Continuous factor VIII infusion therapy in patients with haemophilia A undergoing surgical procedures with plasma-derived or recombinant factor VIII concentrates.

We describe the experience of a single medical centre with continuous factor VIII (FVIII) infusion therapy in a cohort of patients undergoing elective surgery. Twenty-eight patients had a total of 45 procedures. Intraoperative haemostasis was considered excellent in all 45 cases. FVIII levels were maintained between 46% and 191% of normal (median, 103%) for 2-7 days. Bleeding occurred after five procedures (11%) at times when factor VIII levels were within haemostatic range. No patient required reoperation to control bleeding. There were no cases of sepsis related to continuous infusion of factor VIII. We conclude that continuous infusion: (1) is a safe and effective means of replacement therapy in patients with haemophilia undergoing surgery; (2) provides easier monitoring and more constant coagulation factor levels; and (3) has the potential to decrease the cost of replacement therapy by reducing overall usage of product.

Haemorrhage into a popliteal cyst: an unusual complication of haemophilia A.

A 7(1/2)-year-old boy with severe haemophilia A had increasing discomfort and pain in his left knee after sledding on ice and landing on his knees. Left knee pain persisted for days despite recombinant factor VIII replacement. Imaging studies showed that by day 10 a popliteal cyst had ruptured, with diffusion of blood into the calf muscles. This case illustrates another possible bleeding complication in patients with a bleeding disorder and a popliteal cyst.

Intrauterine correction of factor VIII (FVIII) deficiency.

This is the first published report documenting the successful use of intrauterine infusion of factor VIII (FVIII) in order to reduce the risk of intracranial haemorrhage in a foetus with documented haemophilia A. This approach provides another option for management of newborns with documented coagulation factor deficiency. The subsequent development of an inhibitor directed against FVIII is believed to be related to exposure to exogenous FVIII in the presence of an inversion mutation and not to the intrauterine procedure.

Outcomes of treatment of children and adolescents with recurrent non-Hodgkin's lymphoma and Hodgkin's disease with dexamethasone, etoposide, cisplatin, cytarabine, and l-asparaginase, maintenance chemotherapy, and transplantation: Children's Cancer Group Study CCG-5912.

PURPOSE: To determine the toxicity and response rate in children treated with dexamethasone, etoposide, cisplatin, high-dose cytarabine, and L-asparaginase (DECAL) for recurrent non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). PATIENTS AND METHODS: Ninety-seven children with recurrent NHL (n = 68) or HD (n = 29) were enrolled. Treatment consisted of two cycles of DECAL, then bone marrow transplantation or up to four cycles of ifosfamide, mesna, and etoposide alternating with DECAL maintenance therapy. RESULTS: After two cycles of DECAL induction therapy, complete response (CR) or partial response (PR) was reported in 19 (65.5%; 10 CRs and nine PRs) of 29 patients with HD and 29 (41.6%; 23 CRs and six PRs) of 68 patients with NHL. When only 24 patients with HD and 58 patients with NHL who were assessable for response were considered, the response rates were 79.2% (19 of 24 patients) and 50.0% (29 of 58 patients), respectively. Five-year event-free survival was 26% +/- 9% and 23% +/- 5% in patients with HD and NHL, respectively. Five-year survival was 31% +/- 14% and 30% +/- 6%, respectively. Although median time to treatment failure was significantly longer in patients with HD (EFS, P =.002; survival, P =.011), this difference did not translate into a higher long-term survival. Grade 3 or 4 toxic effects were observed during induction in 70 (72%) of 97 patients and during maintenance in 45 (70%) of 64 courses of DECAL therapy. Pancytopenia and systemic infections in particular were frequently observed. Other toxic effects were uncommon. Although not a formal part of the therapy or the study design, 42 patients who responded to therapy who underwent bone marrow transplant did not show any benefit from this approach. CONCLUSION: DECAL is an effective and tolerable salvage regimen for treating patients with recurrent NHL and HD.

Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inherited thiopurine methyltransferase deficiency.

6-thioguanine (6TG) is undergoing investigation for use in the maintenance phase of acute lymphoblastic leukemia (ALL). Just as with 6-mercaptopurine (6MP), it is be expected that 6TG would cause pancytopenia in individuals with inherited thiopurine methyltransferase (TPMT) deficiency. We report the first case of severe and prolonged pancytopenia caused by 6-thioguanine in an 8-year-old boy with ALL and inherited TPMT deficiency. Neutropenia lasted 67 days, whereas anemia and thrombocytopenia did not recover for 96 days. To obviate this life-threatening complication, clinicians should consider assaying TPMT activity before initiating therapy with 6MP and, particularly, 6TG in children with ALL.

Human coagulation factor FVIIa (recombinant) in the management of limb-threatening bleeds unresponsive to alternative therapies: results from the NovoSeven emergency-use programme in patients with severe haemophilia or with acquired inhibitors.

This open-label, emergency-use study evaluated the efficacy and safety of activated human coagulation factor VIIa (recombinant) (rFVIIa) (NovoSeven; Novo Nordisk Pharmaceuticals, Inc., New Jersey, USA) in treating limb-threatening joint or muscle bleeds in 17 patients with haemophilia A or B and six patients with acquired inhibitors to factor VIII or factor IX. All patients had previously failed on one or more alternative therapies. rFVIIa administration was effective or partially effective in controlling joint or muscle bleeds in 34 out of 35 (97%) bleeding episodes; in 23 patients, 14 of 17 (82%) muscle bleeds and 16 of 18 (89%) joint bleeds were effectively controlled. These findings suggest that rFVIIa is an effective and well-tolerated therapeutic option in the management of joint or muscle haemorrhage in patients with haemophilia and in patients with acquired inhibitors.

An evaluation of the impact of a self-care coping intervention on psychological and clinical outcomes in adolescents with newly diagnosed cancer.

The demands of cancer treatment are particularly challenging for newly diagnosed adolescents. If attempts to cope with these demands are unsuccessful, adolescents may not comply with or may refuse treatment. As a result, their chances of survival are decreased. The purpose of this study, guided by the Adolescent Self-Sustaining Model, was to determine the effects of a three-part educational intervention designed to facilitate copying on psychological (hopefulness, hopelessness, self-esteem, self-efficacy and symptom distress) and clinical outcomes (treatment toxicity) among adolescents newly diagnosed with cancer. This two-site study used a longitudinal experimental two-group design with adolescents randomly assigned to the intervention or control group. Four measurement points spanning the first 6 months of treatment were included in the design. Of 93 eligible adolescents, 78 (46 females and 32 males) agreed to participate. No statistically significant differences between the intervention and control groups, or between male and female participants, were detected at any measurement point. Differences in scores over time within groups were noted. Explanations for the lack of group differences are offered, as are recommendations for strengthening the intervention and design for future testing.

Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome.

BACKGROUND: The objective of this descriptive analysis of a large cohort of patients with Langerhans cell histiocytosis (LCH) was to add to the understanding of the natural history, management, and outcome of this disease. METHODS: Three hundred fourteen Mayo Clinic patients with histologically proven LCH were categorized into those patients with multisystem disease and those patients with single system disease. Clinical features, treatment, and outcome were determined from the case history notes and tumor registry correspondence. Treatment included chemotherapy, radiotherapy, and surgical excision. The end points were disease free survival, active disease, or death. The median time of follow-up was 4 years (range, 1 month to 47.5 years). RESULTS: The age of the patients ranged from 2 months to 83 years. Of the 314 patients, there were 28 deaths. Multisystemic LCH was found in 96 patients, 25 of whom had continuing active disease after treatment. Isolated bone LCH lesions were observed in 114 of the 314 patients, 111 of whom (97%) achieved disease free survival after treatment. The most common sites of osseous LCH were the skull and proximal femur. Of the 87 patients with isolated pulmonary involvement, only 3 were nonsmokers. After treatment with corticosteroids (+/- cyclophosphamide or busulphan), 74 patients achieved disease free survival, but 10 patients died. Pituitary-thalamic axis LCH, characterized by diabetes insipidus, was found in 44 patients. After treatment, 30 of these patients had disease free survival, but all required long term hormone replacement with desmopressin acetate. Lymph node involvement was found in 21 patients, and mucocutaneous involvement was found in 77 patients. CONCLUSIONS: Patients with isolated bone LCH lesions have the best prognosis compared with patients with LCH involvement of other systems. By contrast, 20% of patients with multisystem involvement have a progressive disease course despite treatment. The identification of prognostic indicators to facilitate appropriate treatment and long term follow-up surveillance is recommended.

Hopefulness and its characteristics in adolescents with cancer.

Hopefulness in adolescents with cancer serves critical functions related to the adolescents' sense of well-being and commitment to treatment. Given these critical functions, it is important to determine the essential characteristics of hopefulness, which include the degree and dynamism of hopefulness and the nature and attributes of hoped-for objects. The purposes of this two-site study were to describe the degree and dynamism of hopefulness at four time points during the first 6 months of adolescents' treatment for newly diagnosed cancer, to identify and describe the adolescents' hoped-for objects, and to evaluate potential relationships between the characteristics of hopefulness and patient gender, age, diagnosis, and time point in treatment. Seventy-eight adolescents completed the Hopefulness Scale for Adolescents, the Hopelessness Scale, and the Hopefulness Interview Question at each time point. Hopefulness scores were higher and hopelessness scores substantially lower than reported in other tested samples. Adolescents identified a total of 57 different hopes. Differences by age, gender, and diagnosis were found.

Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery.

Recombinant factor VIIa (rFVIIa: NovoSeven; Novo Nordisk) has proven efficacy in the treatment of haemophilic patients with inhibitors. This prospective, double-blind study compared rFVIIa (35 vs. 90 microg/kg) in the initiation and maintenance of haemostasis during and after elective surgery. Patients with inhibitors (FVIII, n = 26; FIX, n = 3) received rFVIIa immediately prior to incision; intraoperatively as needed; every 2 h for the first 48 h; and every 2-6 h for the following 3 days. Haemostasis was evaluated during surgery, at 0, 8, 24 and 48 h and 3, 4 and 5 days after wound closure. After day 5, open-label rFVIIa (90 microg/kg) was available for maintenance. Intraoperative haemostasis was achieved in 28/29 patients. All high-dose patients and 12/15 low dose patients had satisfactory haemostasis during the first 48 h. Twenty-three patients (13/14 high dose) successfully completed the study. Although the 35 microg/kg dose is probably sub-optimal for post-operative management, at least in major procedures, rFVIIa 90 microg/kg is an effective first-line option in surgery for patients with inhibitors.

Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors.

OBJECTIVE: To assess the safety and efficacy of a fixed dose of recombinant activated factor VII (rFVIIa; NovoSeven) in the home setting for mild to moderately severe joint, muscle; and mucocutaneous bleeding episodes in patients with haemophilia A or B with inhibitors. DESIGN: Multicentre, open-label, single arm, phase III study of one year duration. METHODS; Patients or their caregivers administered up to three doses of rFVIIa (90 microg/kg i.v.) at 3 h intervals within 8 h of the onset of a mild to moderate bleeding episode. Once the subject considered that rFVIIa had been "effective" with regard to haemostasis (after 1-3 injections), one further (maintenance) dose of rFVIIa was administered. RESULTS: Of 60 patients enrolled, 56 experienced at least one bleed, and 46 completed the one year study. 614 of 877 bleeds (70%) were evaluable according to protocol definitions. Haemostasis was rated as "effective" in 92% (566/614) of evaluable bleeds after a mean of 2.2 injections. For successfully treated episodes, the time from onset of bleeding until administration of the first injection was 1.1+/-2.0 h (mean+/-SD). Twenty-four hours after initial successful response, haemostasis was reported as having been maintained in 95% of cases. Efficacy was comparable for muscle, joint and target joint, and mucocutaneous bleeding episodes. In an intent-to-treat analysis of all 877 bleeding events, efficacy outcomes were equivalent to the evaluable bleeds, with an effective response in 88% of treated episodes. Treatment-related adverse events occurred in 32 (3% of all) bleeding episodes and consisted of re-bleeds/new bleeds in more than 50% (18/32) of these events. A single episode of superficial thrombophlebitis was the only thrombotic complication encountered, and there were no patient withdrawals due to adverse events. Development of FVII(a) antibodies could not be detected, and hypersensitivity reactions to rFVIIa were not reported. CONCLUSION: rFVIIa is effective and well tolerated when used in the home setting to treat mild to moderate bleeding episodes in patients with haemophilia A or B with inhibitors.

Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia: a joint children's cancer group and pediatric oncology branch study.

We prospectively assessed the pharmacokinetics of methotrexate, mercaptopurine, and erythrocyte thioguanine nucleotide levels in a homogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oral mercaptopurine (75 mg/m2) and weekly oral methotrexate (20 mg/m2). One hundred ninety-one methotrexate doses and 190 mercaptopurine doses were monitored in 89 patients. Plasma drug concentrations of both agents were highly variable. The area under the plasma concentration-time curve (AUC) of methotrexate ranged from 0.63 to 12 micromol*h/L, and the AUC of mercaptopurine ranged from 0.11 to 8 micromol*h/L. Drug dose, patient age, and duration of therapy did not account for the variability. Methotrexate AUC was significantly higher in girls than boys (P =.007). There was considerable intrapatient variability for both agents. Erythrocyte thioguanine nucleotide levels were also highly variable (range, 0 to 10 pmol/g Hgb) and did not correlate with mercaptopurine dose or AUC. A Cox regression analysis showed that mercaptopurine AUC was a marginally significant (P =.043) predictor of outcome, but a direct comparison of mercaptopurine AUC in the remission and relapsed patient groups failed to show a significant difference. Methotrexate and mercaptopurine plasma concentrations and erythrocyte thioguanine nucleotide levels were highly variable, but measurement of these pharmacokinetic parameters at the start of maintenance will not distinguish patients who are more likely to relapse.

MOPP or radiation in addition to ABVD in the treatment of pathologically staged advanced Hodgkin's disease in children: results of the Children's Cancer Group Phase III Trial.

PURPOSE: A randomized trial designed to compare mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, vinblastine, and daccarbazine (ABVD) (regimen A) with ABVD plus low-dose regional (extended-field) radiation therapy (EF RT) (regimen B) for the treatment of children and adolescents with stages III and IV Hodgkin's disease was conducted by the Children's Cancer Group (CCG-521) from 1986 until 1990. PATIENTS AND METHODS: One hundred eleven eligible patients were randomized, 57 to regimen A and 54 to regimen B. All patients had pathologically verified stage III or stage IV Hodgkin's disease. RESULTS: Overall survival (S) is 87% at 4 years and event-free survival (EFS) is 82%. Patients randomized to ABVD plus EF RT have a 4-year EFS of 87% compared with 77% for patients randomized to MOPP/ABVD (P = .09, two-sided). Patients randomized to ABVD plus EF RT have a 4-year S of 90% compared with 84% for patients randomized to MOPP/ABVD (P = .45, two-sided). Significant prognostic factors in multivariate analysis for EFS are stage of disease, erythrocyte sedimentation rate (ESR) at diagnosis, liver size at diagnosis, and, among stage III patients, the size of the mediastinal mass at diagnosis. The acute toxicities of treatment are largely hematopoietic in nature, whereas acute pulmonary and cardiac toxicities are modest and not limiting. CONCLUSION: The results of this study show that, in advanced-stage Hodgkin's disease in children, equivalent results can be obtained by the addition of either MOPP or low-dose EF RT to the ABVD regimen; whether the addition of either contributes to outcome was not addressed in this study and will require additional testing. It is clear, however, that MOPP chemotherapy can safely be eliminated from front-line combination chemotherapy regimens for advanced Hodgkin's disease in pediatric patients.

Intraoperative electron irradiation in the management of pediatric malignancies.

BACKGROUND: External beam irradiation (PBRT), especially in children, is limited by the radiosensitivity of normal tissues. Local control remains a problem in abdominopelvic childhood malignancies. Intraoperative electron irradiation (IOERT) has the potential to increase the dose to the tumor, thereby improving local control, without increasing treatment morbidity. METHODS: Between February 1983 and October 1990, 11 children received IOERT as part of a multidisciplinary treatment program for locally advanced primary or recurrent abdominopelvic malignancies. The 7 boys and 4 girls ranged in age from 2-18 years. Tumor histologies included four neuroblastomas, two desmoid tumors, and one each of the following: embryonal rhabdomyosarcoma, synovial cell sarcoma, neurofibrosarcoma, malignant fibrous histiocytoma, and paraganglioma. Single radiation doses of 10-25 grays were delivered using 6-15-megaelectron volt electron beams to 1-5 IOERT fields. All patients also underwent EBRT and six received chemotherapy. RESULTS: Eight patients (73%) were alive and disease free at a median follow-up of 99 months (range, 37-126 months). All eight patients who underwent gross total resection were locally controlled. Three patients required surgical intervention for IOERT-related complications and two patients developed neuropathies. CONCLUSIONS: IOERT as part of a multidisciplinary treatment approach in patients with locally advanced pediatric malignancies appears to enhance local control in those patients in whom a gross total resection is possible. The long term survival rate was encouraging. Further study, with a larger number of patients, appears warranted to more carefully delineate the efficacy and tolerance of IOERT in the pediatric population.

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.

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.

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.

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.