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1.
J Pediatr Hematol Oncol ; 19(4): 309-12, 1997.
Article in English | MEDLINE | ID: mdl-9256829

ABSTRACT

PURPOSE: To determine the hematopoietic and nonhematopoietic toxicity of a novel dose-intensive chemotherapy regimen for the treatment of children with relapsed solid tumors. PATIENTS AND METHODS: The time to hematopoietic recovery and toxicity experienced during 46 courses of high-dose cyclophosphamide (4.0 g/m2), MESNA, and carboplatin (400 mg/m2) with granulocyte colony stimulating factor (G-CSF) support in 14 children with recurrent solid tumors was reviewed. RESULTS: All patients developed grade 4 neutropenia and thrombocytopenia. Recovery to an absolute neutrophil count (ANC) of 500/microliter and platelet count of 50,000/microliter occurred at a median of 15 days and 23 days respectively. Median time to ANC > 1,000/microliter and platelets > 100,000/microliter was 27 days. Hospitalization for fever and neutropenia occurred during 35 of 46 courses, with documented bacteremia in six courses. There was no grade II or greater nonhematopoietic organ toxicity. Responses (CR + PR) were observed in 6 of 11 evaluable patients. CONCLUSIONS: These data suggest that this regimen is tolerable in heavily pretreated children with solid tumors with myelosuppression as the primary toxicity. Due to the lack of significant nonhematopoietic toxicity, this is a good candidate regimen for dose escalation using peripheral blood progenitor cell infusions and deserves further evaluation for efficacy in children with both recurrent and newly diagnosed high-risk solid tumors.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adolescent , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brain Neoplasms/drug therapy , Carboplatin/administration & dosage , Child , Child, Preschool , Cyclophosphamide/administration & dosage , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Male , Neoplasm Recurrence, Local/drug therapy , Neuroblastoma/drug therapy , Neuroectodermal Tumors, Primitive/drug therapy , Salvage Therapy
2.
J Clin Oncol ; 14(3): 919-24, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8622040

ABSTRACT

PURPOSE: We sought to identify factors assessable at the time of admission for fever and neutropenia that predict bacteremia in children with cancer. PATIENTS AND METHODS: One hundred fifteen consecutive episodes of fever and absolute neutrophil count (ANC) less than 500/microliter in 72 children with cancer were studied prospectively to determine the risk of bacteremia using data assessable at the time of presentation. After exploratory analysis identified admission temperature and absolute monocyte count (AMoC) as the strongest predictive factors, recursive partitioning was used to determine cutpoints for these variables that resulted in discrimination between episodes associated with a lower or higher risk of bacteremia. RESULTS: There were 24 episodes of bacteremia (21% of episodes). Episodes were grouped using the cutpoints for AMoC and temperature: 17% were classified as low risk for bacteremia (AMoC > or = 100/microliter), 65% as intermediate risk (AMoC < 100/microliter and temperature < 39.0 degrees C), and 18% as high risk (AMoC < 100/microliter and temperature > or = 39.0 degrees C). No episodes classified as low risk were associated with bacteremia; 19% of intermediate-risk and 48% of high-risk episodes were associated with bacteremia. The odds ratio of bacteremia for the high-risk versus the intermediate-risk group is 4.4 (95% confidence interval, 1.6 to 12.9). The risk classification was validated using data from 57 different episodes of fever and neutropenia treated in the same hospital. CONCLUSION: Three levels of risk for bacteremia are defined using the AMoC and temperature at the time of admission for fever and neutropenia. Trials now should be conducted to test whether these factors may be used to assign some children to less intensive or outpatient antibiotic therapy at the time of presentation with fever and neutropenia.


Subject(s)
Bacteremia/complications , Fever/complications , Neoplasms/complications , Neutropenia/complications , Adolescent , Bacteremia/diagnosis , Bias , Child , Child, Preschool , Hospitalization , Humans , Infant , Leukocyte Count , Monocytes , Odds Ratio , Predictive Value of Tests , Prospective Studies , Regression Analysis
3.
Semin Pediatr Surg ; 2(1): 2-10, 1993 Feb.
Article in English | MEDLINE | ID: mdl-8062019

ABSTRACT

Investigation in cellular and molecular genetics has yielded a wealth of new information regarding the role of genetic alterations in the etiology of childhood cancer. The recent advancement of molecular biologic techniques has allowed researchers to bridge the gap from the description of chromosomal aberrations in tumor cells to the current identification of oncogenes and tumor suppressor genes involved in malignant transformation. This article reviews the advances in molecular genetics of childhood cancer, briefly outlines the history, and details the current knowledge of the use of cytogenetics, oncogenes, and other tools in the diagnosis, management, and further understanding of pediatric malignancies.


Subject(s)
Cell Transformation, Neoplastic/genetics , Chromosome Aberrations , Neoplasms/genetics , Child , Genes, Tumor Suppressor/genetics , Humans , Molecular Biology , Oncogenes/genetics , Prognosis
4.
J Clin Oncol ; 11(1): 84-90, 1993 Jan.
Article in English | MEDLINE | ID: mdl-8418247

ABSTRACT

PURPOSE: A nonrandomized, single-arm trial was conducted to assess the efficacy of multimodality therapy including intensive chemotherapy with multiple alkylating agents in the treatment of children with Evans stage III neuroblastoma older than 1 year at diagnosis. PATIENTS AND METHODS: Twenty-five patients with a median age of 18 months at diagnosis were treated with multimodality therapy including surgery and chemotherapy using either nitrogen mustard (mechlorethamine), doxorubicin, cisplatin, dacarbazine (DTIC), vincristine, and cyclophosphamide (MADDOC) or cisplatin and cyclophosphamide induction followed by maintenance MADDOC (induction MADDOC) protocols. Sixteen of 25 patients also received radiotherapy to the tumor bed and primary lymph nodes. Event-free survival (EFS) was compared with that reported previously in the literature. N-myc amplification was evaluated prospectively and the Shimada classification was evaluated retrospectively as potential prognostic factors. RESULTS: We report a 72% EFS (95% confidence interval +/- 18%) with a median follow-up of 85 months. EFS was significantly worse for patients with tumors demonstrating N-myc amplification (P = .018). Patients classified as favorable according to the Shimada system experienced a significantly better EFS (P = .04), but unfavorable patients still maintained a 60% EFS. CONCLUSION: Intensive multimodality treatment including MADDOC and induction MADDOC chemotherapy provides a very good EFS for children older than 1 year who have stage III neuroblastoma. Children classified as favorable according to the Shimada system have a better prognosis. Patients whose tumors demonstrate N-myc amplification have a poor prognosis despite therapy.


Subject(s)
Alkylating Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neuroblastoma/drug therapy , Child, Preschool , Combined Modality Therapy , Gene Amplification , Genes, myc , Humans , Infant , Neoplasm Staging , Neuroblastoma/genetics , Neuroblastoma/pathology , Prospective Studies , Survival Analysis , Treatment Outcome
5.
Cancer ; 70(8): 2208-13, 1992 Oct 15.
Article in English | MEDLINE | ID: mdl-1394053

ABSTRACT

BACKGROUND: Recent reports of secondary acute myelogenous leukemia (AML) occurring in children previously treated for acute lymphoblastic leukemia (ALL) prompted a review of patients with ALL treated at the Dana Farber Cancer Institute consortium (DFCI) between 1973 and 1987. Seven hundred fifty-two of 779 children treated for ALL entered complete remission. The mean follow-up time for the 752 patients was 4.4 years. Two children had AML develop 12 and 13 months after the diagnosis of ALL, respectively. METHODS: The estimated overall risk of secondary AML was calculated for the patient population as instances per 1000 patient-years of follow-up. This was compared with recent reported cases from another institution. RESULTS: The estimated overall risk of secondary AML was 0.61 instances per 1000 patient-years of follow-up (95% confidence interval: 0.15, 4.4). The difference between the risk of 0.61 among DFCI patients versus previously reported risk of 5.8 among a differently treated group of patients with ALL was statistically significant (P = 0.0008). No epipodophyllotoxin was used in the patients in the DFCI consortium. In contrast, an epipodophyllotoxin was used in 12 of 13 previously reported patients who had secondary AML develop. CONCLUSIONS: The authors concluded that the use of epipodophyllotoxins may be associated with an increased risk of having secondary AML develop in patients with ALL.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/epidemiology , Neoplasms, Second Primary/epidemiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Child , Child, Preschool , Follow-Up Studies , Humans , Incidence , Infant , Retrospective Studies , Risk
6.
Proc Natl Acad Sci U S A ; 87(13): 5046-50, 1990 Jul.
Article in English | MEDLINE | ID: mdl-1695008

ABSTRACT

The human interleukin 3 (IL-3) promoter is comprised of several cis-acting DNA sequences that modulate T-cell expression of IL-3. These are located within 315 nucleotides upstream of the mRNA start site. Transient expression of reporter genes linked to serially deleted sequences of the IL-3 promoter has allowed mapping of two activator sequences and an interposed repressor sequence. The proximal regulatory region is specific to IL-3 and prerequisite for efficient transcription. Its effect is enhanced by a second, more distal activating sequence consisting of an AP-1 binding site. Between the two activators lies a transcriptional silencer, which is a potent repressor in the absence of the AP-1 site. DNA-nuclear protein binding experiments demonstrate specific complex formation within each of these functional regions. Thus, both positive and negative regulatory elements appear to control expression of the human IL-3 gene in activated T cells.


Subject(s)
Gene Expression Regulation , Interleukin-3/genetics , Promoter Regions, Genetic , Base Sequence , Cell Line , Deoxyribonuclease I , Gene Expression , Humans , Lymphocyte Activation , Molecular Sequence Data , Oligonucleotide Probes , RNA/genetics , RNA/isolation & purification , Ribonucleases , T-Lymphocytes/immunology , Transfection
7.
Nucleic Acids Res ; 9(5): 1191-1202, 1981 Mar 11.
Article in English | MEDLINE | ID: mdl-6894489

ABSTRACT

We have developed a procedure for selectively enriching a mRNA population for inducible sequences. Other than the induced mRNA species, the population of mRNA in control cells is approximately the same as the mRNA population in induced cells. Cytoplasmic mRNA from control cells is bound to oligo (dT)-cellulose and used as a template for reverse transcriptase, the oligo (dT) serving as a primer. After removing the template mRNAs, the cDNA-cellulose column is used to hybridize a population of mRNAs from induced cells. The non-hybridized poly A+ RNAs are greatly enriched in the inducible sequences. We have used this technique of hybridization subtraction chromatography to select a mRNA population enriched for the mRNAs inducible by ecdysterone in Schneider's Line 2 Drosophila cells. This population of RNAs was used to screen a recombinant library. Preliminary results indicate that approximately 10% of the RNA in the probe population represents ecdysterone inducible sequences. Methods are described for optimizing the cDNA synthesis reaction (we obtain greater than or equal to 30% efficiency) and hybridizing RNA to the cDNA-cellulose resin. This method can be used to select induced mRNAs regardless of the way in which the induction is brought about.


Subject(s)
Ecdysterone/pharmacology , Genes , RNA, Messenger/isolation & purification , Animals , Cellulose , Chromatography/methods , Cloning, Molecular , DNA , Drosophila/genetics , Nucleic Acid Hybridization , RNA, Messenger/biosynthesis
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