Improved Survival of Children With Neuroblastoma Between 1979 and 2005: A Report of the Italian Neuroblastoma Registry

Haupt, Riccardo; Garaventa, Alberto; Gambini, Claudio; Parodi, Stefano; Cangemi, Giuliana; Casale, Fiorina; Viscardi, Elisabetta; Bianchi, Maurizio; Prete, Arcangelo; Jenkner, Alessandro; Luksch, Roberto; Cataldo, Andrea Di; Favre, Claudio; D’Angelo, Paolo; Zanazzo, Giulio Andrea; Arcamone, Giampaolo; Izzi, Gian Carlo; Gigliotti, Anna Rita; Pastore, Guido; Bernardi, Bruno

doi:10.1200/jco.2009.24.8351

Cited by 98 publications

(103 citation statements)

References 30 publications

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“…With current treatment protocols, approximately 80% of high-risk patients go into remission [6]. However, long-term survival rates are less than 50% as most of these patients relapse and develop therapy-resistant tumors [7]. This motivates an ongoing effort to develop novel, non-genotoxic targeted therapeutics in order to reduce toxicities and improve survival.…”

Section: Introductionmentioning

confidence: 99%

Effect of MDM2 and vascular endothelial growth factor inhibition on tumor angiogenesis and metastasis in neuroblastoma

et al. 2011

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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.

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Section: Introductionmentioning

confidence: 99%

Effect of MDM2 and vascular endothelial growth factor inhibition on tumor angiogenesis and metastasis in neuroblastoma

et al. 2011

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“…Despite advances in the management of neuroblastoma, many children have primary refractory disease or relapse after initial treatment. The long-term survival rate remains under 40% (2)(3)(4). Improved therapeutic options are therefore required for these children.…”

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confidence: 99%

¹⁷⁷Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma

Gains¹,

Bomanji²,

Fersht³

et al. 2011

J Nucl Med

142

136

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This study tested the principle that 68 Ga-DOTATATE PET/CT may be used to select children with primary refractory or relapsed high-risk neuroblastoma for treatment with 177 Lu-DOTATATE and evaluated whether this is a viable therapeutic option for those children. Methods: Between 2008 and 2010, 8 children with relapsed or refractory high-risk neuroblastoma were studied with 68 Ga-DOTATATE PET/CT. The criterion of eligibility for 177 Lu-DOTATATE therapy was uptake on the diagnostic scan equal to or higher than that of the liver. Results: Of the 8 children imaged, 6 had abnormally high uptake on the 68 Ga-DOTATATE PET/CT scan and proceeded to treatment. Patients received 2 or 3 administrations of 177 Lu-DOTATATE at a median interval of 9 wk and a median administered activity of 7.3 GBq. Of the 6 children treated, 5 had stable disease by the response evaluation criteria in solid tumors (RECIST). Of these 5 children, 2 had an initial metabolic response and reduction in the size of their lesions, and 1 patient had a persistent partial metabolic response and reduction in size of the lesions on CT, although the disease was stable by RECIST. One had progressive disease. Three children had grade 3 and 1 child had grade 4 thrombocytopenia. No significant renal toxicity has been seen. Conclusion: 68 Ga-DOTATATE can be used to image children with neuroblastoma and identify those suitable for molecular radiotherapy with 177 Lu-DOTATATE. We have shown, for what is to our knowledge the first time, that treatment with 177 Lu-DOTATATE is safe and feasible in children with relapsed or primary refractory high-risk neuroblastoma. We plan to evaluate this approach formally in a phase I-II clinical trial.

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“…These infants with rapidly expanding liver disease may require an earlier administration of a more aggressive chemotherapy, to decrease the risk of abdominal distention, resulting in mechanical respiratory failure. The treatment administered to infants with stage IVs NB with massive hepatomegaly should be individualized based on the disease course (25). A sequential approach comprising observation, intravenous chemotherapy and hepatic intra-arterial chemoembolization may improve the outcome of these infants (26,27).…”

Section: Discussionmentioning

confidence: 99%

A single center clinical analysis of children with neuroblastoma

Shao

Huang

et al. 2015

Oncology Letters

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Improved Survival of Children With Neuroblastoma Between 1979 and 2005: A Report of the Italian Neuroblastoma Registry

Abstract: The outcome of children with neuroblastoma has progressively improved. Long-term survivors bear a significant risk of SMN.

Cited by 98 publications

References 30 publications

Effect of MDM2 and vascular endothelial growth factor inhibition on tumor angiogenesis and metastasis in neuroblastoma

Effect of MDM2 and vascular endothelial growth factor inhibition on tumor angiogenesis and metastasis in neuroblastoma

¹⁷⁷Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma

A single center clinical analysis of children with neuroblastoma

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Improved Survival of Children With Neuroblastoma Between 1979 and 2005: A Report of the Italian Neuroblastoma Registry

Abstract: The outcome of children with neuroblastoma has progressively improved. Long-term survivors bear a significant risk of SMN.

Cited by 98 publications

References 30 publications

Effect of MDM2 and vascular endothelial growth factor inhibition on tumor angiogenesis and metastasis in neuroblastoma

Effect of MDM2 and vascular endothelial growth factor inhibition on tumor angiogenesis and metastasis in neuroblastoma

177Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma

A single center clinical analysis of children with neuroblastoma

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¹⁷⁷Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma