Biomedical subjects

Susan Blaney

Publications and source records attributed to Susan Blaney.

14 recordsLinked to original sources

PubMed2005

Etoposide, vincristine, and cyclosporin A with standard-dose radiation therapy in newly diagnosed diffuse intrinsic brainstem gliomas: a pediatric oncology group phase I study.

BACKGROUND: Brainstem gliomas (BSGs) are resistant to all therapy. Based on their imaging characteristics, we postulated that inhibition of P-glycoprotein (P-gp) associated with endothelial cells of the blood-brain barrier might enhance penetration of xenobiotic antineoplastics. PROCEDURE: Seven patients were enrolled in a Phase I study of etoposide, continuous infusion cyclosporine A given with and escalating doses of vincristine and concomitant standard-dose irradiation. RESULTS: Six patients were entered at the first level and one at the second. Closure of the study was mandated by dose-limiting neurotoxicity, consisting of seizures associated with white-matter changes, and alteration of consciousness with bulbar signs. One patient had tumor necrosis at 6 weeks, suggesting some tumor effect. Median survival for the group was 11 months, and for the patients who completed more than 1 month of therapy it was 11 months. CONCLUSION: This regimen proved excessively toxic.

Adolescent↗

PubMed2005

Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy.

PURPOSE: To describe clinical features, therapeutic approaches, and prognostic factors in pediatric patients with atypical teratoid/rhabdoid tumors (ATRT) treated at St Jude Children's Research Hospital (SJCRH). PATIENTS AND METHODS: Primary tumor samples from patients diagnosed with ATRT at SJCRH between July 1984 and June 2003 were identified. Pathology review included histologic, immunohistochemical analysis, and fluorescence in situ hybridization for SMARCB1 (also known as hSNF5/INI1) deletion. Clinical records of patients with pathologic confirmation of ATRT were reviewed. RESULTS: Thirty-seven patients were diagnosed with ATRT at SJCRH during the 19-year study interval. Six patients were excluded from this clinical review based on pathologic or clinical criteria. Of the remaining 31 patients, 22 were younger than 3 years. Posterior fossa primary lesions and metastatic disease at diagnosis were more common in younger patients with ATRT. All patients underwent surgical resection; 30 received subsequent chemotherapy. The majority of patients aged 3 years or older received postoperative craniospinal radiation. Two-year event-free (EFS) and overall survival (OS) of children aged 3 years or older (EFS, 78% + 14%; OS, 89% +/- 11%) were significantly better than those for younger patients (EFS, 11% +/- 6%; OS, 17% +/- 8%); EFS, P = .009 and OS, P = .0001. No other clinical characteristics were predictive of survival. Three of four patients 3 years or older with progressive disease were successfully rescued with ifosfamide, carboplatin, and etoposide therapy. CONCLUSION: Children presenting with ATRT before the age of 3 years have a dismal prognosis. ATRT presenting in older patients can be cured using a combination of radiation and high-dose alkylating therapy. Older patients with relapsed ATRT can have salvage treatment using ICE chemotherapy.

Central Nervous System Neoplasms↗

PubMed2005

A phase I and pharmacokinetic study of ecteinascidin-743 (Yondelis) in children with refractory solid tumors. A Children's Oncology Group study.

PURPOSE: To determine the dose-limiting toxicity (DLT) and the maximum tolerated dose of ecteinascidin-743 (ET-743, Yondelis) in children with refractory solid tumors, to establish the recommended dose for pediatric phase II trials, and to characterize the pharmacokinetics of ET-743 in children. EXPERIMENTAL DESIGN: ET-743 was administered as a 3-hour i.v. infusion every 21 days. The starting dose was 1,100 microg/m(2) with planned dose escalation of 200 microg/m(2) increments. Pharmacokinetic sampling was done during the first treatment course. RESULTS: Twelve evaluable patients received a total of 29 courses. One grade 4 DLT (prolonged grade 4 neutropenia) was noted at the first dose level. At the second dose level (1,300 microg/m(2)), there were two DLTs (reversible grade 4 elevations of hepatic transaminase); hence the maximum tolerated dose was defined as 1,100 microg/m(2). Overall, reversible hepatic toxicity, manifested as grade 3 or 4 elevations in hepatic transaminase, occurred in more than 50% of the patients. No grade 3 or 4 thrombocytopenia was reported at either dose level and only one episode of isolated creatine phosphokinase grade 4 elevation was observed. One complete response was documented after six courses in a patient with metastatic Ewing sarcoma. The pharmacokinetics of ET-743 in 8 children was characterized by a terminal disposition phase with a mean half-life of 43.8 +/- 18.4 hours, a total body clearance of 28.2 +/- 10.5 L/h/m(2), and a 959 +/- 807 L/m(2) steady-state apparent volume of distribution. CONCLUSION: ET-743 is safe. The phase II recommended dose of ET-743 administered as a 3-hour i.v. infusion following premedication with dexamethasone is 1,100 microg/m(2).

Adolescent↗

PubMed2004

Pharmacokinetics of O(6)-benzylguanine in pediatric patients with central nervous system tumors: a pediatric oncology group study.

PURPOSE: To report the results of the first pharmacokinetic study in pediatric patients of O(6)-benzylguanine (O(6)BG), which irreversibly inactivates the DNA repair protein alkylguanine-alkyltransferase, thus enhancing the cytotoxicity of nitrosoureas. EXPERIMENTAL DESIGN: As part of a Pediatric Oncology Group Phase I study, 120 mg/m(2) of O(6)BG was administered i.v. over 1 h, before 1,3-bis(2-chloroethyl)-1-nitrosourea administration in children with recurrent or refractory brain tumors. Serial blood samples for plasma pharmacokinetic studies were obtained. Concentrations of O(6)BG and its active metabolite O(6)-benzyl-8-oxoguanine (8-oxo-O(6)BG) were measured by high-performance liquid chromatography. A pharmacokinetic model and additional first-order elimination rate constants for each compound were developed. RESULTS: O(6)BG concentration versus time data were evaluated for 25 patients. The peak concentration of O(6)BG (mean +/- SD) was 11 +/- 4 microm, and the peak concentration of its active metabolite, 8-oxo-O(6)BG, was 35 +/- 10 microm. O(6)BG was rapidly eliminated with a half-life of 85 +/- 140 min, area under the curve of 795 +/- 320 microm. min and clearance of 760 +/- 400 ml/min/m(2). The area under the curve of 8-oxo-O(6)BG when extrapolated to infinity was 22,700 +/- 11,800 microm. min. The clearance and terminal half-life of 8-oxo-O(6)BG were 30 +/- 15 ml/min/m(2) and 360 +/- 220 min, respectively. CONCLUSIONS: There is rapid elimination of O(6)BG after i.v. administration over 1 h. In contrast, the terminal half-life for the active metabolite, 8-oxo-O(6)BG, is 4-fold longer. The pharmacokinetic parameters for O(6)BG and 8-oxo-O(6)BG are similar to those reported previously in adults.

Adolescent↗

PubMed2004

Phase I trial of tirapazamine and cyclophosphamide in children with refractory solid tumors: a pediatric oncology group study.

PURPOSE: To determine the dose limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic profile of tirapazamine (Sanofi Synthelabo Research, Malvern, PA) combined with cyclophosphamide in children with recurrent solid tumors. PATIENTS AND METHODS: Patients received a 2-hour infusion of tirapazamine, followed by 1,500 mg/m(2) cyclophosphamide, and mesna once every 3 weeks. Dose escalation of tirapazamine began at 250 mg/m(2) and was increased by 30% in subsequent cohorts. If DLT was hematologic, less-heavily pretreated patients were to be enrolled until their DLTs were encountered, and MTDs defined. Pharmacokinetic profiles were also characterized. RESULTS: Twenty-three patients were enrolled onto the study. Pharmacokinetic data were calculated for 22 patients. Prolonged neutropenia was the DLT at 420 mg/m(2) in heavily pretreated patients. Grade 3, reversible ototoxicity was the DLT in less-heavily pretreated patients at 420 mg/m(2). Two (one with neuroblastoma and one with rhabdomyosarcoma) had partial responses. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m(2). This patient had disease detectable in the bone marrow only and all evidence of bone marrow involvement resolved for 17 cycles of therapy. Four other patients had stable disease. An apparent dose-proportional increase in tirapazamine maximal concentration and area under the curve(last) was observed. Tirapazamine clearance, volume of distribution at steady-state, and terminal half-life did not appear to be dose-dependent. CONCLUSION: The recommended dose of tirapazamine given with 1,500 mg/m(2) of cyclophosphamide once every 3 weeks is 325 mg/m(2). Neutropenia and ototoxicity were dose-limiting. Based on early evidence of antitumor activity, additional studies appear warranted.

Adolescent↗

PubMed2004

Phenylbutyrate and phenylacetate induce differentiation and inhibit proliferation of human medulloblastoma cells.

PURPOSE: Phenylbutyrate (PB) and phenylacetate (PA) have antiproliferative and differentiation-inducing effects in malignant tumors, and had been evaluated in Phase I/II clinical trials. This study was undertaken to evaluate their antitumor activities in medulloblastomas. EXPERIMENTAL DESIGN: The biological effects of PB and PA, ranging from 0.1 mM to 3 mM, on two medulloblastoma cell lines (DAOY and D283-MED) were examined using various long-term in vitro and in vivo assays for morphology, proliferation, differentiation, anchorage-independent growth, apoptosis, and tumorigenicity. RESULTS: PB and PA can both induce morphological changes and suppress proliferation in a time- and dose-dependent manner. These effects were more pronounced with PB and became irreversible in D283-MED cells after continuous exposure to 3 mM PB for 28 days. Both PB and PA were able to increase expression of glial marker glial fibriliary acidic protein and neuronal marker synaptophysin in two cell lines. For anchorage-independent growth, PB showed a more significant suppression than PA in D283-MED cells. PB caused more pronounced cell cycle arrest and remarkably reduced tumorigenicity in D283-MED cells than in DAOY cells. Apoptosis was readily induced in D283-MED cells with either low dose of PB or short-term treatment. In contrast, much higher concentrations of PB or longer treatment were required to achieve similar effect with DAOY cells. PB induced increased histones H3 acetylation in both cell lines, but histone H4 acetylation was only observed in D283-MED cells. CONCLUSIONS: PB, through induction of hyperacetylation of histone H3 and H4, is a much more potent antitumor agent than PA. 283-MED cells are more responsive to PB than DAOY cells, which may be dependent on their original state of differentiation as well as the changes of histone H4 acetylation status.

Animals↗

PubMed2004

Cyclin D and cisplatin cytotoxicity in primary neuroblastoma cell lines.

Cyclin D1 is a key cell cycle regulator protein with demonstrated oncogenenic activity in a variety of malignancies. Overexpression of Cyclin D1 protein has been observed in many types of tumors. We hypothesized that Cyclin D1 might be an important determinant of the sensitivity of neuroblastomas to cisplatin. Cyclin D1, D2 and D3, and Cdk4, Cdk6 and Rb protein, and Cyclin D1 mRNA expression were measured in primary patient-derived neuroblastoma cell lines. Cell cycle distribution was examined using flow cytometry. A modified MTT assay was used to determine the sensitivity of the cell lines to cisplatin. All 14 cell lines expressed Cyclin D1 protein to a variable extent (0.22-1.47 normalized to actin protein expression). All cell lines expressed Cyclin D2 and D3. There was no relationship between expression of Cyclin D1 and expression of Cyclin D2 or D3 (p>0.05 and R2<0.2 for both). All cell lines expressed Cdk4 and Cdk6 protein. In addition, Rb and two related proteins, p105 and p130, were detected in all the cell lines. The mean cisplatin IC50 was 19.2 microM (range 0.6-40 microM). We conclude that there was no correlation between the amount of Cyclin D1 expressed and the cisplatin IC50. Our results do not support the hypothesis that Cyclin D1 expression is significantly related to cisplatin resistance.

Cell Cycle↗

PubMed2003

Plasma and cerebrospinal fluid pharmacokinetics of SU5416 after intravenous administration in nonhuman primates.

PURPOSE: SU5416 is a small, lipophilic synthetic molecule that selectively inhibits the tyrosine kinase activity of the VEGF receptor Flk-1/KDR. The role of this agent in brain tumors is currently being investigated. Pharmacokinetic studies of SU5416 have been performed in humans; however, there have been no studies of its penetration in the cerebrospinal fluid (CSF). We studied the pharmacokinetics of SU5416 in plasma and CSF after intravenous (i.v.) administration using a nonhuman primate model that is highly predictive of the CSF penetration in humans. EXPERIMENTAL DESIGN: SU5416 (85 mg/m(2), about 3.8 mg/kg) was administered i.v. over 20 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion for determination of SU5416 concentrations. SU5416 was measured in plasma and CSF using high-performance liquid chromatography (HPLC). Concentration-versus-time data were modeled using model-independent and model-dependent methods. RESULTS: Peak plasma concentrations ranged from 6.3 to 14.5 microM and the mean plasma AUC was 620+/-180 microM.min. Disappearance of SU5416 from the plasma was best described by a one-compartment model with a half-life of 39+/-2.9 min. The volume of distribution was 36+/-11 l/m(2) and the clearance was 0.62+/-0.2 l/min per m(2). SU4516 was not quantifiable in the CSF. CONCLUSIONS: There is minimal penetration of SU5416 into the CSF after i.v. administration. The very low CNS exposure to SU5416 after i.v. dosing suggests that this agent is not optimal for the treatment of leptomeningeal tumors.

Animals↗

PubMed2003

Phase I trial of rebeccamycin analog (NSC #655649) in children with refractory solid tumors: a pediatric oncology group study.

PURPOSE: To conduct a phase 1 trial of rebeccamycin analog (NSC #655649) in children with solid tumors to establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); to establish the pharmacokinetic profile in children, and to document any evidence of antitumor activity. METHODS: A 1-hour infusion of NSC #655649 was administered every 21 days to 17 patients younger than 21 years who had malignant tumors refractory to conventional therapy. Doses ranged from 450 mg/m2 to 760 mg/m2. Pharmacokinetics were done in at least three patients per dose level. The first course was used to determine DLT and MTD. RESULTS: Sixteen patients on three dose levels were assessable for toxicities. At 760 mg/m2, four patients had dose-limiting neutropenia and thrombocytopenia. Pharmacokinetics were assessable in 13 patients. Plasma concentrations declined triexponentially and concentrations above the range of in vitro antitumor activity were maintained for 3 days. Analysis of urine extracts revealed the presence of an N-de-ethylated metabolite and probable involvement of cytochrome P450 isoenzyme(s) in the metabolism of NSC #655649. Pharmacodynamic studies showed a relationship between the area under the curve and percentage change in absolute neutrophil count in the E(max) model (r2 = 0.56, P = 0.001). CONCLUSIONS: The recommended phase 2 dose of NSC #655649 administered as a 1-hour infusion every 21 days to children with solid tumors is 585 mg/m2. Both neutropenia and thrombocytopenia were found to be dose-limiting toxicities.

Adolescent↗

PubMed2003

Phase 1 study of Paclitaxel administered twice weekly to children with refractory solid tumors: a pediatric oncology group study.

PURPOSE: To perform a phase 1 trial to determine the maximum tolerated dose and the dose-limiting toxicities of paclitaxel in children with refractory or recurrent solid tumors. Paclitaxel was administered twice weekly, increasing from four to six doses every 21 to 28 days. METHODS: Paclitaxel was administered as a 3-hour intravenous infusion twice weekly. The initial dose was fixed at 50 mg/m2/dose twice weekly for 2 weeks (four doses), every 21 days. The number of twice-weekly doses per course was increased to six in the next cohort. In subsequent cohorts, the number of twice-weekly doses per course was fixed at six, every 28 days, and dosage was increased in 25% increments. RESULTS: Sixteen assessable patients were enrolled at three levels. Neutropenia was the dose-limiting toxicity at 65 mg/m2/dose, twice weekly x 6 doses, every 28 days. Nonhematologic toxicities were minor. No antitumor responses were observed. CONCLUSIONS: Protracted twice-weekly dosing of paclitaxel is limited by neutropenia. The maximum tolerated dose of paclitaxel administered twice weekly x 6 doses, every 28 days, was 50 mg/m2/dose.

Anemia↗

PubMed2002

Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors: a pediatric oncology group study.

PURPOSE: To determine the maximum tolerated dose and pharmacokinetics of Doxil in children with recurrent or refractory solid tumors. Doxil is pegylated doxorubicin. EXPERIMENTAL DESIGN: Eligible patients were children with refractory tumors who had received cumulative anthracycline doses <300 mg/m(2). Cohorts of at least three patients each received escalating doses of Doxil starting at 40 mg/m(2) at 4-week intervals. If no dose-limiting toxicity occurred, dosages were escalated by increments of 10 mg/m(2) in subsequent cohorts. Originally, Doxil was administered over 60 min, but significant infusion reactions prompted longer infusion times of 4 h. Patients also received premedication with dexamethasone, ranitidine, and diphenhydramine 24 h before infusion, with ranitidine continued 24 h after infusion. Periodic blood samples were collected and plasma doxorubicin concentrations were quantified to characterize the pharmacokinetics of Doxil. RESULTS: Between January 1997 and June 2000, 22 children ages 4-21 years with refractory tumors were treated with Doxil. Most patients had received one to five prior chemotherapy regimens, and all but five had prior radiotherapy (two had no prior therapy). Doxil was escalated to a dosage of 70 mg/m(2). At that level, dose-limiting mucositis was seen during the first cycle in two of six patients, thus defining dose-limiting toxicity, and in one additional patient during a subsequent cycle. Grade 4 neutropenia lasting less than 7 days was documented in two of six patients. The dose-limiting toxicity among two of six patients at 70 mg/m(2) was grade 3 mucositis during the first cycle of therapy. Painful desquamating dermatitis of the hands and feet, palmar-plantar erythrodysesthesia, occurred in six patients. In two of those patients, palmar-plantar erythrodysesthesia started as grade 1 and progressed to grade 2 during subsequent courses. Mean estimates of central volume of distribution, clearance, and elimination half-life were 1.45 liters/m(2), 0.03 liter/h/m(2), and 36.4 h, respectively. CONCLUSION: The maximum tolerated dose of Doxil administered every 4 weeks to pediatric patients was 60 mg/m(2). The effect of Doxil on pediatric patients with malignancies remains to be determined and should be studied in pediatric Phase II trials.

Adolescent↗

PubMed2002

Testing of new agents in childhood cancer preclinical models: meeting summary.

A workshop on pediatric preclinical testing, sponsored by the National Cancer Institute and the Children's Oncology Group Phase 1 Consortium, was held on June 26-27, 2001 in Bethesda, Maryland. Drs. Peter Adamson, Peter Houghton, and Malcolm Smith organized and hosted the meeting. There were 20 participants from 12 institutions. The primary objectives of the workshop included: (a) development of a working inventory of available preclinical models (including human tumor xenografts in immunodeficient mice, transgenic and syngeneic tumors, and selected in vitro models), with a basic understanding of the strengths and weaknesses of each as possible components of a preclinical testing program; (b) identification of the key scientific issues related to establishment of a program for preclinical testing of new agents for their applicability to childhood cancers; and (c) identification of the key infrastructure requirements for a program for preclinical testing of new agents for their applicability to childhood cancers. This report is a synthesis of the workshop's presentations and discussions.

Animals↗

PubMedDate not supplied

New agents for intrathecal administration.

Intrathecal administration of chemotherapy, with or without radiation therapy, is the primary treatment modality for the prevention and treatment of central nervous system (CNS) metastases in patients with leukemia or lymphoma. Although this treatment strategy has been very effective for patients with hematological malignancies, currently available intrathecal agents are relatively ineffective for patients with neoplastic meningitis resulting from an underlying solid or CNS tumor effective. This article provides an overview of some of the practical considerations and limitations associated with intrathecal chemotherapy, and is followed by a comprehensive review of some of the preclinical and early phase clinical trials of novel anticancer agents and treatment strategies using the intrathecal route.

Animals↗

PubMedDate not supplied

Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop.

Childhood atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) is a recently described entity. Diagnosis is based on distinctive light microscopy and immunohistochemical findings, coupled with molecular genetic analysis. Most AT/RTs demonstrate monosomy 22 or deletions of chromosome band 22q11 with alterations of the hSNF5/INI1 gene. The tumor's incidence is still undefined, but it may comprise as high as 1 in 4 primitive CNS tumors in infants. Treatment is far from optimal, but there are occasional long-term survivors, especially among older children. Therapeutic approached have included surgery, chemotherapy, and radiotherapy. Prospective clinical trials are needed for children with AT/RTs.

Antineoplastic Agents↗