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Biomedical subjects

C B Pratt

Publications and source records attributed to C B Pratt.

At least 109 records · Page 6Linked to original sources
PubMed1993

Ifosfamide/etoposide combination in the treatment of recurrent malignant solid tumors of childhood. A Pediatric Oncology Group Phase II study.

BACKGROUND: The prognosis for children with recurrent or resistant malignant solid tumors remains dismal. More effective rescue therapy is needed for these children. METHODS: Between August 1987 and November 1990, 311 children with recurrent or resistant malignant solid tumors were treated by investigators in the Pediatric Oncology Group with intravenous infusions of 2.0 g/m2 of ifosfamide and 100 mg/m2 of etoposide (VP-16) plus mesna as uroprotection three times daily, with courses being repeated every 14-21 days for as long as the patients responded to therapy. RESULTS: Seventy-four percent of the 294 assessable patients entered in the study had metastatic disease and previously had been treated heavily. The complete response/partial response rate was 30%, and the overall response rate was 39.5%. Toxic effects included nephrotoxicity, mild liver dysfunction, neurotoxicity, and myelosuppression. Sixty-eight percent had an absolute neutrophil count (ANC) of less than 500/microliters. In 1606 courses of therapy administered, only 3.6% of patients developed a bacterial infection. Only two patients died of gram-negative sepsis. Four percent of the patients had gross hematuria (> 50 erythrocytes/high-power field), and 18.5% had microscopic hematuria (< 20 erythrocytes/high-power field). Fanconi syndrome developed in eight children. CONCLUSIONS: Ifosfamide/VP-16 is an active combination in children with recurrent malignant solid tumors. Although it was myelosuppressive, the incidence of infection was quite low (3.6%). Mesna was very effective in preventing the development of hematuria.

Adolescent↗
PubMed1993

Saturable elimination and saturable protein binding account for flavone acetic acid pharmacokinetics.

Flavone acetic acid (FAA) is an antineoplastic agent that has undergone extensive study in Phase I trials. Concentration-dependent plasma protein binding has been demonstrated in vitro at concentrations of total drug that are achieved in vivo. Moreover, dose-dependent total systemic clearance has been described when FAA has been administered as a short iv infusion. When administered as a prolonged 24-hr infusion, total FAA (bound plus unbound) plasma pharmacokinetics are well described with a first-order two-compartment model. However, measurement of unbound FAA intra- and post-intravenous infusion in eight patients revealed a twofold increase in fraction of FAA unbound in plasma intrainfusion. We attempted to fit pharmacokinetic structural models of varying complexity to the unbound concentrations alone and simultaneously to the unbound and bound FAA plasma concentrations. The data were adequately described only by a model that incorporated simultaneous saturable plasma protein binding and a Michaelis-Menten process for elimination. A comparison among models is presented, as well as pharmacokinetic parameter estimates for FAA in children. These clinical data are consistent with predictions of the clearance model in which both saturable protein binding (resulting in a dynamically increasing unbound fraction) and saturable elimination (resulting in gradually decreasing unbound intrinsic clearance) are operative.

Antineoplastic Agents↗
PubMed1993

Radiographic findings in 13q-syndrome.

Of 169 children with retinoblastoma treated at our institution between 1962 and 1993, 5 had concurrent severe mental retardation, hypotonia, and abnormalities of constitutional chromosome 13. The associated skeletal abnormalities of these 5 children are described and include delayed skeletal maturation, metaphyseal abnormalities, microcrania, facial bone abnormalities, and gracile long bones.

Abnormalities, Multiple↗
PubMed1993

Phase I clinical trial of recombinant human tumor necrosis factor in children with refractory solid tumors: a Pediatric Oncology Group study.

PURPOSE: A phase I study was undertaken to determine the toxicity and maximum-tolerated dose (MTD) of recombinant human tumor necrosis factor (rTNF) in children. PATIENTS AND METHODS: Twenty-seven patients with recurrent or refractory solid tumors were enrolled on the study. rTNF was administered daily for 5 days by 30-minute intravenous (IV) infusion, and doses were escalated in cohorts of three to six patients. Courses were repeated after a 9-day rest period, if toxicity was tolerable. Daily doses ranged from 100 to 350 micrograms/m2. RESULTS: Most courses were associated with grade I/II fever, rigors, nausea, or vomiting. Three patients experienced moderate dyspnea that responded to supplemental oxygen. All abnormalities resolved on discontinuation of the infusion. One patient had a cardiac arrest 90 minutes after receiving the first dose of rTNF and died 10 days later of related complications. In two other patients, rTNF was discontinued due to persistent grade IV hypotension. Toxicities were not consistently related to dose and no cumulative effects were noted. The dose-limiting toxicity was transient hepatic dysfunction, which occurred in three of six patients receiving 350 micrograms/m2; this toxicity was rapidly reversed on discontinuation of the rTNF. One patient, whose non-Hodgkin's lymphoma had recurred after bone marrow transplantation, had a partial response. Disease was stabilized in two patients. CONCLUSION: We recommend that phase II testing proceed at a dose of 300 micrograms/m2/d on the schedule described.

Adolescent↗
PubMed1993

Phase I trial of paclitaxel in children with refractory solid tumors: a Pediatric Oncology Group Study.

PURPOSE: A phase I study was performed to describe the principal toxicities and identify the maximum-tolerated dose (MTD) of Taxol (paclitaxel; Bristol-Myers Squibb Co, Wallingford, CT) in children with therapy-resistant solid tumors. Additionally, the pharmacokinetic disposition of Taxol in children was studied, and preliminary evidence of the activity of Taxol against pediatric solid tumors was assessed. PATIENTS AND METHODS: Twenty-four-hour continuous infusions of Taxol were administered every 21 days to children (median age, 12 years; range, 2 to 22) with refractory solid tumors. Doses ranged from 200 to 420 mg/m2, there was no intrapatient dose escalation. RESULTS: A total of 62 courses of Taxol were administered to 31 patients. Two patients developed acute anaphylaxis during their second infusion of taxol at doses of 200 mg/m2 and 350 mg/m2, respectively. No other allergic reactions were documented. Myelosuppression occurred at all dose levels, but was of short duration (< or = 7 days) and did not appear to increase with consecutive courses or at higher dosage levels. A stocking-and-glove peripheral neuropathy became evident at doses > or = 290 mg/m2. Dose-limiting neurotoxicity occurred at 420 mg/m2 and comprised a significant fine-motor and peripheral neuropathy in one patient, and a tonic-clonic seizure in another. End-of-infusion plasma concentrations ranged from 0.40 to 6.4 mumol/L, and were not found to be dose-dependent over the range of doses studied. A complete response was documented in one patient, partial response in two, and minimal response in one for an overall response rate of 13%. CONCLUSION: Neurotoxicity was dose-limiting when Taxol was administered by 24-hour continuous infusion to pediatric patients with relapsed solid tumors. In this population, the recommended dose for phase II trials is 350 mg/m2/d.

Adolescent↗
PubMed1992

Improved prognosis of children with osteosarcoma metastatic to the lung(s) at the time of diagnosis.

BACKGROUND: A poor outcome is traditionally ascribed to osteosarcoma metastatic to the lungs, but data have been unavailable regarding the outcome of such patients after systematic treatment on clinical trials. METHODS: The clinical course and outcome of 31 patients who had osteosarcoma metastatic to the lungs diagnosed between 1962 and 1990 at St. Jude Children's Research Hospital were reviewed to determine whether the use of increasingly aggressive multimodality therapy has improved their outcome. The patients were grouped by treatment eras, based on major changes in therapy (i.e., single-agent or two-agent era, 1962-1972; standard multiagent era, 1972-1982; and intensive multiagent era, 1982-1990). RESULTS: With increasingly intensive chemotherapy, more aggressive efforts to resect metastatic disease, and earlier detection of pulmonary metastases by computed tomography, the survival of these patients has improved significantly over the 28-year study period. Those treated since 1982 have a 50% estimated probability of survival at 3 years, whereas there were no survivors at 3 years in the two earlier eras. Survival for the former group reached a plateau of 30% at 4 years. CONCLUSIONS: The use of aggressive multimodality therapy, coupled with modern pediatric imaging techniques to detect pulmonary disease, has improved the traditionally dismal outlook in pediatric patients with osteosarcoma and synchronous pulmonary metastases.

Adolescent↗
PubMed1992

Carcinoembryonic antigen and carbohydrate 19-9 antigen as markers for colorectal carcinoma in children and adolescents.

Colorectal cancer is rare in patients younger than 20 years of age (incidence, 1 in 10 million). Although carcinoembryonic antigen (CEA) and carbohydrate 19-9 antigen (CA 19-9) have been used widely as markers for the efficacy of therapy or detection of recurrent colorectal carcinomas in adults, no studies evaluating their efficacy in children and adolescents have been performed. Between 1986 and 1989, serial measurements of serum CEA and CA 19-9 levels were obtained from 11 patients (aged 8 to 18 years) treated at the institution of the authors. In contrast to the experience in adults, most (9 of 11) of the tumors were localized in the right or transverse colon. Histologically, 10 of 11 carcinomas were mucinous. Most patients had either Dukes' C (5 of 11) or D (5 of 11) lesions. After surgery, all patients were treated with a combination of 5-fluorouracil with Leucovorin (Lederle Laboratories, Pearl River, NY). With the use of the adult normal standards (CEA less than 3.0 ng/ml and CA 19-9 less than 37 ng/ml)6 for the patients, the specificity and sensitivity of CEA were 77% and 64%, respectively, whereas the specificity of CA 19-9 was 79% and the sensitivity was significantly low (10%). The combined specificity of the two markers was 71%, and the combined sensitivity was 60%. On the basis of these results, the authors believe that CEA and CA 19-9 are not effective markers for detection of recurrent or progressive colorectal carcinomas in children and adolescents.

Adenocarcinoma, Mucinous↗
PubMed1992

Use of GM-CSF in children after high-dose chemotherapy.

The toxicity and efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) is established in adults, but limited information is available on its use in children. The profound myelotoxicity induced by cisplatin (40 mg/m2 daily x 5) and etoposide (150 mg/m2 daily x 3) provides a model to test the clinical value of recombinant human granulocyte-macrophage colony-stimulating factor in pediatric cancer patients; myelosuppression occurred (absolute neutrophil count [ANC] < 500/microL) during 99 of 118 (84%) courses given to 44 children with refractory solid tumors. Fifty-nine courses (50%) resulted in hospitalizations for fever. Subsequently, rhuGM-CSF was added to this treatment regimen to: (i) determine the dose-limiting toxicity of this agent in children; and (ii) to determine whether it can decrease the duration and severity of neurtropenia and attendant complications. Here we summarize and update our experience with this glycoprotein in children with relapsed solid tumors.

Adolescent↗
PubMed1992

Ifosfamide plus etoposide in newly diagnosed Ewing's sarcoma of bone.

PURPOSE: We assessed the activity of ifosfamide plus etoposide against newly diagnosed Ewing's sarcoma of bone by administering this drug pair before standard induction therapy (the upfront window approach). PATIENTS AND METHODS: Twenty-six children and adolescents with newly diagnosed, previously untreated Ewing's sarcoma of bone were enrolled onto this pilot study (EW-87). Eighteen were at a higher risk of treatment failure, with a primary tumor size of more than 8 cm or metastases at diagnosis. Window therapy with ifosfamide (1.6 g/m2/d with mesna uroprotection) and etoposide (100 mg/m2/d) was given in three 5-day cycles at 21-day intervals. Responses were evaluated clinically and radiologically. Subsequent induction therapy comprised three cycles of cyclophosphamide and doxorubicin. Radiation therapy was the primary local control modality; surgery was limited to biopsy or resection of expendable bones. After the local control phase, alternating courses of vincristine plus dactinomycin, ifosfamide plus etoposide, and cyclophosphamide plus doxorubicin were given as maintenance therapy. RESULTS: There were four complete responses and 21 partial responses to ifosfamide/etoposide window therapy (overall response rate 96%; 95% confidence interval [CI], 80% to 99%). Disease progression was observed in four patients during the cyclophosphamide/doxorubicin phase. Chemotherapy was well tolerated; only 16% (20 of 125) of all ifosfamide/etoposide window and maintenance cycles resulted in hospitalization for fever and neutropenia. Two patients developed chemotherapy-induced cystitis. CONCLUSIONS: The combination of ifosfamide and etoposide is highly active against previously untreated Ewing's sarcoma and generally is well tolerated. The ultimate impact of these two agents on outcome will be determined in randomized multicenter studies.

Adolescent↗
PubMed1992

Recombinant human TNF-alpha stimulates the secretion of granulocyte colony-stimulating factor in vivo.

Tumor necrosis factor (TNF) is a macrophage-derived cytokine that causes hemorrhagic necrosis of several human tumors in vitro. It has a wide range of biologic effects including stimulation of secretion of both granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) by normal adult lung fibroblasts in culture. No in vivo data are available on the effect of exogenously administered TNF on cytokine production. In the studies reported here, we show that G-CSF accumulates in the serum in vivo in response to recombinant TNF (rTNF) administration. At the peak of the response circulating levels of 2-6 ng/ml of biologically active G-CSF are detectable. Surprisingly, circulating levels of GM-CSF, interleukin-3 as well as a number of other cytokines were not detectable within the limits of the assays. The results indicate that the levels of GM-CSF or interleukin-3 are minimally 100-fold lower than the peak levels of G-CSF. These data illustrate the complex interplay that cytokines have in vivo. Understanding these interactions in humans is crucial to the correct use of this new class of agents in the clinic.

Adenocarcinoma↗
PubMed1992

Current studies of ifosfamide for pediatric solid tumors and leukemia in the United States.

This paper reviews current approaches to the use of ifosfamide/mesna alone or in combination with other agents or modalities in the treatment of pediatric malignancies. Included are data from current or recently completed studies conducted by major pediatric oncology cooperative groups and large individual oncology centers for patients with newly diagnosed or recurrent tumors. Sarcomas, neuroblastoma, lymphomas, recurrent solid tumors, brain tumors, and acute lymphoblastic leukemia are discussed. Randomized trials to determine the relative efficacy of ifosfamide and cyclophosphamide in various childhood malignancies are under way. The long-term consequences of ifosfamide in survivors of childhood cancer, in terms of development of bladder cancer or other malignancies thought to be associated with alkylating agents, are not known, and will only be determined through follow-up studies of adult survivors. Ifosfamide's future role in pediatric oncology will depend on evaluation of its therapeutic benefits against long-term toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Pediatric nonrhabdomyosarcomas of the extremities. Influence of size, invasiveness, and grade on outcome.

Surgery alone or supplemental radiation is effective in local control in a majority of patients with nonrhabdomyosarcoma of the soft tissue. To determine the factors influencing subsequent survival, a retrospective review of 64 children with nonrhabdomyosarcoma of the soft tissue of the extremities was performed. Using the American Joint Committee on Cancer staging system, 32 patients had noninvasive T1 lesions, and 31 of these patients survived disease free. Twenty-two patients had lesions that were smaller than 5 cm; 19 of these lesions were grade G1-2. All 22 patients survived. Ten patients had tumors that were 5 cm or larger, and all were G1-2; nine of these patients survived. Thirty-two patients had invasive (T2) lesions; seven of these lesions were smaller than 5 cm, but four were G3. Only one patient survived. Eighteen (72%) of 25 lesions that were 5 cm or larger were G3. Fifteen (83%) of these 18 patients underwent relapse, with 12 patients dying of the disease. Important prognostic factors included G3 lesions, with a 72% (18 of 25 patients) failure rate, and T2 lesions, which were generally larger than 5 cm, of higher grade, and underwent relapse more frequently than T1 lesions. These patients with histologic G3 and T2 lesions may benefit from chemotherapy.

Adolescent↗