISHED: 05-06-2014
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An 11.5-month-old male, diagnosed with bilateral Wilms tumor at 10 months of age, received 6 weeks of chemotherapy and subsequently underwent bilateral partial nephrectomies. On postoperative day 5, he had crampy abdominal pain and bilious vomiting. Abdominal ultrasound confirmed the presence of an intussusception in the right lower quadrant. Laparotomy demonstrated two separate areas of small intestinal intussusception located at jejuno-jejunal and ileo-ileal locations. The patient was successfully treated with manual reduction. A high index of suspicion is necessary to diagnose and treat patients with two different points of intussusception.
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Long-term pulmonary function after metastasectomy for childhood osteosarcoma: a report from the St Jude lifetime cohort study.
J. Am. Coll. Surg.
PUBLISHED: 03-04-2014
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Complete resection of lung metastases improves survival in patients with osteosarcoma. We evaluated the long-term effect of metastasectomy on pulmonary function of patients treated for osteosarcoma during childhood.
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Seven In Absentia Homolog 2 (SIAH2) downregulation is associated with tamoxifen resistance in MCF-7 breast cancer cells.
J. Surg. Res.
PUBLISHED: 02-07-2014
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A significant percentage of estrogen receptor (ER)-positive breast cancers are resistant to tamoxifen therapy. Seven in Absentia Homolog 2 (SIAH2), an E3 ubiquitin protein ligase, has been shown to be associated with resistance to antiestrogens. We sought to assess its role in the resistance of a breast cancer cell line, MCF-7, to the ER antagonist, tamoxifen.
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Repeat nephron-sparing surgery for children with bilateral Wilms tumor.
J. Pediatr. Surg.
PUBLISHED: 01-21-2014
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Renal insufficiency is a significant complication of Wilms tumor treatment in the 5% with bilateral disease. Nephron-sparing surgery (NSS) is recommended after neoadjuvant chemotherapy initially. However, the role of NSS in recurrent disease is unknown. We reviewed our experience to assess the feasibility and oncologic and functional outcomes of repeat NSS for children with recurrent disease.
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Progress towards gene therapy for haemophilia B.
Int. J. Hematol.
PUBLISHED: 01-03-2014
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Haemophilia B is an X-linked recessive bleeding disorder, arising from a deficiency of coagulation factor IX. It has been a target for gene therapy ever since the factor IX gene was cloned in 1982. Several distinct approaches have been evaluated in humans over the last 30 years, but none has resulted in tangible corrections of the bleeding phenotype in humans until recently. Our group has now shown that lasting clinical improvement of the bleeding phenotype in patients with haemophilia B is possible following a single systemic administration of a self-complementary adeno-associated virus vector to deliver an optimised factor IX expression cassette to the liver. Success in this trial raises hope for patients with severe haemophilia B as well as others with inherited monogenetic disorders of the liver where current treatment options are limited.
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T Lymphocytes Expressing a CD16 Signaling Receptor Exert Antibody-Dependent Cancer Cell Killing.
Cancer Res.
PUBLISHED: 11-06-2013
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To expand applications for T-cell-based immunotherapy in cancer, we designed a receptor that binds the Fc portion of human immunoglobulins and delivers activation signals. The construct included the high-affinity CD16 (FCGR3A) V158 variant, CD8? hinge, and transmembrane domains, along with signaling domains from CD3? and 4-1BB (TNFRSF9), forming a chimeric receptor termed CD16V-BB-?. After retrovirus-mediated expression in human T cells, CD16V-BB-? bound humanized antibodies with higher affinity than a control receptor containing the more common F158 variant. Engagement of CD16V-BB-? provoked T-cell activation, exocytosis of lytic granules, and sustained proliferation, with a mean cell recovery after 4-week coculture with Daudi lymphoma cells and rituximab of nearly 70-fold relative to input cells. In contrast, unbound antibody alone produced no effect. CD16V-BB-? T cells specifically killed lymphoma cells and primary chronic lymphocytic leukemia cells in combination with rituximab at a low effector:target ratio, even when assayed on mesenchymal cells. Trastuzumab triggered CD16V-BB-?-mediated killing of HER2 (ERBB2)(+) breast and gastric cancer cells; similar results were obtained with an anti-GD2 antibody in neuroblastoma and osteosarcoma cells. Furthermore, coadministration of CD16V-BB-? T cells with immunotherapeutic antibodies exerted considerable antitumor activity in vivo. Signaling mediated by 4-1BB-CD3? induced higher T-cell activation, proliferation, and cytotoxicity than CD3? or Fc?RI?, and the receptor was expressed effectively after mRNA electroporation without viral vectors, facilitating clinical translation. Our results offer preclinical proof of concept for CD16V-BB-? as a universal, next-generation chimeric receptor with the potential to augment the efficacy of antibody therapies for cancer. Cancer Res; 74(1); 1-11. ©2013 AACR.
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Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor ?B signaling in glioblastoma cancer stem cells regulates the Notch pathway.
J. Biol. Chem.
PUBLISHED: 07-31-2013
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Malignant gliomas are locally aggressive, highly vascular tumors that have a dismal prognosis, and present therapies provide little improvement in the disease course and outcome. Many types of malignancies, including glioblastoma, originate from a population of cancer stem cells (CSCs) that are able to initiate and maintain tumors. Although CSCs only represent a small fraction of cells within a tumor, their high tumor-initiating capacity and therapeutic resistance drives tumorigenesis. Therefore, it is imperative to identify pathways associated with CSCs to devise strategies to selectively target them. In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-?B signaling. Glioma CSCs were isolated and maintained in vitro using an adherent culture system, and the biological properties were compared with the traditional cultures of CSCs grown as multicellular spheres under nonadherent culture conditions. Interestingly, both adherent and spheroid glioma CSCs show constitutive activation of the STAT3/NF-?B signaling pathway and up-regulation of STAT3- and NF-?B-dependent genes. Gene expression profiling also identified components of the Notch pathway as being deregulated in glioma CSCs, and the deregulated expression of these genes was sensitive to treatment with STAT3 and NF-?B inhibitors. This finding is particularly important because Notch signaling appears to play a key role in CSCs in a variety of cancers and controls cell fate determination, survival, proliferation, and the maintenance of stem cells. The constitutive activation of STAT3 and NF-?B signaling pathways that leads to the regulation of Notch pathway genes in glioma CSCs identifies novel therapeutic targets for the treatment of glioma.
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Clinical management of infantile fibrosarcoma: a retrospective single-institution review.
Pediatr. Surg. Int.
PUBLISHED: 05-14-2013
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Infantile fibrosarcoma (IFS) is an uncommon soft-tissue sarcoma. Here we review our experience treating this tumor.
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Targeting oxidative stress in embryonal rhabdomyosarcoma.
Cancer Cell
PUBLISHED: 05-03-2013
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Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.
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Is adrenalectomy necessary during unilateral nephrectomy for Wilms Tumor? A report from the Childrens Oncology Group.
J. Pediatr. Surg.
PUBLISHED: 04-26-2013
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To determine whether performing adrenalectomy at the time of nephrectomy for unilateral Wilms tumor impacts clinical outcome.
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Thoracoscopic resection of computed tomography-localized lung nodules in children.
J. Pediatr. Surg.
PUBLISHED: 04-16-2013
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Detection and treatment of small lung nodules are important in managing pediatric cancer. We studied the effectiveness of preoperative localization of pulmonary nodules by CT-guided needle hook wire placement followed by thoracoscopic resection in children with cancer.
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Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma.
Clin. Cancer Res.
PUBLISHED: 03-27-2013
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Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG.
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Surgical treatment of pediatric desmoid tumors. A 12-year, single-center experience.
Ann. Surg. Oncol.
PUBLISHED: 03-04-2013
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Pediatric desmoid tumors (PDTs) represent a group of rare, distinct lesions. While sparse, available literature suggests that PDT are particularly aggressive and difficult to control when compared with their adult counterpart.
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Ex vivo activation of CD56(+) immune cells that eradicate neuroblastoma.
Cancer Res.
PUBLISHED: 02-25-2013
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Despite the use of intensive contemporary multimodal therapy, the overall survival of patients with high-risk neuroblastoma is still less than 50%. Therefore, immunotherapy without cross-resistance and overlapping toxicity has been proposed. In this study, we report the development of a novel strategy to specifically activate and expand human CD56(+) (NCAM1) natural killer (NK) immune cells from normal donors and patients with neuroblastoma. Enriched CD56(+) cells from peripheral blood were mixed with CD56(-) fraction at 1:1 ratio and cultured in the presence of OKT3, interleukin (IL)-2, and -15 for five days and then without OKT3 for 16 more days. The final products contained more than 90% CD56(+) cells and could kill neuroblastoma cells effectively that were originally highly resistant to nonprocessed NK cells. Mechanistically, cytolysis of neuroblastoma was mediated through natural cytotoxicity receptor (NCR), DNAX accessory molecule-1 (DNAM-1; CD226), perforin, and granzyme B. Successful clinical scale-up in a good manufacturing practices (GMP)-compliant bioreactor yielded effector cells that in a neuroblastoma xenograft model slowed tumor growth and extended survival without GVHD. Investigation of CD56(+) cells from patients with neuroblastoma revealed a similar postactivation phenotype and lytic activity. Our findings establish a novel and clinically expedient strategy to generate allogeneic or autologous CD56(+) cells that are highly cytotoxic against neuroblastoma with minimal risk of GVHD.
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Imaging analysis of hepatoblastoma resectability across neoadjuvant chemotherapy.
J. Pediatr. Surg.
PUBLISHED: 02-22-2013
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Hepatoblastomas often require neoadjuvant chemotherapy to facilitate partial hepatectomy, which necessitates freedom of tumor borders from the confluence of hepatic veins (COHV), portal vein bifurcation (PVB), and retrohepatic inferior vena cava (IVC). This study aimed to clarify the effect of incremental neoadjuvant cycles on the AHEP0731 protocol criteria of hepatoblastoma resectability.
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Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant.
Blood
PUBLISHED: 02-20-2013
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Recombinant adeno-associated virus (rAAV) vectors encoding human factor VIII (hFVIII) were systematically evaluated for hemophilia A (HA) gene therapy. A 5.7-kb rAAV-expression cassette (rAAV-HLP-codop-hFVIII-N6) containing a codon-optimized hFVIII cDNA in which a 226 amino acid (aa) B-domain spacer replaced the entire B domain and a hybrid liver-specific promoter (HLP) mediated 10-fold higher hFVIII levels in mice compared with non-codon-optimized variants. A further twofold improvement in potency was achieved by replacing the 226-aa N6 spacer with a novel 17-aa peptide (V3) in which 6 glycosylation triplets from the B domain were juxtaposed. The resulting 5.2-kb rAAV-HLP-codop-hFVIII-V3 cassette was more efficiently packaged within AAV virions and mediated supraphysiologic hFVIII expression (732 ± 162% of normal) in HA knock-out mice following administration of 2 × 10(12) vector genomes/kg, a vector dose shown to be safe in subjects with hemophilia B. Stable hFVIII expression at 15 ± 4% of normal was observed at this dose in a nonhuman primate. hFVIII expression above 100% was observed in 3 macaques that received a higher dose of either this vector or the N6 variant. These animals developed neutralizing anti-FVIII antibodies that were abrogated with transient immunosuppression. Therefore, rAAV-HLP-codop-hFVIII-V3 substantially improves the prospects of effective HA gene therapy.
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Establishment and characterization of the first pediatric adrenocortical carcinoma xenograft model identifies topotecan as a potential chemotherapeutic agent.
Clin. Cancer Res.
PUBLISHED: 02-13-2013
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Pediatric adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy. Conventional chemotherapeutic agents have shown limited utility and are largely ineffective in treating children with advanced ACC. The lack of cell lines and animal models of pediatric ACC has hampered the development of new therapies. Here we report the establishment of the first pediatric ACC xenograft model and the characterization of its sensitivity to selected chemotherapeutic agents.
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Curcumin potentiates rhabdomyosarcoma radiosensitivity by suppressing NF-?B activity.
PLoS ONE
PUBLISHED: 02-07-2013
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Ionizing radiation (IR) is an essential component of therapy for alveolar rhabdomyosarcoma. Nuclear factor-kappaB (NF-??) transcription factors are upregulated by IR and have been implicated in radioresistance. We evaluated the ability of curcumin, a putative NF-?? inhibitor, and cells expressing genetic NF- ?? inhibitors (I?B? and p100 super-repressor constructs) to function as a radiosensitizer. Ionizing radiation induced NF-?? activity in the ARMS cells in vitro in a dose- and time-dependent manner, and upregulated expression of NF-?? target proteins. Pretreatment of the cells with curcumin inhibited radiation-induced NF-?? activity and target protein expression. In vivo, the combination of curcumin and IR had synergistic antitumor activity against Rh30 and Rh41 ARMS xenografts. The greatest effect occurred when tumor-bearing mice were treated with curcumin prior to IR. Immunohistochemistry revealed that combination therapy significantly decreased tumor cell proliferation and endothelial cell count, and increased tumor cell apoptosis. Stable expression of the super-repressor, SR-I?B?, that blocks the classical NF-?B pathway, increased sensitivity to IR, while expression of SR-p100, that blocks the alternative pathway, did not. Our results demonstrate that curcumin can potentiate the antitumor activity of IR in ARMS xenografts by suppressing a classical NF-?? activation pathway induced by ionizing radiation. These data support testing of curcumin as a radiosensitizer for the clinical treatment of alveolar rhabdomyosarcoma. IMPACT OF WORK: The NF-?? protein complex has been linked to radioresistance in several cancers. In this study, we have demonstrated that inhibiting radiation-induced NF-?? activity by either pharmacologic (curcumin) or genetic (SR-I?B?) means significantly enhanced the efficacy of radiation therapy in the treatment of alveolar rhabdomyosarcoma cells and xenografts. These data suggest that preventing the radiation-induced activation of the NF-?? pathway is a promising way to improve the antitumor efficacy of ionizing radiation and warrants clinical trials.
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Margin status and tumor recurrence after nephron-sparing surgery for bilateral Wilms tumor.
J. Pediatr. Surg.
PUBLISHED: 01-31-2013
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Nephron-sparing surgery (NSS) has been advocated for patients with bilateral Wilms tumor (BWT). We sought to determine whether margin status impacted local tumor recurrence.
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Rapamycin increases neuroblastoma xenograft and host stromal derived osteoprotegerin inhibiting osteolytic bone disease in a bone metastasis model.
J. Pediatr. Surg.
PUBLISHED: 01-22-2013
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Osteoprotegerin (OPG) is a decoy receptor for the Receptor of NF-?B (RANK) ligand that can inhibit osteoclastogenesis. Previous studies have suggested that Mammalian Target of Rapamycin (mTOR) inhibition upregulates OPG production. We tested the hypothesis that the mTOR inhibitor rapamycin could inhibit neuroblastoma bone metastases through its action on OPG.
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HIF-1? activation mediates resistance to anti-angiogenic therapy in neuroblastoma xenografts.
J. Pediatr. Surg.
PUBLISHED: 01-22-2013
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The anti-tumor activity of angiogenesis inhibitors is often limited by the development of resistance to these drugs. Here we establish HIF-1? as a major factor in the development of this resistance in neuroblastoma xenografts.
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Developments in the treatment of hemophilia B: focus on emerging gene therapy.
Appl Clin Genet
PUBLISHED: 01-01-2013
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Hemophilia B is a genetic disorder that is characterized by a deficiency of clotting factor IX (FIX) and excessive bleeding. Advanced understanding of the pathophysiology of the disease has led to the development of improved treatment strategies that aim to minimize the acute and long-term complications of the disease. Patients with hemophilia B are ideal candidates for gene therapy, mostly because a small increase in protein production can lead to significantly decreased bleeding diathesis. Although human clotting FIX was cloned and sequenced over 30 years ago, progress toward achieving real success in human clinical trials has been slow, with long-term, therapeutically relevant gene expression only achieved in one trial published in 2011. The history of this extensive research effort has revealed the importance of the interactions between gene therapy vectors and multiple arms of the host immune system at multiple stages of the transduction process. Different viral vector systems each have unique properties that influence their ability to deliver genes to different tissues, and the data generated in several clinical trials testing different vectors for hemophilia have guided our understanding toward development of optimal configurations for treating hemophilia B. The recent clinical success implementing a novel adeno-associated virus vector demonstrated sufficient FIX expression in patients to convert a severe hemophilia phenotype to mild, an achievement which has the potential to profoundly alter the impact of this disease on human society. Continued research should lead to vector designs that result in higher FIX activity at lower vector doses and with reduced host immune responses to the vector and the transgene product.
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AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous hemorrhage.
Blood
PUBLISHED: 12-01-2011
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We explored adeno-associated viral vector (AAV)-mediated gene transfer in the perinatal period in animal models of severe congenital factor VII (FVII) deficiency, a disease associated with early postnatal life-threatening hemorrhage. In young adult mice with plasma FVII < 1% of normal, a single tail vein administration of AAV (1 × 10(13) vector genomes [vg]/kg) resulted in expression of murine FVII at 266% ± 34% of normal for ? 67 days, which mediated protection against fatal hemorrhage and significantly improved survival. Codon optimization of human FVII (hFVIIcoop) improved AAV transgene expression by 37-fold compared with the wild-type hFVII cDNA. In adult macaques, a single peripheral vein injection of 2 × 10(11) vg/kg of the hFVIIcoop AAV vector resulted in therapeutic levels of hFVII expression that were equivalent in males (10.7% ± 3.1%) and females (12.3% ± 0.8%). In utero delivery of this vector in the third trimester to fetal monkeys conferred expression of hFVII at birth of 20.4% ± 3.7%, with a gradual decline to > 1% by 7 weeks. Re-administration of an alternative serotype at 12 months postnatal age increased hFVII levels to 165% ± 6.2% of normal, which remained at therapeutic levels for a further 28 weeks without toxicity. Thus, perinatal AAV-mediated gene transfer shows promise for disorders with onset of pathology early after birth.
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Self-complementary adeno-associated viral vectors for gene therapy of hemophilia B: progress and challenges.
Expert Rev Hematol
PUBLISHED: 09-24-2011
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Therapies currently used for hemophilia involve injection of protein concentrates that are expensive, invasive and associated with side effects such as development of neutralizing antibodies (inhibitors) that diminish therapeutic efficacy. Gene transfer is an attractive alternative to circumvent these issues. However, until now, clinical trials using gene therapy to treat hemophilia have failed to demonstrate sustained efficacy, although a vector based on a self-complementary adeno-associated virus has recently shown promise. This article will briefly outline a novel gene-transfer approach using self-complementary adeno-associated viral vectors using hemophilia B as a target disorder. This approach is currently being evaluated in the clinic. We will provide an overview of the development of self-complementary adeno-associated virus vectors as well as preclinical and clinical data with this vector system.
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Stable human FIX expression after 0.9G intrauterine gene transfer of self-complementary adeno-associated viral vector 5 and 8 in macaques.
Mol. Ther.
PUBLISHED: 05-31-2011
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Intrauterine gene transfer (IUGT) offers ontological advantages including immune naiveté mediating tolerance to the vector and transgenic products, and effecting a cure before development of irreversible pathology. Despite proof-of-principle in rodent models, expression efficacy with a therapeutic transgene has yet to be demonstrated in a preclinical nonhuman primate (NHP) model. We aimed to determine the efficacy of human Factor IX (hFIX) expression after adeno-associated-viral (AAV)-mediated IUGT in NHP. We injected 1.0-1.95 × 10(13) vector genomes (vg)/kg of self-complementary (sc) AAV5 and 8 with a LP1-driven hFIX transgene intravenously in 0.9G late gestation NHP fetuses, leading to widespread transduction with liver tropism. Liver-specific hFIX expression was stably maintained between 8 and 112% of normal activity in injected offspring followed up for 2-22 months. AAV8 induced higher hFIX expression (P = 0.005) and milder immune response than AAV5. Random hepatocellular integration was found with no hotspots. Transplacental spread led to low-level maternal tissue transduction, without evidence of immunotoxicity or germline transduction in maternal oocytes. A single intravenous injection of scAAV-LP1-hFIXco to NHP fetuses in late-gestation produced sustained clinically-relevant levels of hFIX with liver-specific expression and a non-neutralizing immune response. These data are encouraging for conditions where gene transfer has the potential to avert perinatal death and long-term irreversible sequelae.
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Childhood hemangiopericytoma: review of St Jude Childrens Research Hospital.
J. Pediatr. Hematol. Oncol.
PUBLISHED: 05-24-2011
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Hemangiopericytoma (HPC) is a heterogeneous, highly vascularized malignant soft-tissue neoplasm with 2 different clinical presentations: adult-type and infantile-type HPC. Intracranial HPC represents a special subtype with a high proclivity toward recurrence and metastasis.
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Isolated subcutaneous metastasis of osteosarcoma 5 years after initial diagnosis.
J. Pediatr. Surg.
PUBLISHED: 05-18-2011
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The pediatric malignancies most likely to metastasize to the skin are neuroblastoma, leukemia, and rhabdomyosarcoma. Cutaneous and subcutaneous metastases from osteosarcoma are extremely rare, with only a few cases reported in pediatric patients with multifocal synchronous osteosarcoma. We describe the case of a 19-year-old woman with a single subcutaneous nodule of the abdominal wall that, on histologic evaluation, proved to be a metastatic high-grade osteosarcoma 5 years after her initial diagnosis.
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A single-arm pilot phase II study of gefitinib and irinotecan in children with newly diagnosed high-risk neuroblastoma.
Invest New Drugs
PUBLISHED: 05-02-2011
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Gefitinib potently inhibits neuroblastoma proliferation in vitro, and the gefitinib/irinotecan combination shows greater than additive activity against neuroblastoma xenografts. This Phase II pilot study estimated the rate of response to two courses of intravenous irinotecan plus oral gefitinib in children with untreated high-risk neuroblastoma.
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Vaginal tumors in childhood: the experience of St. Jude Childrens Research Hospital.
J. Pediatr. Surg.
PUBLISHED: 03-28-2011
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The aim of this study was to retrospectively analyze the clinical presentation, histology, treatment, and outcomes of children with vaginal tumors who were treated at a single institution.
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Good manufacturing practice production of self-complementary serotype 8 adeno-associated viral vector for a hemophilia B clinical trial.
Hum. Gene Ther.
PUBLISHED: 03-18-2011
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To generate sufficient clinical-grade vector to support a phase I/II clinical trial of adeno-associated virus serotype 8 (AAV8)-mediated factor IX (FIX) gene transfer for hemophilia B, we have developed a large-scale, good manufacturing practice (GMP)-compatible method for vector production and purification. We used a 293T-based two-plasmid transient transfection system coupled with a three-column chromatography purification process to produce high-quality self-complementary AAV2/8 FIX clinical-grade vector. Two consecutive production campaigns using a total of 432 independent 10-stack culture chambers produced a total of ?2?×?10(15) vector genomes (VG) by dot-blot hybridization. Benzonase-treated microfluidized lysates generated from pellets of transfected cells were purified by group separation on Sepharose beads followed by anion-exchange chromatography. The virus-containing fractions were further processed by gel filtration and ultrafiltration, using a 100-kDa membrane. The vector was formulated in phosphate-buffered saline plus 0.25% human serum albumin. Spectrophotometric analysis suggested ?20% full particles, with only low quantities of nonviral proteins were visible on silver-stained sodium dodecyl sulfate-polyacrylamide gels. A sensitive assay for the detection of replication-competent AAV was developed, which did reveal trace quantities of such contaminants in the final product. Additional studies have confirmed the long-term stability of the vector at -80°C for at least 24 months and for at least 24?hr formulated in the clinical diluent and stored at room temperature within intravenous bags. This material has been approved for use in clinical trials in the United States and the United Kingdom.
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Cooperation of the HDAC inhibitor vorinostat and radiation in metastatic neuroblastoma: efficacy and underlying mechanisms.
Cancer Lett.
PUBLISHED: 03-06-2011
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Histone deacetylase (HDAC) inhibitors can radiosensitize cancer cells. Radiation is critical in high-risk neuroblastoma treatment, and combinations of HDAC inhibitor vorinostat and radiation are proposed for neuroblastoma trials. Therefore, we investigated radiosensitizing effects of vorinostat in neuroblastoma. Treatment of neuroblastoma cell lines decreased cell viability and resulted in additive effects with radiation. In a murine metastatic neuroblastoma in vivo model vorinostat and radiation combinations decreased tumor volumes compared to single modality. DNA repair enzyme Ku-86 was reduced in several neuroblastoma cells treated with vorinostat. Thus, vorinostat potentiates anti-neoplastic effects of radiation in neuroblastoma possibly due to down-regulation of DNA repair enzyme Ku-86.
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Recombinant adeno-associated virus-mediated in utero gene transfer gives therapeutic transgene expression in the sheep.
Hum. Gene Ther.
PUBLISHED: 02-02-2011
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Somatic in utero gene therapy aims to treat congenital diseases where pathology develops in perinatal life, thereby preventing permanent damage. The aim of this study was to determine whether delivery of self-complementary (sc) adeno-associated virus (AAV) vector in utero would provide therapeutic long-term transgene expression in a large animal model. We performed ultrasound-guided intraperitoneal injection of scAAV2/8-LP1-human Factor IX (hFIX)co (1 × 10(12) vector genomes/kg) in early (n = 4) or late (n = 2) gestation fetal sheep. The highest mean hFIX levels were detected 3 weeks after injection in late gestation (2,055 and 1,687.5 ng/ml, n = 2) and 3 days after injection in early gestation (435 ng/ml, n = 1). Plasma hFIX levels then dropped as fetal liver and lamb weights increased, although low levels were detected 6 months after late gestation injection (75 and 52.5 ng/ml, n = 2). The highest vector levels were detected in the fetal liver and other peritoneal organs; no vector was present in fetal gonads. hFIX mRNA was detectable only in hepatic tissues after early and late gestation injection. Liver function tests and bile acid levels were normal up to a year postnatal; there was no evidence of liver pathology. No functional antibodies to hFIX protein or AAV vector were detectable, although lambs mounted an antibody response after injection of hFIX protein and Freunds adjuvant. In conclusion, hFIX expression is detectable up to 6 months after delivery of scAAV vector to the fetal sheep using a clinically applicable method. This is the first study to show therapeutic long-term hFIX transgene expression after in utero gene transfer in a large animal model.
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MicroRNA-34a is a potent tumor suppressor molecule in vivo in neuroblastoma.
BMC Cancer
PUBLISHED: 01-25-2011
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Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system and accounts for 15% of childhood cancer mortalities. With regards to the role of miRNAs in neuroblastoma, miR-34a, mapping to a chromosome 1p36 region that is commonly deleted, has been found to act as a tumor suppressor through targeting of numerous genes associated with cell proliferation and apoptosis.
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Long-term safety and efficacy following systemic administration of a self-complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins.
Mol. Ther.
PUBLISHED: 01-18-2011
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Adeno-associated virus vectors (AAV) show promise for liver-targeted gene therapy. In this study, we examined the long-term consequences of a single intravenous administration of a self-complementary AAV vector (scAAV2/ 8-LP1-hFIXco) encoding a codon optimized human factor IX (hFIX) gene in 24 nonhuman primates (NHPs). A dose-response relationship between vector titer and transgene expression was observed. Peak hFIX expression following the highest dose of vector (2 × 10(12) pcr-vector genomes (vg)/kg) was 21 ± 3 µg/ml (~420% of normal). Fluorescent in-situ hybridization demonstrated scAAV provirus in almost 100% of hepatocytes at that dose. No perturbations of clinical or laboratory parameters were noted and vector genomes were cleared from bodily fluids by 10 days. Macaques transduced with 2 × 10(11) pcr-vg/kg were followed for the longest period (~5 years), during which time expression of hFIX remained >10% of normal level, despite a gradual decline in transgene copy number and the proportion of transduced hepatocytes. All macaques developed serotype-specific antibodies but no capsid-specific cytotoxic T lymphocytes were detected. The liver was preferentially transduced with 300-fold more proviral copies than extrahepatic tissues. Long-term biochemical, ultrasound imaging, and histologic follow-up of this large cohort of NHP revealed no toxicity. These data support further evaluation of this vector in hemophilia B patients.
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Partial splenectomy for hereditary spherocytosis: a multi-institutional review.
J. Pediatr. Surg.
PUBLISHED: 01-18-2011
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Partial splenectomy has emerged as a surgical option for selected children with hereditary spherocytosis, with the goal of reducing anemia while preserving splenic function. This multi-institutional study is the largest series to date examining outcomes data for partial splenectomy in patients with hereditary spherocytosis.
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Continuous local delivery of interferon-? stabilizes tumor vasculature in an orthotopic glioblastoma xenograft resection model.
Surgery
PUBLISHED: 01-08-2011
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High-grade glioblastomas have immature, leaky tumor blood vessels that impede the efficacy of adjuvant therapy. We assessed the ability of human interferon (hIFN)-? delivered locally via gene transfer to effect vascular stabilization in an orthotopic model of glioblastoma xenograft resection.
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MicroRNA-542-5p as a novel tumor suppressor in neuroblastoma.
Cancer Lett.
PUBLISHED: 01-05-2011
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Several studies have implicated the dysregulation of microRNAs in neuroblastoma pathogenesis, an often fatal paediatric cancer arising from precursor cells of the sympathetic nervous system. Our group and others have demonstrated that lower expression of miR-542-5p is highly associated with poor patient survival, indicating a potential tumor suppressive function. Here, we demonstrate that ectopic over-expression of this miRNA decreases the invasive potential of neuroblastoma cell lines in vitro, along with primary tumor growth and metastases in an orthotopic mouse xenograft model, providing the first functional evidence for the involvement of miR-542-5p as a tumor suppressor in any type of cancer.
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MicroRNA-184-mediated inhibition of tumour growth in an orthotopic murine model of neuroblastoma.
Anticancer Res.
PUBLISHED: 12-01-2010
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Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system. Previous studies have shown that miR-184 expression has anti-proliferative effects in neuroblastoma cells grown in culture. Therefore, it was of interest to evaluate this effect in vivo.
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Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma.
J. Clin. Oncol.
PUBLISHED: 10-04-2010
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To evaluate the safety, maximum-tolerated dose, pharmacokinetics, and pharmacodynamics of vandetanib, an oral vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor inhibitor, administered once daily during and after radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma.
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Pediatric oncology.
Semin. Pediatr. Surg.
PUBLISHED: 07-09-2010
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Cancer is a disease whose progression is driven by a series of accumulating genetic and epigenetic changes influenced by hereditary factors and the somatic environment. These changes result in individual cells acquiring a phenotype that provides those cells with a survival advantage over surrounding normal cells. Our understanding of the processes that occur in malignant transformation is increasing, with many discoveries in cancer cell biology having been made through the study of childhood tumors. The processes involved in oncogenesis and cancer progression will be discussed in this review.
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Regression of a congenital mesoblastic nephroma.
Pediatr Blood Cancer
PUBLISHED: 06-29-2010
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Histologically, the cellular variant of congenital mesoblastic nephroma (CMN) is very similar to another rare tumor of infancy, infantile fibrosarcoma (IFS). In addition to the histologic similarities, these tumor types share cytogenetic abnormalities including translocation t(12;15)(p13;q25). We describe herein the case of a child who did not have immediate surgical resection of a CMN and whose tumor was untreated for 8 months. During that time, the tumor demonstrated a significant degree of regression. The shared translocation with IFS, a tumor with well-documented potential for spontaneous regression, suggests that this genetic abnormality may have contributed to the favorable clinical course.
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Radiation therapy as part of local control of metastatic neuroblastoma: the St Jude Childrens Research Hospital experience.
J. Pediatr. Surg.
PUBLISHED: 04-14-2010
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The purpose of the study was to compare outcomes of pediatric patients with high-risk metastatic neuroblastoma who received radiotherapy (RT) with those of patients who did not.
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Jaw dysfunction related to pterygoid and masseter muscle dosimetry after radiation therapy in children and young adults with head-and-neck sarcomas.
Int. J. Radiat. Oncol. Biol. Phys.
PUBLISHED: 03-29-2010
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To investigate the relationship between jaw function, patient and treatment variables, and radiation dosimetry of the mandibular muscles and joints in children and young adults receiving radiation for soft-tissue and bone sarcomas.
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Improved intratumoral oxygenation through vascular normalization increases glioma sensitivity to ionizing radiation.
Int. J. Radiat. Oncol. Biol. Phys.
PUBLISHED: 03-27-2010
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Ionizing radiation, an important component of glioma therapy, is critically dependent on tumor oxygenation. However, gliomas are notable for areas of necrosis and hypoxia, which foster radioresistance. We hypothesized that pharmacologic manipulation of the typically dysfunctional tumor vasculature would improve intratumoral oxygenation and, thus, the antiglioma efficacy of ionizing radiation.
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IFN-beta restricts tumor growth and sensitizes alveolar rhabdomyosarcoma to ionizing radiation.
Mol. Cancer Ther.
PUBLISHED: 03-02-2010
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Ionizing radiation is an important component of multimodal therapy for alveolar rhabdomyosarcoma (ARMS). We sought to evaluate the ability of IFN-beta to enhance the activity of ionizing radiation. Rh-30 and Rh-41 ARMS cells were treated with IFN-beta and ionizing radiation to assess synergistic effects in vitro and as orthotopic xenografts in CB17 severe combined immunodeficient mice. In addition to effects on tumor cell proliferation and xenograft growth, changes in the tumor microenvironment including interstitial fluid pressure, perfusion, oxygenation, and cellular histology were assessed. A nonlinear regression model and isobologram analysis indicated that IFN-beta and ionizing radiation affected antitumor synergy in vitro in the Rh-30 cell line; the activity was additive in the Rh-41 cell line. In vivo continuous delivery of IFN-beta affected normalization of the dysfunctional tumor vasculature of both Rh-30 and Rh-41 ARMS xenografts, decreasing tumor interstitial fluid pressure, increasing tumor perfusion (as assessed by contrast-enhanced ultrasonography), and increasing oxygenation. Tumors treated with both IFN-beta and radiation were smaller than control tumors and those treated with radiation or IFN-beta alone. Additionally, treatment with high-dose IFN-beta followed by radiation significantly reduced tumor size compared with radiation treatment followed by IFN-beta. The combination of IFN-beta and ionizing radiation showed synergy against ARMS by sensitizing tumor cells to the cytotoxic effects of ionizing radiation and by altering tumor vasculature, thereby improving oxygenation. Therefore, IFN-beta and ionizing radiation may be an effective combination for treatment of ARMS.
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Targeting multiple angiogenic pathways for the treatment of neuroblastoma.
J. Pediatr. Surg.
PUBLISHED: 01-19-2010
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Resistance to angiogenesis inhibition can occur through the upregulation of alternative mediators of neovascularization. We used a combination of angiogenesis inhibitors with different mechanisms of action, interferon-beta (IFN-beta) and rapamycin, to target multiple angiogenic pathways to treat neuroblastoma xenografts.
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Bevacizumab-induced tumor vessel remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation.
J. Pediatr. Surg.
PUBLISHED: 01-18-2010
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Inhibition of vascular endothelial growth factor (VEGF) may effect transient "normalization" of tumor vasculature by pruning immature vessels, resulting in improved tumor perfusion and oxygenation. This may improve the efficacy of adjuvant ionizing radiation (IR). We tested this hypothesis using bevacizumab, an anti-VEGF antibody, in rhabdomyosarcoma (RMS) xenografts.
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Wilms tumor.
Curr. Opin. Pediatr.
PUBLISHED: 05-07-2009
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Wilms tumor accounts for nearly 6% of all pediatric cancers and more than 95% of all kidney tumors in children. Fortunately, survival for patients with Wilms tumor is generally excellent. This review will outline the results of prior clinical trials that have led to this excellent outcome and how information gleaned from these trials has led to the development of the current series of clinical trials for the management of children with Wilms tumor.
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Should contralateral exploratory thoracotomy be advocated for children with osteosarcoma and early unilateral pulmonary metastases?
J. Pediatr. Surg.
PUBLISHED: 04-14-2009
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Children presenting with osteosarcoma and pulmonary metastases have poor survival rates. The standard approach to treating unilateral metastases is ipsilateral thoracotomy with complete resection of the metastases whenever possible. We analyzed whether contralateral exploratory thoracotomy is beneficial in these patients.
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Preliminary results from a prospective study using limited margin radiotherapy in pediatric and young adult patients with high-grade nonrhabdomyosarcoma soft-tissue sarcoma.
Int. J. Radiat. Oncol. Biol. Phys.
PUBLISHED: 02-13-2009
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To demonstrate the safety and efficacy of limited margin radiotherapy in the local control of pediatric and young adult patients with high-grade nonrhabdomyosarcoma soft tissue sarcoma (NRSTS).
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AAV-mediated local delivery of interferon-beta for the treatment of retinoblastoma in preclinical models.
Neuromolecular Med.
PUBLISHED: 02-10-2009
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Interferon-beta (IFN-beta) has been found to have anti-tumor properties against a variety of malignancies through different mechanisms. However, clinical trials involving systemic administration of IFN-beta have been hampered by secondary toxicity and the short half-life of IFN-beta in the circulation. In order to circumvent these limitations, we have developed an adeno-associated viral (AAV) vector gene-therapy approach to deliver IFN-beta to tumors. In this study, we tested the efficacy of AAV-mediated local delivery of IFN-beta for the treatment of retinoblastoma in preclinical models. Retinoblastoma is an ideal candidate for gene-therapy-based anti-cancer treatment because target cell transduction and, therefore, IFN-beta delivery can be contained within the ocular environment, thereby minimizing systemic toxicity. We report here that retinoblastoma cell lines exhibit pleiotropic responses to IFN-beta consistent with previous studies on a variety of tumor cell lines. Intravitreal injection of AAV-IFN-beta resulted in efficient retinal infection and sustained IFN-beta production in the eye with minimal systemic exposure. Vector spread outside of the eye was not detected. Using our orthotopic xenograft model of retinoblastoma, we found that intravitreal injection of AAV-IFN-beta had a potent anti-tumor effect in vivo. These data suggest that AAV-mediated delivery of IFN-beta may provide a complementary approach to systemic chemotherapy which is the standard of care for retinoblastoma around the world.
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Body wall and visceral nonrhabdomyosarcoma soft tissue sarcomas in children and adolescents.
J. Pediatr. Surg.
PUBLISHED: 02-04-2009
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Predictors of outcome have not been established for pediatric visceral and body wall nonrhabdomyosarcoma soft tissue sarcomas (NRSTS).
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A phase 1/pilot study of radiofrequency ablation for the treatment of recurrent pediatric solid tumors.
Cancer
PUBLISHED: 01-31-2009
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This prospective study was designed to be the first to evaluate the toxicity of radiofrequency ablation (RFA) in patients with recurrent pediatric solid tumors.
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Neural progenitor cell-mediated delivery of osteoprotegerin limits disease progression in a preclinical model of neuroblastoma bone metastasis.
J. Pediatr. Surg.
PUBLISHED: 01-23-2009
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Osteoprotegerin (OPG) inhibits osteoclast activation and reduces osteolysis in bone tumors. We hypothesized that tumor-tropic neural progenitor cells (NPCs) engineered to express OPG would reduce neuroblastoma disease burden in the bone.
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Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors.
Clin. Cancer Res.
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To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors.
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Clinical management of Ewing sarcoma of the bones of the hands and feet: a retrospective single-institution review.
J. Pediatr. Surg.
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Bones of the hands and feet are uncommon sites for Ewing sarcoma. In this study, we reviewed our experience in the management of these tumors.
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Intensity modulated radiation therapy provides excellent local control in high-risk abdominal neuroblastoma.
Pediatr Blood Cancer
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Locoregional failure is a significant concern in patients with high-risk abdominal neuroblastoma (NB) receiving radiotherapy. Locoregional control outcomes were studied in children with NB receiving intensity modulated radiotherapy (IMRT).
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A dedicated automated injection system for dynamic contrast-enhanced MRI experiments in mice.
J Magn Reson Imaging
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To develop a reproducible small-animal dynamic contrast-enhanced (DCE) MRI set-up for mice through which volumes <100 ?L can be accurately and safely injected and to test this set-up by means of DCE measurements in resting muscle and tumor tissue.
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The case for intrauterine gene therapy.
Best Pract Res Clin Obstet Gynaecol
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Single-gene disorders can cause perinatal mortality or severe permanent morbidity. Intrauterine gene therapy seeks to correct the genetic defect in the early stages of pathogenesis through delivery of a vector system expressing the therapeutic transgene to the fetus. Advantages of intrauterine gene therapy include prevention of irreversible organ damage, potentially inducing central tolerance and wider bio-distribution, including the brain after delivery of vector. Already, proof-of-cure has been demonstrated in knockout animal models for several diseases. Long-term outcomes pertaining to efficacy and durability of transgene expression and safety are under investigation in clinically relevant non-human primate models. Bystander effects in the mother from transplacental vector trafficking require further assessment. In this chapter, we discuss the candidate diseases amenable to intrauterine gene therapy, current state-of-the-art evidence, and potential clinical applications.
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Wilms tumor.
Adv Pediatr
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Significant improvement has been made in the treatment of children with Wilms tumor. New protocols are in place designed to maintain a high rate of cure for these patients while minimizing toxicity, based on refinement of the risk-stratification system.
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Timing of surgery and the role of adjuvant radiotherapy in ewing sarcoma of the chest wall: a single-institution experience.
Ann. Surg. Oncol.
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Ewing sarcoma (ES) is the most common chest wall malignancy in adolescents. Current therapy incorporates chemotherapy to treat systemic disease and radiotherapy to assist with local control. We sought to evaluate the timing of surgery and role of adjuvant radiotherapy.
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Analysis of prognostic factors in extraosseous Ewing sarcoma family of tumors: review of St. Jude Childrens Research Hospital experience.
Ann. Surg. Oncol.
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Advances in the treatment of Ewing sarcoma family of tumors (ESFT) are the result of improvements in systemic and local therapies. Clinical data of extraosseous ESFT are scarce.
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Patients with osteosarcoma with a single pulmonary nodule on computed tomography: a single-institution experience.
J. Pediatr. Surg.
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The purpose of this study is to determine if patients with osteosarcoma (OS) with metachronous metastatic pulmonary disease presenting with a single pulmonary nodule (SPN) on computed tomography (CT) were found to have other lesions at the time of thoracotomy.
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Inhibition of neuroblastoma tumor growth by targeted delivery of microRNA-34a using anti-disialoganglioside GD2 coated nanoparticles.
PLoS ONE
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Neuroblastoma is one of the most challenging malignancies of childhood, being associated with the highest death rate in paediatric oncology, underlining the need for novel therapeutic approaches. Typically, patients with high risk disease undergo an initial remission in response to treatment, followed by disease recurrence that has become refractory to further treatment. Here, we demonstrate the first silica nanoparticle-based targeted delivery of a tumor suppressive, pro-apoptotic microRNA, miR-34a, to neuroblastoma tumors in a murine orthotopic xenograft model. These tumors express high levels of the cell surface antigen disialoganglioside GD2 (GD(2)), providing a target for tumor-specific delivery.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.