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Biomedical subjects

S Culbert

Publications and source records attributed to S Culbert.

At least 19 recordsLinked to original sources
PubMed2001

Severe osteopenia in a young boy with Kostmann's congenital neutropenia treated with granulocyte colony-stimulating factor: suggested therapeutic approach.

Kostmann's syndrome is a congenital disorder that causes an impairment of myeloid differentiation in the bone marrow characterized by severe neutropenia, which can be treated with recombinant human granulocyte colony-stimulating factor (G-CSF). We present the case of a 13-year-old boy with Kostmann's syndrome who was treated with recombinant human G-CSF from age 3.5 years. His growth and development was normal, although complicated by intermittent infections. Bone mineral density (BMD) measurement revealed severe osteopenia at the spine and hips (lumbar spine BMD 0.486 g/cm(2); Z score -3.6), and he was referred to the Endocrine Service. Relevant laboratory evaluation showed a pretreatment ionized calcium level at the upper limit of normal (1.28 mmol/L; range: 1.13-1.32 mmol/L), suppressed intact parathyroid hormone (iPTH) level (12 pg/mL; range: 10-65 pg/mL), and a low 1,25-dihydroxy vitamin D level (21 pg/mL; range: 24-65 pg/mL). He had evidence of increased bone turnover evidenced by elevated urinary deoxypyridinoline (DPD) cross-links (46.9 nmol/mmol creatinine; range: 2-34 nmol/mmol creatinine) and a simultaneous increase in markers of bone formation with elevated osteocalcin level (200 ng/mL; normal: 20-80 ng/mL) and alkaline phosphatase level (236 IU/mL; normal: 38-126 IU/mL). Because of clinical concern for his skeletal health, bisphosphonate therapy with intravenous pamidronate was initiated. One month after treatment, the iPTH and DPD cross-links were in the normal range (54 pg/mL and 17.7 nmol/mmol creatinine, respectively) and the 1,25-dihydroxy vitamin D level was elevated (111 pg/mL). Four months after treatment, there was a striking increase in BMD at the lumbar spine (+30.86%), femoral necks (left, +20.02%; right, +17.98%), and total hips (left, +18.40%; right, +15.94%). Seven months after bisphosphonate therapy, his biochemical parameters showed a return toward pretreatment levels with increasing urinary DPD cross-links (28.7 nmol/mmol creatinine) and decreasing iPTH (26 pg/mL). However, the BMD continued to increase (8 months posttreatment), but the magnitude of the increment was attenuated (lumbar-spine, +4.8%; left total hip, +1.2% and right total hip +2.4%), relative to BMD at 4 months. Eight months after the initial treatment, his iPTH was suppressed at 14 pg/mL and he again received pamidronate (at a lower dose); 3 months later, he had an additional increase in BMD (lumbar spine +7.4%, left total hip +3.9%, right total hip +2.7%), relative to the previous study. We hypothesize that prolonged administration of G-CSF as treatment for Kostmann's syndrome is associated with increased bone resorption, mediated by osteoclast activation and leading to bone loss. In children, the resulting osteopenia can be successfully managed with antisreorptive bisphosphonate therapy with significant improvement in bone density. Measurements of biochemical parameters of bone turnover can be used to monitor the magnitude and duration of the therapeutic response and the need for BMD reassessment and, perhaps, retreatment.

Adolescent↗
PubMed2000

Spontaneous remission of granulocyte colony-stimulating factor-associated leukemia in a child with severe congenital neutropenia.

Leukemia is observed with increased frequency in patients with severe congenital neutropenia (SCN). In the past decade, recombinant human granulocyte colony-stimulating factor (rh G-CSF) has prolonged the survival of patients with SCN increasingly reported to have leukemias. In this communication acute myelogenous leukemia (AML) associated with a mutation of the G-CSF receptor (G-CSF-R) developed in a patient with SCN maintained on long-term G-CSF therapy. The blast count in the blood and bone marrow fell to undetectable levels twice on withholding G-CSF and without chemotherapy administration, but the mutant G-CSF-R was detectable during this period. The patient subsequently underwent successful allogeneic bone marrow transplantation. After transplantation, the patient's neutrophil elastase (ELA-2) mutation and G-CSF-R mutation became undetectable by polymerase chain reaction. This report provides novel insights on leukemia developing in congenital neutropenia.

Bone Marrow Transplantation↗
PubMed1999

Hematopoietic stem cell transplantation for childhood myeloid malignancies after high-dose thiotepa, busulfan and cyclophosphamide.

Seventeen children with advanced myeloid malignancies (induction failure, relapse, myelodysplasia, secondary AML, or CR >1) received thiotepa 750 mg/m2 i.v., busulfan 12 mg/kg or 640 mg/m2 p.o., and cyclophosphamide 120 mg/kg i.v. as a preparative regimen for allogeneic or autologous hematopoietic stem cell (HSC) transplantation. Of the 15 allogeneic transplants, eight were from matched siblings, one was from a mismatched sibling, and six were from unrelated donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine or tacrolimus and methotrexate. Regimen-related toxicity was common but tolerable, affecting mainly the skin and gastrointestinal tract. Three patients died early and were not evaluable for engraftment; engraftment occurred in the remaining patients. Nine patients with active disease at the time of transplant were evaluable for response; all achieved remission. With a median follow-up of 40 months (range, 10-71 months), nine patients are alive and disease-free. The 3-year actuarial event-free survival was 51% (95% confidence interval (CI) 27-76%). Seven patients died of transplant-related complications: infection (n = 4), chronic GVHD (n = 1), veno-occlusive disease, VOD, (n= 1) and pulmonary alveolar hemorrhage (n = 1). Only one patient had leukemia relapse and died. We conclude that the use of high-dose thiotepa, busulfan and cyclophosphamide is an effective conditioning regimen for childhood myeloid malignancies and may be tested in patients with less advanced disease (eg CR1).

Adolescent↗
PubMed1996

Fractionated high-dose cyclophosphamide for advanced pediatric solid tumors.

PURPOSE: The objective of this study was to determine the tolerance and toxicities of high-dose cyclophosphamide (CPA) at 7 g/m2 given in four fractions over 8 h in children with advanced solid tumors. PATIENTS AND METHODS: Twenty children aged 1 1/2-19 years (median, 12 years) received 24 courses of high-dose CPA at 7 g/m2 for the treatment of advanced malignant solid tumor. CPA was given in four 1-h infusions of 1.75 g/m2 each, with 1 h of rest between each dose. MESNA was used as a uroprotective agent and was continued for 24 h after the final dose of CPA. With only one exception, all patients were discharged at the end of MESNA infusion and received granulocyte colony-stimulating factor, prophylactic ciprofloxacin, and co-trimoxazole. RESULTS: Severe but transient myelosuppression was observed. The median time to neutrophil and platelet recovery was 17 and 19 days, respectively. Fever developed after 13 of the 24 courses, and hospitalization was required. Extramedullary toxicities were mild. No patient showed cardiomyopathy or hemorrhagic cystitis. Forty-six percent of the courses were managed entirely on an outpatient basis. Objective tumor response was seen in five patients. CONCLUSIONS: CPA at 7 g/m2 is well tolerated by children with advanced malignancies and should be considered in earlier phases of antineoplastic therapy.

Adolescent↗
PubMed1996

Safety and efficacy of monoclonal antibody purified factor IX concentrate in previously untreated patients with hemophilia B.

The safety and efficacy of a monoclonal antibody purified factor IX concentrate were evaluated in two continuing trials of 32 previously untreated patients with mild, moderate, or severe hemophilia B. Patients were evaluated every 2 weeks for 24 weeks and every 3 months thereafter for at least 1 year. No patients became positive for human immunodeficiency virus antibody or hepatitis C virus antibody during the trial. Two patients developed a false-positive hepatitis B core antibody, one transiently, but neither had elevated levels of alanine aminotransferase (ALT). None of the 25 patients evaluable for non-A, non-B, non-C hepatitis by strict International Society of Thrombosis and Hemostasis criteria developed elevated levels of ALT indicative of posttransfusion infection. Anaphylaxis occurred in one subject who also developed an inhibitor to factor IX (19.3 Bethesda units). Five of the eight adverse events reported (63%) were mild in severity, and the relationship of three of these to therapy was considered remote. Hemostasis with monoclonal antibody purified factor IX concentrate was excellent in all patients.

Adolescent↗
PubMed1996

Ganciclovir prophylaxis for cytomegalovirus infection in pediatric allogeneic bone marrow transplant recipients.

Twenty-nine pediatric allogeneic bone marrow transplant (BMT) recipients, ages 2-17 years, were followed prospectively for cytomegalovirus (CMV) infection. Patients at risk received ganciclovir (GCV) prophylactically at a dose of 5 mg/kg/day i.v., 3 to 5 days per week, until day 100. Surveillance blood and urines were obtained weekly. Twelve patients developed DMV infection: one patient died with CMV interstitial pneumonitis on day 19 post-transplant prior to initiating GCV prophylaxis; 10 patients developed CMV viremia (n = 9) or viruria (n = 1) between day 30 and day 95 (median day 50) while receiving GCV prophylaxis; and one patient developed asymptomatic CMV viruria on day 130, 1 month after completing GCV prophylaxis. Patients with breakthrough infections on prophylaxis were treated with intensified GCV and i.v. immunoglobulin. No patient developed visceral involvement, although five patients had recurrent viremia. Six of the seven long-term survivors continued to excrete CMV in the urine intermittently for 6 to 28 months post-transplant. GCV was well tolerated with transient, mild neutropenia in five patients and thrombocytopenia in four patients. No extramedullary toxicity was encountered. GCV prophylaxis at a dose of 15-25 mg/kg/week is not adequate to prevent CMV reactivation in children receiving marrow transplants from unrelated donors and/or T cell-depleted grafts.

Adolescent↗
PubMed1993

Apparatus to measure the step and frequency responses of gas analysis instruments.

The dynamic characteristics of gas analysers are often assessed by measuring the step response. It is difficult to generate a verifiable instantaneous step change in gas composition. We constructed a 0.06 ml measurement chamber connected via high-speed valves (0.5 ms response time) to two 31 reservoirs pressurized to 50 kPa with gases containing different concentrations of CO2. An electronic system opens the valves alternately depending on the polarity of a control voltage Vc. Two walls of the chamber contain narrow-band infra-red filters centered at 4.24 microns (50% transmission points at 4.16 and 4.32 microns) where CO2 absorption is high. A photoconductive infra-red sensor and an infra-red source are positioned on either side of the chamber. The output of the sensor is amplified by an instrumentation amplifier. Signal averaging of the sensor output in either the time or frequency domain was used to overcome the noise of the infra-red sensor. Step changes in Vc yielded exponentially changing outputs with a time constant of 1.1 ms. A quadrupole mass spectrometer's response to step changes in CO2 concentration generated in the measurement chamber fitted single exponential curves well with a maximum time constant of 37.7 ms and transport delay of 194 ms. The frequency response of the infra-red system, from Vc to the sensor output, fell by 0.7 dB with a phase lag of 30 degrees between 1 and 50 Hz. Using the infra-red system to measure the true input to the mass spectrometer, the frequency response of the mass spectrometer was found to fall by 35 dB with a phase lag of over 3000 degrees between 0.2 and 50 Hz. A first-order model with delay fitted to the step response predicted the mass spectrometer frequency response well below 10 Hz but overestimated the response above 10 Hz. A third-order model with delay fitted to the frequency response predicted the step response very well. Our results suggest that low-order models cannot predict the high-frequency performance of a mass spectrometer.

Carbon Dioxide↗
PubMed1991

A comparison of induction and maintenance therapy for acute nonlymphocytic leukemia in childhood: results of a Pediatric Oncology Group study.

Two hundred fifty-six children with previously untreated acute nonlymphocytic leukemia (ANLL) were evaluated on a Pediatric Oncology Group (POG) phase III randomized trial of both induction and continuation chemotherapies. Induction therapy compared vincristine, cytarabine, and dexamethasone (VADx) with daunorubicin, cytarabine, and thioguanine (DAT). The complete remission (CR) rate using DAT was superior (82% v 61%, P = .02). Postremission therapy consisted of either "standard" two-cycle therapy or a more intensive four-cycle regimen given for 2 years. Overall, there was no difference in outcome for patients randomized to either continuation regimen. The overall complete continuous remission rate (CCR) for the "best" induction/continuation therapy combination at 2 years was .50 (SE = .06), at 3 years was .35 (.04), and at 4 years was .34 (.05). Analysis of selected clinical and laboratory parameters demonstrated differences in induction responses favoring DAT induction but did not impact eventual disease-free survival. There were two subgroups of patients who responded better to four-cycle continuation therapy. These were patients with French-American-British (FAB) M1/M2 (2-year CCR was .20 v .44, P = .01) and patients older than 10 years at diagnosis (.32 v .62, P = .004).

Agranulocytosis↗
PubMed1987

High dose cyclophosphamide, BCNU, and VP-16 (CBV) as a conditioning regimen for allogeneic bone marrow transplantation for patients with acute leukemia.

A high dose combination chemotherapy regimen (CBV) consisting of cyclophosphamide (1.5 gm/m2 day 1 to day 4); BCNU (300 mg/m2 day 1) and etoposide (100 mg/m2 every 12 hours for 6 doses), followed by bone marrow transplant from human leukocyte antigen (HLA) identical sibling donors, was evaluated in 29 patients in whom acute leukemia was in relapse or remission. Engraftment of donor cell type occurred in all but one of 21 patients, in whom marker differences between donor and recipient were established. Two of 11 patients transplanted during relapse of the disease, lived beyond 1 year after bone marrow transplantation. One patient died free of leukemia, 41 months after transplantation of meningitis. Two of seven patients transplanted during the second remission of the disease, are alive and free of leukemia at 42+, and 8+ months. All patients transplanted during the third or fourth remission of the disease have died from either a further relapse, or transplant related causes. The low incidence of organ toxicity with CBV allows for further dose escalation of its drug components.

Acute Disease↗
PubMed1985

Allogeneic bone marrow transplantation for acute leukemia refractory to induction chemotherapy.

This article compares the outcome of 14 patients with primary refractory acute leukemia who underwent bone marrow transplantation from human leukocyte antigen (HLA)-identical donors with that of 18 age-matched control patients who received chemotherapy. Complete clearing of leukemia was seen in all 14 transplanted patients. Five of the transplanted patients are alive 98 to 1790 days posttransplant, and four are free of leukemia. Nine patients have died, eight with severe graft-versus-host disease associated with interstitial pneumonia or systemic infections and one with relapse from chemotherapy-associated infections. Engraftment was seen in all patients. Severe graft-versus-host disease (grades III and IV) was seen in ten patients and resolved in three patients following high-dose corticosteroid treatment. Three of the 18 control patients are alive, none of them in complete remission. It appears that the combination of piperazinedione and total-body irradiation followed by allogeneic transplant is effective induction treatment for primary refractory acute leukemia and will be considered in the future as first salvage treatment for patients failing induction treatment.

Acute Disease↗
PubMed1985

Comparison of maintenance treatment regimens for first central nervous system relapse in children with acute lymphocytic leukemia. A Pediatric Oncology Group study.

Eighty-seven children with central nervous system (CNS) leukemia were randomized to receive either induction intrathecal chemotherapy (ITC) and cranial irradiation (CRT) plus maintenance ITC, or induction ITC and craniospinal irradiation (CSpRT) with no maintenance ITC. ITC consisted of six weekly injections of methotrexate, hydrocortisone, and arabinosylcytosine. Also, intensification of systemic induction and maintenance chemotherapy was given. CRT + ITC was given as CRT, 2400 rad in 12 fractions followed by ITC maintenance bimonthly for 2 years. Craniospinal irradiation consisted of CRT + 1400 rad in ten fractions to the spine. Randomization was stratified according to whether CNS leukemia occurred at initial diagnosis of acute lymphocytic leukemia (ALL) (Stratum I, 15 patients), during first bone marrow (BM) remission (Stratum II, 49 patients), simultaneous with first BM relapse (Stratum III, 12 patients), or during second BM remission (Stratum IV, 11 patients). The median follow-up for patients who remain at risk is 15 + months. Eight children (seven on CRT + ITC, one on CSpRT) developed presumed therapy related encephalopathy. In Stratum II, 16 of 29 (55%) patients receiving CRT + ITC experienced adverse events: 3 deaths during continuous complete remission (CCR) and 13 relapses (2 CNS, 1 CNS + BM, 1 BM + testes, and 2 testes) as compared with only 5 relapses in 20 (25%) patients on CSpRT (1 CNS, 1 CNS + BM, 1 BM, and 2 testes). The children on both regimens were comparable for sex, race, age at initial ALL diagnosis, time from ALL diagnosis to first episode of CNS leukemia, systemic therapy both before and after CNS relapse, and number of blasts in the spinal fluid at diagnosis of CNS leukemia. The conclusion is that children with isolated CNS leukemia can achieve prolonged survival with aggressive therapy, and that CSpRT is possibly less toxic and more likely than is CRT + ITC to prevent subsequent BM and testicular relapse (P less than 0.02), but not subsequent CNS relapse (P = 0.7). A possible systemic therapy effect of spinal irradiation is postulated to explain the superiority of CSpRT.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Mezlocillin pharmacokinetics in pediatric oncology patients.

The pharmacokinetics of mezlocillin were studied in 31 children (age, 2 to 19 years) with malignancies and normal renal and hepatic functions. Mezlocillin was administered intravenously over 30 min every 4 h at doses ranging from 12.2 to 125 mg/kg. Blood samples were obtained over one dosage interval at steady state. For all patients, the mean clearance was 0.21 +/- 0.11 liter/h per kg, the mean distribution volume was 0.26 +/- 0.13 liter/kg, and the mean elimination half-life was 0.97 +/- 0.51 h. Trough concentrations were 23.0 +/- 29.9 mg/liter before the dose was administered and 20.4 +/- 27.5 mg/liter at the end of the dosing interval. Peak concentrations averaged 245 +/- 90.4 mg/liter, and average concentrations for the dosing interval were 83.7 +/- 40.4 mg/liter. There were no apparent effects of sex, malignancy, age, or dose on either the kinetic parameters or plasma concentrations. Overall, the disposition parameters for mezlocillin in this patient group were comparable to those reported in adults.

Adolescent↗
PubMed1984

Effect of retinoic acid on the clonal growth of childhood myeloid and lymphoid leukemias: a pediatric oncology group study.

We have studied the effects of retinoic acid (RA) on bone marrow leukemic cells from children with acute nonlymphocytic leukemia (ANLL) at the time of diagnosis, and on cells from four ALL/lymphoma cell lines (common-ALL, pre-B-ALL, T-ALL, and Burkitt's lymphoma) derived from children with these diseases. Cells were cultured in methylcellulose medium with clinically attainable concentrations (0.25-2.0 microM) of RA for two weeks prior to colony and cluster quantitation. Myeloid progenitor cells (CFU-GM) obtained from children with hematologically normal bone marrows were also cultured with RA. Of 19 patients with ANLL whose cells formed colonies, 16 (84%) were inhibited by RA; three patients showed either increased or unchanged colony numbers with RA. RA had a similar effect on both ANLL cluster and colony growth. RA (1-2 microM) also inhibited colony growth of the pre-B-ALL, common-ALL, and Burkitt's lymphoma lines; the T-ALL line and normal bone marrow CFU-GM were not inhibited. The inhibitory effects of RA on pediatric ANLL bone marrow cells and on some ALL/lymphoma cell lines compared with CFU-GM indicate that RA may be of value in the treatment of these malignancies in children.

B-Lymphocytes↗
PubMed1979

Amikacin pharmacokinetics in pediatric patients with malignancy.

The pharmacokinetics of amikacin were evaluated in 50 pediatric patients (1 to 17 years of age) with malignancies and normal renal function. Dosage regimens of 5 mg/kg per dose were administered intravenously (i) over 30 min every 8 h, (ii) over 60 min every 8 h, and (iii) over 60 min every 6 h. Administration of amikacin over 30 min produced concentrations in serum of 29.3 +/- 5.7 micrograms/ml at the end of the infusion and subtherapeutic concentrations 4 h after the infusion. The regimen of 20 mg/kg per 24 h, divided into doses given every 6 h infused over 60 min, achieved concentrations in serum at the end of the infusion of 17.2 +/- 1.7 micrograms/ml and at 6 h of 1.2 +/- 0.3 microgram/ml. The serum half-life was 1.24 +/- 0.09 h, volume of distribution was 0.26 +/- 0.02 liter/kg, and total body clearance rate was 131 +/- 10 ml/min per 1.73 m2. No accumulation of amikacin was noted, and no significant side effects could be attributed to the drug. This study suggests that the optimal initial dosage regimen of amikacin in children is 20 mg/kg per 24 h administered in equal doses every 6 h over 60 min; however, optimal therapy requires individualization of dosage based on measured serum concentrations and susceptibility data on bacterial pathogens isolated.

Adolescent↗