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1.
Bone Marrow Transplant ; 51(9): 1204-10, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27159174

ABSTRACT

The optimal autologous stem cell rescue (HDC-SCR) regimen for children with high-risk neuroblastoma (HR-NBL) is not defined. Carboplatin/etoposide/melphalan (CEM) is the current US standard; however, European data suggest busulfan/melphalan (Bu/Mel) may have less toxicity. Published data regarding toxicities associated with CEM and Bu/Mel are limited. We conducted a single-institution retrospective cohort study of children with HR-NBL who received CEM or Bu/Mel preparative regimens. Toxicity data were analyzed using χ(2) or Fisher's exact, Wilcoxon two-sample or log-rank tests. Sinusoidal obstruction syndrome (SOS) was observed in 7/44 CEM (15.9%) and 5/21 (24%) Bu/Mel patients (P=0.50). Median time to SOS was longer following Bu/Mel than CEM (20 versus 9 days, P=0.02). Pulmonary hypertension (PHTN) was observed in ~20% of children after Bu/Mel and none after CEM (P=0.01). CEM patients had more nephrotoxicity (P=0.001), packed red blood cell (P=0.02) and platelet transfusions (P=0.008), and days on maximum pain support (P=0.0007). Time to engraftment, length of stay, documented infection rates and HDC-SCR-related mortality were similar. Nephrotoxicity and resource utilization associated with cytopenias and mucositis were greater after CEM. Pulmonary toxicities were more severe after Bu/Mel, and increased vigilance for PHTN may be warranted, particularly in children with hypoxemia out of proportion to respiratory distress.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/toxicity , Myeloablative Agonists/toxicity , Neuroblastoma/complications , Neuroblastoma/drug therapy , Transplantation Conditioning/adverse effects , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Busulfan/administration & dosage , Carboplatin/administration & dosage , Child , Child, Preschool , Cohort Studies , Etoposide/administration & dosage , Female , Hepatic Veno-Occlusive Disease/chemically induced , Humans , Hypertension, Pulmonary/chemically induced , Infant , Kidney Diseases/chemically induced , Male , Melphalan/administration & dosage , Mucositis/chemically induced , Myeloablative Agonists/administration & dosage , Neuroblastoma/mortality , Neuroblastoma/therapy , Pancytopenia/chemically induced , Retrospective Studies , Stem Cell Transplantation/adverse effects , Stem Cell Transplantation/methods , Stem Cell Transplantation/mortality , Transplantation Conditioning/methods , Transplantation Conditioning/mortality , Young Adult
2.
Curr Oncol ; 21(2): e345-8, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24764718

ABSTRACT

Patients with neurofibromatosis type 1 (nf1) are at increased risk for both benign and malignant tumours, and distinguishing the malignant potential of an individual tumour is a common clinical problem in these patients. Here, we review two cases of uncommon malignancies (Hodgkin lymphoma and mediastinal germ-cell tumour) in patients with nf1. Although (18)F-fluorodeoxyglucose positron-emission tomography (fdg-pet) has been used to differentiate benign neurofibromas from malignant peripheral nerve sheath tumours, fdg-pet characteristics for more rare tumours have been poorly described in children with nf1. Here, we report the role of pet imaging in clinical decision-making in each case. In nf1, fdg-pet might be useful in the clinical management of unusual tumour presentations and might help to provide information about the malignant potential of uncommon tumours.

3.
Clin Cancer Res ; 17(3): 611-9, 2011 Feb 01.
Article in English | MEDLINE | ID: mdl-21127194

ABSTRACT

PURPOSE: This pediatric phase I study was designed to identify the doses of RG1507, a monoclonal antibody against the Type 1 Insulin-like Growth Factor Receptor (IGF1R), that achieves exposures equivalent to those achieved in adults at recommended doses. EXPERIMENTAL DESIGN: Children with relapsed or refractory solid tumors were treated using the same doses and administration schedules of RG1507 (3 and 9 mg/kg/wk, and 16 mg/kg every 3 weeks [q3W]) as those studied in adults. Detailed pharmacokinetic (PK) sampling was performed after the first dose; selected peak and trough levels were subsequently obtained. Target exposures were ≥85% of mean areas under concentration x time curves (AUCs) in adults at doses of 9 mg/kg/wk and 16 mg/kg q3W. A maximum tolerated dose could be identified if dose-limiting toxicities (DLT) occurred. RESULTS: Thirty-one evaluable patients aged 3-17 years were enrolled at 3 mg/kg/wk (n = 3), 9 mg/kg/wk (n = 18), or 16 mg/kg q3W (n = 10). There were no DLTs. At 9 mg/kg/wk the mean AUC(0-7d) (21,000 µg h/mL) exceeded the target (16,000 µg h/mL). At 16 mg/kg q3W, the mean AUC(021d) (70,000 µg h/mL) exceeded the target (59,400 µg h/mL). Clearance normalized to body weight was age dependent. There were no objective responses. Seven patients had stable disease for >12 weeks, including two patients with osteosarcoma with stable disease for 52+ and 78+ weeks. CONCLUSIONS: The recommended doses of RG1507 in children with solid tumors are 9 mg/kg/wk and 16 mg/kg q3W. This flexible design is well suited for trials of agents associated with limited toxicity.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Receptor, IGF Type 1/antagonists & inhibitors , Adolescent , Antibodies, Monoclonal/pharmacokinetics , Child , Child, Preschool , Drug Resistance, Neoplasm , Female , Humans , Male , Recurrence
4.
Clin Cancer Res ; 7(7): 2076-84, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11448926

ABSTRACT

Steroid hormone receptors have become an important target in the management of breast cancers. Despite a good initial response rate, however, most tumors become refractory to current hormonal therapies within a year of starting treatment. To address this problem, we evaluated the effects of agents that bind the molecular chaperone heat shock protein 90 (Hsp90) on estrogen receptor function in breast cancer. Unstimulated estrogen and progesterone receptors exist as multimolecular complexes consisting of the hormone-binding protein itself and several essential molecular chaperones including Hsp90. We found that interaction of the Hsp90-binding drugs geldanamycin and radicicol with the chaperone destabilizes these hormone receptors in a ligand-independent manner, leading to profound and prolonged depletion of their levels in breast cancer cells cultured in vitro. Consistent with these findings, in vivo administration of the geldanamycin derivative 17-allylaminogeldanamycin (17AAG; NSC330507) to estrogen-supplemented, tumor-bearing SCID mice resulted in marked depletion of progesterone receptor levels in both uterus and tumor. Drug administration also delayed the growth of established, hormone-responsive MCF-7 and T47D human tumor xenografts for up to 3 weeks after the initiation of therapy. We conclude that in light of their novel mechanism of anti-hormone action, consideration should be given to examining the activity of 17AAG and other Hsp90-binding agents in patients with refractory breast cancer in future clinical trials, either alone or in combination with conventional hormone antagonists.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , HSP90 Heat-Shock Proteins/metabolism , Quinones/pharmacology , Receptors, Steroid/drug effects , Animals , Antibiotics, Antineoplastic/metabolism , Benzoquinones , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Division/drug effects , Estrogens/therapeutic use , Female , Humans , Lactams, Macrocyclic , Ligands , Mice , Mice, SCID , Neoplasm Transplantation , Protein Binding , Quinones/chemistry , Quinones/metabolism , Receptors, Estrogen/drug effects , Receptors, Estrogen/metabolism , Receptors, Progesterone/drug effects , Receptors, Progesterone/metabolism , Receptors, Steroid/metabolism , Time Factors , Tumor Cells, Cultured , Uterus/drug effects , Uterus/metabolism , Xenograft Model Antitumor Assays
5.
Clin Cancer Res ; 6(8): 3312-8, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10955818

ABSTRACT

In addition to its classic role in the cellular stress response, heat shock protein 90 (Hsp90) plays a critical but less well appreciated role in regulating signal transduction pathways that control cell growth and survival under basal, nonstress conditions. Over the past 5 years, the antitumor antibiotics geldanamycin and radicicol have become recognized as selective Hsp90-binding agents (HBA) with a novel ability to alter the activity of many of the receptors, kinases, and transcription factors involved in these cancer-associated pathways. As a consequence of their interaction with Hsp90, however, these agents also induce a marked cellular heat shock response. To study the mechanism of this response and assess its relevance to the anticancer action of the HBA, we verified that the compounds could activate a reporter construct containing consensus binding sites for heat shock factor 1 (HSF1), the major transcriptional regulator of the vertebrate heat shock response. We then used transformed fibroblasts derived from HSF1 knock-out mice to show that unlike conventional chemotherapeutics, HBA increased the synthesis and cellular levels of heat shock proteins in an HSF1-dependent manner. Compared with transformed fibroblasts derived from wild-type mice, HSF1 knock-out cells were significantly more sensitive to the cytotoxic effects of HBA but not to doxorubicin or cisplatin. Consistent with these in vitro data, we found that systemic administration of an HBA led to marked increases in the level of Hsp72 in both normal mouse tissues and human tumor xenografts. We conclude that HBA are useful probes for studying molecular mechanisms regulating the heat shock response both in cells and in whole animals. Moreover, induction of the heat shock response by HBA will be an important consideration in the clinical application of these drugs, both in terms of modulating their cytotoxic activity as well as monitoring their biological activity in individual patients.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , DNA-Binding Proteins/physiology , HSP90 Heat-Shock Proteins/metabolism , Heat-Shock Response/drug effects , 3T3 Cells , Animals , Antibiotics, Antineoplastic/metabolism , Benzoquinones , Cell Transformation, Viral , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Heat Shock Transcription Factors , Heat-Shock Response/physiology , Humans , Lactams, Macrocyclic , Lactones/metabolism , Lactones/pharmacology , Macrolides , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, SCID , Papillomaviridae , Quinones/metabolism , Quinones/pharmacology , Rifabutin/analogs & derivatives , Rifabutin/metabolism , Rifabutin/pharmacology , Transcription Factors , Transcriptional Activation/drug effects , Xenograft Model Antitumor Assays
6.
Methods ; 18(3): 296-303, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10454988

ABSTRACT

Antisense RNA expression vectors have been developed relatively recently as a means to study the role of specific oncogenes in malignant transformation. In this paper, strategies for the construction of antisense plasmid vectors from commercially available reagents are described. Techniques for the introduction of these vectors into cell lines and tumors are also described and preferred methods for the evaluation of biological effects are presented. Lastly, using specific examples, the limitations and potential artifacts associated with antisense vector use in the study of tumorigenesis are discussed.


Subject(s)
Gene Expression Regulation/drug effects , Oncogenes/genetics , RNA, Antisense/pharmacology , Cloning, Molecular , DNA, Complementary/genetics , Eukaryotic Cells , Flow Cytometry , Gene Targeting/methods , Genetic Vectors , RNA, Antisense/biosynthesis , Transfection
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