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Biomedical subjects

G D Hammond

Publications and source records attributed to G D Hammond.

At least 55 records · Page 3Linked to original sources
PubMed1992

A phase I study of interleukin-2 in children with cancer.

Recombinant interleukin-2 (IL-2) produces clinical responses in approximately 20% of adult patients with renal cell carcinoma and melanoma, with both high-dose bolus and continuous infusion regimens. Because of the lower toxicity of continuous infusion, we elected to investigate in a Phase I trial a 5-day continuous infusion repeated for three weeks in children with malignancies refractory to standard therapy. Nineteen children with solid tumors and eight children with hematologic malignancies were entered into the study. The maximum tolerated dose was 3 x 10(6) U/m2/day, with dose-limiting toxicities occurring in five of seven patients treated at the 5 x 10(6) U/m2/day dose level. Dose-limiting toxicities included hypotension, hyperbilirubinemia, thrombocytopenia, pulmonary/pleural effusion, and nephrotoxicity. Serum IL-2 levels were detectable at the higher dose levels and were comparable to those observed in adult patients. Hematologic changes at the higher dose levels included rebound lymphocytosis occurring within 48 h of discontinuation of IL-2, eosinophilia, and decreased platelet counts. No objective responses to therapy were seen. We have identified a dose and schedule of administration for IL-2 in pediatric patients that can be given without intensive care unit support. Pediatric Phase II trials examining the anti-tumor activity of IL-2 given by this schedule are in progress.

Adolescent↗
PubMed1991

Second neoplasms after acute lymphoblastic leukemia in childhood.

BACKGROUND: Effective forms of treatment for acute lymphoblastic leukemia (ALL) in childhood now result in survival rates above 70 percent at five years, but the treatments are potentially carcinogenic. To determine the magnitude of this risk and identify possible risk factors for the development of second neoplasms, we studied a large cohort of children treated for ALL. METHODS AND RESULTS. We undertook a retrospective cohort study of 9720 children who had been given a diagnosis of ALL between June 1972 and August 1988 and had been treated according to the therapeutic protocols of the Children's Cancer Study Group. The median follow-up was 4.7 years (range, 2 months to 16 years). We found that 43 second neoplasms occurred among the children in the cohort, including 24 neoplasms of the central nervous system, 10 new leukemias and lymphomas, and 9 other neoplasms. This represented a 7-fold excess of all cancers and a 22-fold excess of neoplasms of the central nervous system. The estimated cumulative proportion of children in whom a second neoplasm developed was 2.53 percent 15 years after diagnosis (95 percent confidence limits, 1.74 percent and 3.38 percent). An even higher risk, particularly of central nervous system tumors, was evident in children five years of age or less at the time of the diagnosis of ALL (P = 0.012). All central nervous system neoplasms developed in children who had previously undergone irradiation. There was no association with exposure to cyclophosphamide or anthracyclines. CONCLUSIONS: There is a substantial excess of second neoplasms, especially of the central nervous system, among children treated for ALL. Children five years old or younger and those receiving radiation are at higher risk, especially for second tumors arising in the central nervous system.

Central Nervous System Neoplasms↗
PubMed1991

Pharmacology and phase I trial of high-dose oral leucovorin plus 5-fluorouracil in children with refractory cancer: a report from the Children's Cancer Study Group.

Because of the synergy seen in adult trials when 5-fluorouracil is combined with leucovorin, we initiated a Phase I trial of this combination in children's refractory cancer. Leucovorin, an equal mixture of the (6R,S)-diastereoisomers, was administered p.o. for 6 consecutive days as 4 equal doses at 0, 1, 2, and 3 h totaling 500 mg/m2/day. 5-Fluorouracil was given daily on days 2 to 6 as an i.v. bolus immediately following the last dose of leucovorin. The leucovorin dose was held constant while the 5-fluorouracil dose was escalated in cohorts of patients from 300 mg/m2/day to its maximally tolerated dose. Thirty-five patients (19 with acute leukemia and 16 with solid tumors) were evaluable for toxicity. The maximally tolerated dose of FUra was 450 mg/m2/day for 5 treatments for patients with solid tumors and 650 mg/m2/day for 5 treatments for the children with leukemia. The dose-limiting toxicities were myelosuppression and stomatitis. Other side effects included transient, mild elevations of serum transaminases, mild nausea, vomiting, and diarrhea. The pharmacokinetics of high-dose p.o. leucovorin was studied in 23 children. There was considerable interpatient variability in the plasma concentrations of total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid. The maximum plasma concentration (Cmax) of TBAF was 821 +/- 97 (SE) nM, occurring at a median of 8 h; the Cmax of (6S)-leucovorin was 77 +/- 11 nM, occurring at 4 h. The TBAF concentration fell to 146 +/- 42 nM by 24 h. (6S)-5-Methyltetrahydrofolic acid accounted for 90 +/- 7% of the TBAF at the Cmax. The plasma concentration of (6R)-leucovorin, the unnatural isomer, was equal to that of TBAF. Thus, p.o. leucovorin reduced the 5-fold excess of (6R)-leucovorin over TBAF seen after i.v. doses. The relative amounts of the three major plasma species were approximately the same as in adults, even though the Cmax of each compound was lower.

Administration, Oral↗
PubMed1991

Successful reinduction therapy with amsacrine and cyclocytidine in acute nonlymphoblastic leukemia in children. A report from the Childrens Cancer Study Group.

Amsacrine (AMSA) and cyclocytidine were studied as retrieval therapy in 122 pediatric patients with acute nonlymphoblastic leukemia (ANLL). Patients either failed to achieve sustained initial remissions or were in relapse. Induction therapy consisted of intravenous (IV) AMSA (75 mg/m2) from days 1 to 5 and subcutaneous cyclocytidine (600 mg/m2) from days 1 to 7. Maintenance therapy consisted of IV etoposide (VP-16) (100 mg/m2) for 5 days and IV AMSA (100 mg/m2) on day 1. Of 122 patients, 109 were evaluable. There were 13 early deaths. Ninety-six patients received adequate therapy defined as completion of two courses of therapy. Of these 96 patients, 52 achieved complete remission. Fifteen of 33 patients who failed initial induction achieved complete remission. Eighteen of 39 patients who were resistant to anthracyclines had complete responses. There was no direct evidence of AMSA-induced cardiotoxicity. Remission duration was 28 days to 3 or more years (median, 98 days). AMSA and cyclocytidine were effective retrieval therapy for patients who were in relapse or unresponsive to frontline therapy. Duration of remission was short (median, 98 days).

Adolescent↗
PubMed1991

Prognostic value of immunocytologic detection of bone marrow metastases in neuroblastoma.

BACKGROUND: Morphologic evaluation of bone marrow for neuroblastoma cells is a routine and important component of clinical staging. Specific immunostaining of malignant cells with monoclonal antibodies should be more sensitive, however, and may improve the detection of metastases and provide additional prognostic information. METHODS: We looked for tumor cells in bone marrow from 197 patients with newly diagnosed neuroblastoma, using immunoperoxidase staining with monoclonal antibodies (immunocytologic analysis) and examination of smears and specimens obtained by trephine biopsy (conventional analysis). RESULTS: Routine smears and trephine-biopsy specimens were positive for tumor cells in 46 percent of the patients, whereas 67 percent were positive on immunocytologic analysis (P less than 0.0001). Immunocytologic analysis detected bone marrow metastases in 34 percent of patients considered to have only localized or regional disease (Stage I, II, or III). It also identified tumor cells that were not detected by conventional analysis in patients with widespread disease (Stage IV or IVS). Tumor content, as determined by immunocytologic analysis, predicted clinical outcome in relation to the age of the patient at diagnosis. Patients with Stage II or III disease diagnosed after one year of age who did not have occult marrow metastases did well, whereas those with metastases did poorly (P = 0.006). Patients in whom Stage IV disease was diagnosed before they were one year of age did well if bone marrow metastases were few or absent, but had poor survival if the marrow contained more than 0.02 percent tumor cells (P = 0.03). CONCLUSIONS: Immunocytologic analysis of bone marrow aspirates is more sensitive than conventional analysis in detecting tumor cells and provides prognostic information. The relations among marrow metastases, age at diagnosis, and clinical outcome illustrate the biologic heterogeneity of neuroblastoma.

Age Factors↗
PubMed1991

Association of delivered drug dose and outcome for children with acute lymphoblastic leukemia and unfavorable presenting features.

Dose and dose intensity are believed critical for attaining a maximal therapeutic effect in drug-responsive tumor systems. Childhood acute lymphoblastic leukemia may be an example of such a drug-responsive system as it is cured with current chemotherapy in a majority of cases. Between August 1981 and May 1983, the Childrens Cancer Study Group enrolled 209 children with ALL and unfavorable presenting features in CCG-193P, a trial based on the Berlin Frankfurt Munster 76/79 regimen. The cumulative delivered dose of each medication was recorded prospectively. Patients who completed the intensive portion of therapy in continuous complete remission were ranked by the percentage of protocol required drug delivered from the initiation of therapy to that date. No association was found between delivery of any single drug and subsequent disease-free survival. However, when patients were ranked by the sum of the percentages of protocol vincristine, l-asparaginase, and anthracycline delivered, children in the approximate middle and lower tertiles were 3 and 5 times more likely to have had a subsequent relapse than were those in the upper tertile (P = 0.025, test for trend). Delivery of the full protocol prescribed dose of these agents may have been critical, but corroboration is certainly needed. Only prospective trials can determine if children with acute lymphoblastic leukemia and unfavorable presenting features might benefit from greater use of vincristine, l-asparaginase, and/or anthracycline.

Adolescent↗
PubMed1991

Intellectual function in long-term survivors of childhood acute lymphoblastic leukemia: protective effect of pre-irradiation methotrexate? A Childrens Cancer Study Group study.

Having demonstrated in a laboratory model that the neurotoxicity of CNS irradiation can be ameliorated with pre-irradiation methotrexate, we retrospectively compared two methods of CNS prophylaxis in childhood acute lymphoblastic leukemia which differed only in the timing of intrathecal methotrexate and radiotherapy. The results of standard IQ tests conducted 2-11 years after 24 Gy of cranial radiotherapy were obtained in 72 patients, of whom 27 had pre-irradiation methotrexate and 45 did not (control group). The two groups were otherwise comparable. In girls, the full-, performance-, and verbal-scale IQ scores were consistently higher in the pre-irradiation methotrexate group than in the corresponding control group (P less than 0.025). Among girls less than 5 years of age when irradiated, the mean IQ scores were 25-29 points higher after pre-irradiation methotrexate than after the control treatment (P less than 0.0007). These results suggest that pre-irradiation methotrexate may help prevent CNS radiotoxicity in children, and that the benefit is dependent on patient age and gender.

Asparaginase↗
PubMed1991

CNS prophylaxis of childhood leukemia: what are the long-term neurological, neuropsychological, and behavioral effects?

Current medical treatments for childhood acute lymphoblastic leukemia (ALL) have improved the outlook to where more than 50% can be expected to survive five years or more. The use of CNS prophylaxis has contributed in a significant way to these improved survival statistics by reducing the likelihood of CNS relapses. The literature relating to the potential adverse psychological consequences of CNS prophylaxis, which include cranial radiation therapy (CRT), is reviewed and analyzed. The majority of published papers of children in first remission report that CNS prophylaxis, which include both CRT and intrathecal methotrexate, results in a variety of learning problems in many children who were younger than age 5 when treated. The available literature on the social, emotional, and educational sequelae of childhood ALL is also reviewed.

Brain↗
PubMed1991

Aggressive surgery combined with intensive chemotherapy improves survival in poor-risk neuroblastoma.

One hundred eighteen children with metastatic (Childrens Cancer Study Group [CCSG] stage IV), extensive regional (stage III), or stage II neuroblastoma with N-myc amplification received an intensive chemotherapeutic regimen of cis-platinum, etoposide, doxorubicin, and cyclophosphamide combined with persistent aggressive attempts at complete primary tumor resection. Fourteen patients were unevaluable and 42 left the study to be placed on bone marrow transplant protocols. The remaining 62 children were evaluated in detail. Complete excision was eventually accomplished in 39 patients (63%), 23 of whom are disease-free survivors after 8 to 47 months (median, 20 months). Twenty-three patients underwent partial excision or biopsy of their lesion and only 6 are alive without evidence of disease (P = .0011). Timing of surgery or site of tumor did not influence surgical outcome. N-myc oncogene expression could not predict which lesions would be completely resectable. Surgical complications occurred 21% of the time but the impact on the clinical course and chemotherapy administration was minimal. The ipsilateral kidney was removed with the tumor in 18 cases, 14 of which were during complete resection. Twelve of these children are disease-free survivors. With new intensive chemotherapy capable of eliciting an effective response from primary and metastatic neuroblastoma, aggressive surgical approaches for complete tumor resection are warranted and can be expected to improve patient outcome.

Adolescent↗
PubMed1991

Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group.

On study CCG-161 of the Childrens Cancer Study Group (CCSG), 631 children with acute lymphoblastic leukemia (ALL) at low risk for relapse were randomized to receive monthly pulses of vincristine-prednisone (VCR-PDN ) during maintenance therapy in addition to standard therapy with mercaptopurine (6MP) and methotrexate (MTX), and either cranial irradiation during consolidation or intrathecal (IT) MTX every 3 months during maintenance. All patients received six doses of IT MTX during induction and consolidation. With a minimum follow-up time of 4.25 years, 76.7% receiving VCR-PDN were in continuous complete remission at 5 years, in contrast to 63.9% receiving GMP-MTX alone (P = .002). The difference in relapse-free survival was due primarily to bone marrow relapse (P = .0008), and in boys also to testicular relapse (P = .003). Among the nonirradiated patients, the 5-year disease-free survival (DFS) was 79.4% for patients randomized to the VCR-PDN pulses, in contrast to 61.2% for the patients randomized to receive 6MP-MTX alone (P = .0002). Among the irradiated patients, the DFS was not significantly different. Of the four combinations of maintenance and CNS therapy studied, the highest DFS was achieved with VCR-PDN pulses and maintenance IT MTX.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Carboplatin in childhood brain tumors. A Children's Cancer Study Group Phase II trial.

Between October 1985 and March 1988, Children's Cancer Study Group institutions entered 95 patients with recurrent brain tumors into a Phase II trial of carboplatin 560 mg/m2 every 4 weeks. Complete or partial responses were observed for one of 19 evaluable children with brainstem glioma, two of 14 with ependymoma, six of 19 with medulloblastoma or central nervous system primitive neuroectodermal tumor (PNET), and none of 15 with high-grade astrocytoma. Of 33 children with medulloblastoma, ependymoma, or central nervous system PNET, five of 12 with no prior cisplatin exposure had responses, and two of 21 with prior cisplatin exposure had responses (P = 0.03). Thirty-four percent of patients had absolute neutrophil count nadirs less than 500/microliters, and 37% had platelet count nadirs less than 25,000/microliters. Sixteen percent had moderate to severe otoxicity, 10% had nausea and vomiting, and none had nephrotoxicity.

Adolescent↗
PubMed1990

Pharmacology of fludarabine phosphate after a phase I/II trial by a loading bolus and continuous infusion in pediatric patients.

Fludarabine phosphate is a nucleotide analogue of adenine arabinoside with antitumor activity in murine and human lymphoid malignancies; it has occasional, unpredictable neurotoxicity after high dose bolus injections in adults. To avoid this toxicity, we studied a loading dose plus 5-day continuous infusion in 47 evaluable pediatric patients. Dose limiting myelosuppression was seen in children with solid tumors after a loading dose of 8 mg/m2 followed by 23.5 mg/m2/day for 5 days. In children with leukemia, no dose limiting toxicity was seen at dose level 6, consisting of a loading dose of 10 mg/m2 and an infusion of 30.5 mg/m2/day for 5 days. One complete and 3 partial remissions were seen in 26 evaluable children with acute lymphoblastic leukemia. 9-beta-D-arabinofuranosyl-2-fluoroadenine plasma concentrations and the area under the moment curve increased linearly with dose. The terminal half-life was similar, while the total body clearance was shorter than that reported for adults receiving bolus or continuous doses. Lymphoblasts isolated from 2 patients during fludarabine phosphate (9-beta-D-arabinofuranosyl-2-fluoroadenine) treatment increased their ability to convert 1-beta-D-arabinofuranosylcytosine to 1-beta-D-arabinofuranosylcytosine 5'-triphosphate by more than 10-fold. The antileukemic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-phosphate and its ability to alter the metabolism of 1-beta-D-arabinofuranosylcytosine indicate that timed combinations of these 2 agents should be tested.

Antimetabolites, Antineoplastic↗
PubMed1990

Occupations of parents of children with retinoblastoma: a report from the Children's Cancer Study Group.

A matched case-control study was conducted by the Children's Cancer Study Group to investigate the role of parental occupation in the etiology of sporadic heritable and nonheritable retinoblastoma. Eligible cases were those patients with retinoblastoma diagnosed in 1982-1985 at any of the Children's Cancer Study Group member hospitals. Telephone interviews of 201 parents of cases and their pair-matched controls selected by random digit dialing were completed. Of the 201 cases, 19 were familial, 67 were sporadic heritable, and 115 were nonheritable. The 19 familial cases were excluded from the analysis. Paternal employment in the military [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.1-8.8, P = 0.04] and in the metal industry (OR infinity, 95% CI 1.4-infinity, P = 0.02) was associated with sporadic heritable retinoblastoma (N = 67). For nonheritable retinoblastoma (N = 115), a significant association was observed for a job cluster consisting mostly of welders and machinists (OR 4.0, 95% CI 1.1-22.1, P = 0.04). Occupations of maternal grandparents were also studied and an association was observed with farming and nonheritable retinoblastoma (OR 10.0, 95% CI 1.4-433, P = 0.02). Many comparisons were made and the number of significant findings did not exceed that expected by chance. Thus, the results need to be interpreted very cautiously. However, the findings related to metal exposure corroborate observations on other childhood cancers.

Case-Control Studies↗
PubMed1990

Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: a Childrens Cancer Study Group report.

Idarubicin (4-demethoxydaunomycin) is an anthracycline analogue with striking in vitro and in vivo activity against murine leukemias. Based on activity in adults with acute lymphoblastic leukemia, the Childrens Cancer Study Group initiated studies to evaluate idarubicin in children with leukemia in second or subsequent relapses. As part of those studies, we have characterized the plasma pharmacokinetics of idarubicin and the major circulating metabolite idarubicinol in 21 patients. Idarubicin plasma elimination was described by a three-compartment open model following i.v. infusion (10-15 mg/m2) on a schedule of weekly for 3 weeks and on a schedule of daily for 3 days every 3 weeks (total dose, 30-45 mg/m2). There was substantial variability in idarubicin elimination among patients, but no indication of dose-dependent or of schedule-dependent changes in pharmacokinetic parameters. The mean terminal half-life, total body clearance, and steady state volume of distribution were 17.6 h, 679 ml/min/m2, and 562 l/m2, respectively. Idarubicinol elimination was prolonged compared to that of the parent drug with a terminal half-life of 56.8 h. This metabolite clearly accumulated in plasma during the 3 days of treatment on the schedule of daily for 3 days. Urinary recoveries (48 h) of idarubicin and idarubicinol after a single dose of idarubicin were 2.4 and 10.1%, respectively. Idarubicin was detected in 2 of 21 cerebrospinal fluid samples obtained 18-30 h after administration. In marked contrast, idarubicinol was detected in 20 of those 21 samples. Concentrations in the 20 samples varied from 0.22-1.05 ng/ml with a mean value of 0.51 ng/ml.

Adolescent↗
PubMed1990

Wilms' tumor and paternal occupation.

A case-control study was conducted to examine the relationship between Wilms' tumor and paternal occupational exposures. The case group consisted of 200 children diagnosed as having Wilms' tumor who were registered at selected National Wilms' Tumor Study institutions during the period June 1, 1984, to May 31, 1986. Disease-free controls were matched to each case using a random digit dialing procedure. The parents of cases and controls completed a self-administered questionnaire. There was no consistent pattern of increased risk for paternal occupational exposure to hydrocarbons or lead found in this study. However, certain paternal occupations were found to have an elevated odds ratio (OR) of Wilms' tumor, including vehicle mechanics, auto body repairmen, and welders. Offspring of fathers who were auto mechanics had a 4- to 7-fold increased risk of Wilms' tumor for all 3 time periods. The largest increased odds ratio for auto mechanics was in the preconception period [OR = 7.58; 95% confidence interval (CI) = 0.90-63.9]. Welders had a 4- to 8-fold increased odds ratio, with the strongest association during pregnancy (OR = 8.22; CI = 0.95-71.3). Although chance cannot be excluded as a possible explanation, association of Wilms' tumor with these occupations has been reported in previous studies. Further study is needed to provide data on the specific occupational exposures involved.

Boron↗