Acute idiopathic thrombocytopenic purpura--management in childhood.
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Adrenal Cortex Hormones↗
Biomedical subjects
G S Gilchrist
Publications and source records attributed to G S Gilchrist.
Dose reduction of chemotherapeutic agents after weight loss.
The aim of dose reduction of chemotherapeutic agents following weight loss is to avoid excessive toxicity while maintaining an equivalent therapeutic effect. Several methods of calculating this dose reduction are currently in use, including dose reduction in proportion to the reduction in body surface area (BSA) or the amount of weight lost and no dose reduction unless significant toxicity occurs. Each of these methods results in the administration of a different dose and therefore different drug exposure, as measured by the area under the time versus concentration curve (AUC). We have used pharmacokinetic modeling software and normative data on the pharmacokinetics of high-dose methotrexate to determine the change in AUC resulting from dose reduction by each of the methods cited for patients with weight loss. Dose reduction in proportion to the reduction in weight results in the same AUC and therefore equivalent drug exposure as before weight loss. In contrast, the more common practice of dose reduction in proportion to the decrease in BSA (as determined by recalculating BSA) results in a higher AUC than before weight loss. This results in increased drug exposure and potentially increased toxicity, which may be avoided if dose reduction is carried out in proportion to the decrease in weight rather than in BSA. The same principles are applicable to other drugs, particularly those associated with dose-dependent toxicity.
Antineoplastic Agents↗
Genetic analysis and functional characterization of prothrombins Corpus Christi (Arg382-Cys), Dhahran (Arg271-His), and hypoprothrombinemia.
The structural abnormalities and functional characteristics of dysfunctional prothrombin variants in two new kindreds have been determined. Prothrombin Corpus Christi (family 1) was purified and found to have markedly reduced fibrinogen clotting activity, yet normal amidolytic and near-normal platelet aggregating activity. A transition (C to T) at nucleotide position 8885, present in the heterozygous form in affected family members, resulted in the substitution of Cys for Arg 382. This substitution results in the loss of a positive charge within the fibrinogen-binding exosite of thrombin, thus accounting for the observed functional defect. A heterozygous C to T transition was also present at position 19994 in other family members with a hypoprothrombinemic phenotype. This mutation results in the replacement of Gln 541 (CAA) by a premature stop codon (TAA). Prothrombin Dhahran (family 2) was found to have markedly reduced fibrinogen clotting activity, but normal amidolytic activity. Affected family members were found to have a G to A transition at nucleotide position 7312 resulting in the substitution of His for Arg 271. This substitution results in the abolition of a factor Xa cleavage site, yielding meizothrombin rather than thrombin, on activation of prothrombin Dhahran by factor Xa. All but one of the above mutations occur at CpG dinucleotides, thus further supporting the observation of a high incidence of CpG transitions in hereditary dysprothrombinemia. The significant bleeding tendencies of individuals homozygous for prothrombin Dhahran (prothrombin clotting activity 5% to 7%) contrast sharply with the absence of significant chronic bleeding in the proband expressing prothrombin Corpus Christi (prothrombin clotting activity 2%). Our findings underscore the capacity of thrombin to contribute to clinical hemostasis by mechanisms other than its fibrinogen clotting activity.
Adult↗
Spinal extradural hematoma in an infant with hemophilia A: an unusual presentation of a rare complication.
Epidural hematomas are a rare complication of hemophilia. This article documents the first case of an infant who initially had irritability alone without neurologic symptoms. The infant's disease was diagnosed and treated early and the child had a good neurologic outcome.
Factor VIII↗
Childhood acute lymphoblastic leukemia: are routine end-of-therapy bone marrow and cerebrospinal fluid examinations necessary?
OBJECTIVE: To ascertain the usefulness of bone marrow and cerebrospinal fluid (CSF) examinations in identifying or predicting relapse in children with acute lymphoblastic leukemia (ALL) before discontinuation of chemotherapy. MATERIAL AND METHODS: We retrospectively reviewed the medical records of 113 children with ALL in first continuous complete remission who had undergone routine end-of-therapy bone marrow aspiration and CSF examinations. RESULTS: One patient had frank bone marrow relapse at the completion of therapy, which was evident by the presence of blasts in the peripheral blood. None of the other 112 patients had morphologic evidence of bone marrow relapse or positive CSF cytologic findings. The seven subsequent relapses could not have been predicted by the results of end-of-therapy bone marrow or CSF studies. CONCLUSION: Routine morphologic examination of the bone marrow and CSF at the completion of therapy for ALL has no diagnostic or prognostic value.
Adolescent↗
Langerhans' cell histiocytosis (histiocytosis X) of bone. A clinicopathologic analysis of 263 pediatric and adult cases.
BACKGROUND: Langerhans' cell histiocytosis (LCH) of bone is a disorder of histiocytic proliferation with variable and often unpredictable behavior. METHOD: The authors evaluated the clinical and pathologic features of 263 patients (172 children, 91 adults) with biopsy-proven LCH examined during an 80-year period at the Mayo Clinic. Only patients with bone involvement pathologically and/or radiographically were included in the study. Clinical follow-up was available for 245 patients and ranged from 3 months to 50 years (mean, 12 years; median, 10 years). Chi-square tests were used to determine associations between age, gender, extent of osseous involvement, visceral disease, and pathologic features. Survival analyses were performed by univariate and multivariate Cox regression methods. RESULTS: Age at presentation ranged from 2 months to 71 years with a clear predominance in children. The most common presenting complaint was pain, often worse at night. The skull was the most frequent osseous site in children and adults. Diabetes insipidus was documented in 40 patients. Forty-four children developed skeletal recurrence and/or new bone lesions, 19 of whom had diabetes insipidus. Fourteen children and 3 adults died either directly or indirectly from LCH. One adult patient developed systemic amyloidosis. All but two of these pediatric patients were 3 years of age or younger at presentation. All children with hepatosplenomegaly (7 patients) and/or thrombocytopenia (9 patients) died. Nine of the 14 children who died presented initially with three or more bone lesions. CONCLUSIONS: The clinical behavior of LCH of bone is often unpredictable; however, young age at diagnosis, hepatosplenomegaly, thrombocytopenia, and polyostotic (> or = 3 bones involved) disease are associated with a poor prognosis (P < 0.005). Recrudescence in children, but not in adults, strongly correlates with the presence of diabetes insipidus (P < 0.0005).
Adolescent↗
Variation in the practice of dose reduction of chemotherapeutic agents after weight loss or amputation.
PURPOSE: Dose reduction of chemotherapeutic agents in response to weight loss or amputation is important in avoiding excessive therapy-related toxicity. Several methods of calculating this dose reduction are currently in use, including dose reduction in proportion to (a) the reduction in body surface area (BSA), (b) the amount of weight lost, and (c) no dose reduction unless toxicity is observed. Each of these methods results in the administration of a different dose, and few guidelines exist as to the preferred method. METHODS: We conducted a survey of a large group of pediatric oncologists, pediatric oncology nurses, and data managers to determine the methods of dose reduction currently in use for patients (a) with weight loss, (b) after amputation, and (c) with further weight loss after amputation. RESULTS: Responses were obtained from 237 of 294 individuals surveyed (80.6%). The most popular method was to dose reduce in proportion to the reduction in BSA in patients with weight loss alone (88%), amputees (60%), and amputees with ongoing weight loss (66%). Other methods were chosen by 7%, 31%, and 24% of participants in each of these clinical settings, respectively. CONCLUSION: The chosen methods result in a discrepancy of administered doses of up to 37%. Our results highlight the need for the standardization of practice, and the determination of the optimal method of dose reduction after weight loss or amputation.
Amputation, Surgical↗
Successful hemostasis during a major orthopedic operation by using recombinant activated factor VII in a patient with severe hemophilia A and a potent inhibitor.
The treatment of bleeding episodes and the provision of perioperative hemostasis in patients with hemophilia in whom coagulation factor inhibitors have developed are a major therapeutic challenge because ordinary replacement therapy is usually ineffective. Herein we report the use of recombinant activated factor VII (rFVIIa) in providing successful hemostasis in a patient with hemophilia A and a high-titer inhibitor to factor VIII during a major orthopedic operation. rFVIIa (102 micrograms/kg) was administered intravenously every 2 to 3 hours for a total of 9 days. No excessive bleeding occurred intraoperatively or postoperatively, and no adverse effects attributable to rFVIIa were observed. This surgical procedure probably represented a greater hemostatic challenge than any previously reported operation in which rFVIIa was used. Thus, this article adds considerably to the growing body of literature that suggests the safety and efficacy of rFVIIa in providing perioperative hemostasis and treating severe bleeding episodes in patients with hemophilia and inhibitors refractory to other treatment modalities.
Adolescent↗
Vancouver hybrid: preliminary experience in the treatment of Hodgkin's disease in childhood and adolescence.
OBJECTIVE: To describe our preliminary experience with 19 young patients with newly diagnosed Hodgkin's disease who received the Vancouver hybrid chemotherapeutic regimen. DESIGN: We summarized the characteristics of our 19 study patients, the treatment administered (between June 1988 and June 1992), and the outcome. RESULTS: The Vancouver hybrid, which consists of mechlorethamine, vincristine sulfate (Oncovin), procarbazine hydrochloride, prednisone, doxorubicin hydrochloride (Adriamycin), bleomycin, and vinblastine sulfate (MOPP/ABV), was based on the hypothesis of preventing drug resistance by early introduction and alternation of all active agents and was aimed at decreasing the severity and frequency of treatment-related complications. Of our 19 patients with Hodgkin's disease (age range, 6 to 20 years) treated with this regimen, 2 had clinical stage I disease, 10 had stage II, 6 had stage III, and 1 had stage IV. Only two patients had systemic symptoms, and nodular sclerosis was the most common histologic feature. Patients were given four to eight cycles of chemotherapy, depending on the clinical stage of disease. In addition, 10 patients received irradiation, including 6 of 9 patients with bulky disease. In all patients, complete remission was achieved. After a median follow-up of 3.3 years, only two patients had had a relapse; both underwent autologous bone marrow transplantation and were alive and well with no evidence of disease at last follow-up. The treatment was well tolerated, and delivery of treatment was excellent. The only severe toxicity was myelosuppression; 8 patients experienced a total of 15 episodes of fever and neutropenia that necessitated hospitalization and antibiotic therapy, but no systemic infections were confirmed during 104 cycles of therapy. CONCLUSION: The MOPP/ABV hybrid is an effective and well-tolerated therapy in most young patients with Hodgkin's disease. Long-term monitoring is needed to evaluate late effects.
Adolescent↗
Low numbers of CSF blasts at diagnosis do not predict for the development of CNS leukemia in children with intermediate-risk acute lymphoblastic leukemia: a Childrens Cancer Group report.
PURPOSE: This study was designed to evaluate the effect on CNS relapse (CNSR) and overall relapse rates of blast cells in the CSF containing < or = 5 cells/microL at the time of diagnosis of intermediate-risk acute lymphoblastic leukemia (ALL) in children entered onto a large randomized multicenter prospective therapeutic trial (Childrens Cancer Group [CCG]-105). PATIENTS AND METHODS: We studied outcome in terms of CNSR and event-free survival (EFS) in 1,544 patients who successfully completed remission-induction therapy and had been randomized to one of four systemic chemotherapy regimens and to one of two CNS prophylaxis regimens. We compared outcome between 1,450 patients who had varying degrees of pleocytosis but no blasts in the CSF at diagnosis (blast-negative group) with 94 who had blasts detected in the CSF after cytocentrifugation but had a total CSF WBC count of < or = 5/microL (blast-positive group). RESULTS: No statistically significant differences in overall CNSR or EFS rates were observed between the two groups and no differences were found when analyzed according to age or WBC count at diagnosis, sex, or type of CNS prophylaxis (intrathecal [IT] methotrexate [MTX] alone v IT MTX plus 18 Gy cranial irradiation [CXRT]). CONCLUSION: In intermediate-risk ALL, there was no significant difference in CNSR and systemic relapse rates after standard presymptomatic CNS therapy between patients with a CSF WBC count < or = 5/microL and those without identifiable blasts in the CSF. These findings suggest that certain approaches to therapy, such as that used in this study, may eliminate the need for any additional special treatment directed at this subset of patients with CSF blasts.
Antineoplastic Combined Chemotherapy Protocols↗
Blasts in CSF with a normal cell count do not justify alteration of therapy for acute lymphoblastic leukemia in remission: a Childrens Cancer Group study.
PURPOSE: The Childrens Cancer Group (CCG) requires both a CSF WBC count of more than five cells per microliter and demonstration of blast cells in the cytocentrifuge specimen to support a diagnosis of CNS relapse. We reviewed the CSF examinations of patients with intermediate-risk acute lymphoblastic leukemia (ALL) to determine the clinical significance of blast cells reported in the cytocentrifuge when the total CSF cell count was normal. PATIENTS AND METHODS: Children treated on CCG-105 for ALL had CSF examinations every 12 weeks during maintenance therapy. The outcome of children who had a positive CSF cytocentrifuge examination without an elevated CSF WBC count was compared with that of children who did not have any CSF blast cells observed. RESULTS: Sixty-four patients had 81 CSF examinations with blast cells and a normal cell count. By Cox life-table regression analysis, patients with blasts had a different disease-free survival (DFS) distribution, with relapses tending to occur earlier (P = .008). However, the DFS for these patients was 63% +/- 9.6% at 5 years from the time of the abnormal cytocentrifuge result as compared with 69% +/- 1.5% for 1,490 children who did not have blasts in their CSF. This difference is not significant. CONCLUSION: Blast cells were infrequently identified in cytocentrifuge preparations of CSF when the cell count was normal. The majority of patients in whom such an event was observed have not experienced a subsequent relapse as measured by life-table analysis at 5 years. The data do not justify changing or augmenting therapy based on cytocentrifuge results alone.
Adolescent↗
Access, insurance, and personpower.
This presentation will focus on the issues of access to care, insurance, and personpower in pediatric oncology. The invitation to participate in this workshop was addressed to me as former Chairman of the Section of Hematology/Oncology of the American Academy of Pediatrics and current Chairman of the sub-board of Pediatric Hematology/Oncology of the American Board of Pediatrics. I am particularly indebted to my colleagues in these two organizations for supplying me with much of the information included in this report.
Cancer Care Facilities↗
Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Childrens Cancer Group report.
PURPOSE: This study (Childrens Cancer Group [CCG]-105) was designed in part to determine in a prospective randomized trial whether intrathecal methotrexate (IT MTX) administered during induction, consolidation, and maintenance could provide protection from CNS relapse equivalent to that provided by cranial radiation (CXRT) in children with acute lymphoblastic leukemia (ALL) and intermediate-risk features. PATIENTS AND METHODS: We randomized 1,388 children with intermediate-risk ALL to the two CNS regimens. They received either IT MTX at intervals throughout their course of therapy or CXRT (18 Gy) during consolidation with IT MTX during induction, consolidation, and delayed intensification. Systemic therapy was randomized to one of four treatment regimens derived from a regimen used by CCG in recent studies for this patient population and three more intensive regimens based on the Berlin-Frankfurt-Munster trials. RESULTS: Life-table estimates at 7 years show a 93% and 91% CNS relapse-free survival rate for the CXRT and IT MTX groups, respectively. The corresponding event-free survival (EFS) rates are 68% and 64%. The differences are not significant. Patients who received more intensive systemic therapy had a 94% CNS relapse-free survival rate on either CXRT or IT MTX, while patients who received standard systemic therapy had 90% and 80% rates for CXRT and IT MTX, respectively (P < .0001). Patients less than 10 years of age who received CXRT or IT MTX had 72% and 71% EFS rates if they received more intensive systemic therapy. Patients 10 years or older who received CXRT had an improved EFS (61% v 53%) with a more intensive systemic program. This was primarily due to fewer bone marrow relapses (P = .04). CONCLUSIONS: IT MTX during induction, consolidation, and maintenance provides protection from CNS relapse in patients with intermediate-risk ALL equivalent to that provided by CXRT if more intensive systemic therapy is given. The CNS relapse rate with either CXRT or IT MTX is in part dependent on the associated systemic therapy. For intermediate-risk patients less than 10 years of age, IT MTX with an intensified systemic regimen provided CNS prophylaxis comparable to that provided by CXRT, whereas older patients had fewer systemic relapses if they received CXRT.
Adolescent↗
Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial.
PURPOSE: The Berlin-Frankfurt-Munster (BFM) 76/79 trial of acute lymphoblastic leukemia (ALL) in children produced impressive disease-free survival (DFS) rates with a protocol that began with 8 weeks of intensive therapy, followed by 8 weeks of maintenance therapy, and then another 6 weeks of intensive treatment. The current study was conducted to determine the relative contributions of each of these periods of intense therapy on the DFS rates of ALL patients with intermediate presenting features. In addition, due to concerns regarding the toxicity of CNS irradiation, we compared cranial irradiation (CXRT) with intrathecal methotrexate (IT MTX) administered during induction and consolidation to IT MTX during all phases of the treatment program. PATIENTS AND METHODS: Between May 1983 and April 1989, more than 1,600 children with ALL and intermediate presenting features, as defined by the Childrens Cancer Group (CCG), were entered into a randomized trial that tested four systemic therapy regimens and two CNS programs. RESULTS: The results with a median follow-up of 57 months show that systemic regimens with a delayed intensification (Delint) phase of therapy had a 5-year event-free survival (EFS) rate of 73% compared with the control regimen EFS rate of 61% (p = .006). For children less than 10 years of age, standard three-drug induction and Delint produced a 77% 5-year EFS. IT MTX during all phases of therapy provided CNS protection comparable to the CXRT regimen in children less than 10 years of age. Children 10 years of age or older appear to have a better EFS rate with intensive induction, Delint, and CXRT. CONCLUSION: Delint improves the EFS rate of children with ALL and intermediate presenting features. Maintenance IT MTX can be safely substituted for CXRT for presymptomatic CNS therapy in children with intermediate-risk characteristics less than 10 years of age.
Adolescent↗
Osteosarcoma in adolescents and young adults: new developments and controversies. The Mayo Clinic studies.
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Adult↗
Isoleucine397 is changed to threonine in two females with hemophilia B.
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Factor IX↗
The intergroup Hodgkin's disease in children. A study of stages I and II.
A total of 228 previously untreated and eligible children with pathologic Stage I or II Hodgkin's disease were registered in the Intergroup Study of Hodgkin's Disease in Children between February 1977 and April 1981. Patients were randomized in the Southwest Oncology Group (later the Pediatric Oncology Group [POG] to involved-field (IF) radiotherapy alone or IF radiotherapy followed by six courses of mechlorethamine, vincristine, prednisone, and procarbazine (MOPP) chemotherapy; patients in the Children's Cancer Study Group (CCSG) and Cancer and Leukemia Group B (CALGB) were randomized to receive extended-field (EF) radiotherapy or IF radiotherapy followed by six courses of MOPP. An estimated 97% of patients receiving IF + MOPP were relapse-free and surviving (RFS) at 5 years, which was significantly better than 41% for patients receiving IF alone; however there was essentially no overall difference in survival experience between groups. Patients in CCSG and CALGB receiving IF + MOPP had significantly superior RFS at 5 years than patients receiving EF. Survival rate was not different between these two groups, an estimated 93% of patients surviving 5 years or longer. Although patients were not randomized between IF or EF radiotherapy, they were similar with respect to patient characteristics. There was some statistical evidence that RFS was superior at 5 years for patients receiving EF than for IF; however, there was no evidence of a difference in survival experience. The percentages of patients with late effects of therapy were not significantly different by treatment. The most common types of late effects were endocrine dysfunction and impaired resistance to infection. Overall, the response rate to therapy for relapse patients was good, being 83% among all patients who relapsed. Patient characteristics related to poor prognosis were the presence of constitutional (B) symptoms (fever, night sweats, and weight loss) and poor performance status.
Adolescent↗