Autologous bone marrow transplantation for children with AML in first remission.

In Children's cancer group (CCG) 2891, newly diagnosed patients with AML were randomized between standard and intensive timing induction therapies. Patients in first remission who lacked an HLA matched family donor were randomized between an autologous bone marrow transplantation (ABMT) where marrow was purged with 4 hydroperoxycyclophosphamide and consolidation chemotherapy. One hundred and thirty seven patients received an ABMT. Myeloid and platelet engraftment occurred at a median of 44 and 42 days, respectively. Disease-free survival (DFS), relapse-free survival and overall survival at 8 years post induction were 47% (95% confidence interval (CI): 38-55), 50% (CI: 42-59) and 55% (CI: 46-63), respectively. Multivariate analysis of DFS showed WBC <50 000/microl and having received intensively timed induction therapy were associated with improved DFS. Recipients who received intensive timed induction therapy and whose WBC was less than 50 000/microl had a DFS at 8 years of 62% (CI: 49-73). Conversely, recipients who received intensive timed induction therapy patients whose WBC was > or =50 000/microl had a DFS of 33% (CI: 17-50), P=0.003. The results confirm previous studies that ABMT is effective post remission therapy for pediatric patients with AML in first remission.

Granulocyte-macrophage colony-stimulating factor treatment before doxorubicin and cyclophosphamide chemotherapy priming in women with early-stage breast cancer.

PURPOSE: To determine if inhibition of stem-cell activity induced by granulocyte-macrophage colony-stimulating factor ([GM-CSF]; Sargramostim; Immunex Corporation, Seattle, WA) withdrawal or priming protects hematopoietic stem cells from the cytotoxic effects of adjuvant chemotherapy for early-stage breast cancer. PATIENTS AND METHODS: Serial blood counts were performed in 20 women with early-stage breast cancer receiving four courses of cyclophosphamide and doxorubicin chemotherapy. By a double-blind, placebo-controlled, balanced randomization, subjects received GM-CSF priming on days 5 to 1 for courses 1 and 3 or courses 2 and 4. RESULTS: Compared with before priming, after priming the times to neutrophil nadir (12.8 +/- 2.5 days v 14.8 +/- 1.5 days, respectively; P =.0001) and platelet nadir (mean +/- SD, 10.1 +/- 1.9 days v 11.1 +/- 2.2 days, P <.05) were shorter, indicating a shift of cytotoxicity to later progenitors. The neutrophil nadir was similar with and without priming (mean +/- SD, 490 +/- 310/microL v 550 +/- 350/microL, respectively; P =.2); however, on day 16 the mean neutrophil count was higher (mean +/- SD, 1030 +/- 580/microL v 690 +/- 370/microL, P =.004), and the proportion of patients with a neutrophil count less than 500/microL was lower after priming than before (six of 35 or 17. 1% v 12 of 34 or 35.3%, respectively; P =.04). The platelet nadir was higher (mean +/- SD, 166,000 +/- 51,000/microL after priming v 151,000 +/- 45,000/microL before priming, P =.007), and the duration of thrombocytopenia, ie, a platelet count less than 150,000/microL, was shorter (1.5 +/- 2.1 days v 2.8 +/- 2.9 days, P =.0025) after priming. Episodes of fever and neutropenia were not observed. CONCLUSIONS: GM-CSF priming from days 5 to 1 before doxorubicin and cyclophosphamide chemotherapy was associated with an earlier neutrophil and platelet nadir. On day 16, a higher mean neutrophil count and a lower proportion of patients with severe (< 500/microL) neutropenia were observed. Beneficial effects on the severity and duration of thrombocytopenia were also noted. These observations support the hypothesis that GM-CSF priming protects hematopoietic progenitors from the cytotoxic effects of chemotherapy.

Intensively timed induction therapy followed by autologous or allogeneic bone marrow transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: a Childrens Cancer Group pilot study.

PURPOSE: Childrens Cancer Group (CCG) protocol 2861 was designed to test the feasibility of aggressively timed induction therapy followed by autologous or allogeneic bone marrow transplantation (BMT) as the sole postremission therapy for newly diagnosed children with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Between April 1988 and October 1989, 142 patients were eligible for study. All patients entered received a timing-intensive five-drug induction of dexamethasone, cytarabine (Ara-C), thioguanine, etoposide, and daunorubicin (DCTER) over 4 days with a second cycle administered after 6 days of rest, irrespective of hematologic status at that time. Most patients subsequently received a second two-cycle induction course. Those who achieved remission were eligible for bone marrow ablative therapy with busulfan and cyclophosphamide, followed by 4-hydroperoxy-cyclophosphamide (4-HC)-purged autologous or allogeneic BMT rescue. RESULTS: One hundred eight (76%) patients achieved remission: 19 (13%) died of complications of the leukemia and/or chemotherapy, and 15 (11%) failed to achieve remission. Seventy-four patients subsequently underwent BMT with either autologous (n = 58) or allogeneic (n = 16) rescue. For patients who received autologous rescue with 4-HC-purged grafts, the actuarial disease-free survival (DFS) rate at 3 years from the day of transplant is 51%, compared with 55% for patients who received allogeneic grafts (P = .92). At 3 years, the overall actuarial survival rate for all 142 patients entered on this study is 45%, with an event-free survival (EFS) rate of 37%. Adverse prognostic factors for outcome included an elevated WBC count or the presence of CNS leukemia at the time of AML diagnosis. CONCLUSION: Results suggest that aggressively timed induction therapy followed by marrow ablation and BMT rescue with either autologous or allogeneic grafts for children with newly diagnosed AML or MDS is both feasible and effective.

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.

Morphologic, immunologic, and cytogenetic classification of acute myeloid leukemia and myelodysplastic syndrome in childhood: a report from the Childrens Cancer Group.

The purposes of this report are to reaffirm concordance difficulties with the acute myeloid leukemia (AML) French-American-British (FAB) classification, to present the frequency of previously delineated AML syndromes in pediatric patients and to describe additional characteristic AML profiles utilizing composite morphologic, cytogenetic and immunophenotypic data. Profiles of 124 children with acute myeloid leukemia (AML) and 13 children with myelodysplastic syndrome entered on the Childrens Cancer Group (CCG) pilot study CCG-2861 were examined. Concordance between institutions and reviewers for FAB designation was 65%. Discordance was found principally between M1 and M2, M2 and M4, and M4 and M5. In 49% of marrow specimens, leukemic blasts expressed at least one T lineage-related antigen; 24% expressed the B lineage-related antigen CD19. CDw14 correlated with FAB M4 or M5 morphology and was the only surface antigen associated with a specific FAB subtype. Normal karyotypes were found for 15% of the 75 children with satisfactory karyotype preparations. Recurring aberrations, found in 76% of children, included t(15;17)(q22;q11), t(8;21)(q22;q22), inv(16)(p13q22), rearrangements of band 11q23, t(6;9) (p23;q34), trisomy 8 and monosomy 7. Results from this pilot study and from the current CCG randomized trial correlating morphology, immunophenotyping and cytogenetics, will help to classify AML into unique subgroups with differing clinical consequences or therapy requirements.

A role for prostacyclin in bruising symptomatology.

The relationship between bleeding and bruising and the production of prostacyclin and thromboxane was assessed in children who were to have a tonsillectomy and/or an adenoidectomy. Eicosanoids in the blood oozing from the bleeding time incision were measured and correlated with the reported frequency of bruising and epistaxis. A striking association (P = .0003) between prostacyclin production and the frequency of bruising was found; children reporting bleeding at least biweekly had the highest prostacyclin synthesis. Successively lower levels of the prostacyclin metabolite, 6-keto-prostaglandin F1 alpha, were found in children reporting less frequent bruising. Prostacyclin production in bleeding time blood was also correlated inversely with systolic blood pressure and hemoglobin level, although neither of these variables could explain the association between prostacyclin production and bruising. There was no correlation between thromboxane formation, systolic blood pressure, hemoglobin level, age, or bleeding time and the frequency of bruising. The ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha was correlated inversely with the length of the bleeding time (P = .016). It is concluded that vascular prostacyclin production may have a role in bruising symptomatology. It is suggested that prostacyclin formed at the injured vessel surface collects within the first few seconds after injury inside the tissue space at the site of the bruise and, by influencing the formation of the platelet/fibrin plug and/or the leakage of blood from the vessels, plays a significant role in modifying the development of bruising.

Modulation of membrane transport of alkylating agents and amino acids by an analog of vasopressin in murine L5178Y lymphoblasts in vitro.

The synthetic vasopressin analog 1-deamino-8-D-arginine vasopressin (dDAVP) has been shown to influence a wide range of cell-membrane-related events. Accordingly, the effect of dDAVP on membrane transport of various alkylating agents and amino acids was evaluated in L5178Y lymphoblasts in vitro. dDAVP stimulated melphalan uptake but conversely inhibited uptake of nitrogen mustard, choline (the natural transport substrate for the nitrogen mustard carrier), and leucine. No effect on the uptake of cyclophosphamide or glutamine was observed. Increased melphalan uptake was due to effects on both substrate influx and efflux. The effect of dDAVP on melphalan influx was particularly complex: dDAVP stimulated melphalan influx by amino acid transport system ASC but inhibited influx by system L, resulting in a net increase in unidirectional drug influx. Melphalan efflux was inhibited by dDAVP. Decreased uptake of nitrogen mustard, choline and leucine was due, at least in part, to decreased substrate influx. However, the mechanisms of inhibition were dissimilar: inhibition of substrate influx was non-competitive for choline but competitive for leucine. In conclusion, dDAVP induced diverse but apparently specific effects on membrane transport of several alkylating agents and amino acids. Since the accumulation of alkylating agents such as melphalan within tumor cells is a major determinant of cytotoxicity, dDAVP may have a role as a biological response modifier.

Prevention of insulin-dependent diabetes mellitus by 2'-deoxycoformycin in the BB Wistar rat.

The effect of the adenosine deaminase (ADA) inhibitor 2'-deoxycoformycin (dCF) on the development of insulin-dependent diabetes mellitus (IDDM) was assessed in the BB Wistar rat. Sixty-one male rats were treated from days 30 to 120 with 0, 0.5, 1.0 or 1.5 mg dCF/kg/week. The incidence of IDDM was 78% in the controls and was significantly (P < 0.01) decreased in rats receiving 1.5 mg dCF/kg/week (32%), but not in rats receiving lower doses of the drug. However, for those rats that became diabetic the mean time to the development of IDDM was unchanged in animals receiving dCF compared with control. dCF treatment did not produce significant weight loss in the animals or gross changes in the thymus, spleen or kidneys. Although the protective effect of dCF against IDDM was likely produced by immunosuppression, the different dCF dosages had similar effects on ADA suppression in spleen or thymus and on dATP accumulation in these organs.

Evaluation of families wherein a single male manifests a phenotype of X-linked lymphoproliferative disease (XLP).

The Epstein-Barr virus (EBV)-induced diseases of males with X-linked lymphoproliferative disease (XLP) include fatal infectious mononucleosis (IM), non-Hodgkin lymphoma (ML), agammaglobulinemia, and aplastic anemia. These phenotypes also occur as sporadic cases in families, and EBV seronegative males in these families must be considered at risk for XLP until they seroconvert normally to EBV. Given that 50% of males inheriting the defective XLP gene die following primary EBV infection, it is vital that they be identified pre-EBV infection. Here we report results using molecular genetic techniques to provide information as to the relative risks of EBV negative males and potential carrier females in ten families wherein a single male had died of IM.

Endocrine effects of vasectomy in man.

Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T) and free testosterone index (FTI) were measured serially in 11 fertile men, ages 25 to 40, 4 weeks before to 40 weeks after elective vasectomy. During the 1st week postvasectomy there was a significant fall in FSH levels (P less than 0.001) and FTI (P less than 0.05), with recovery by 2 weeks. This acute response may be due to general surgical stress. Thereafter, the over-all mean FSH level was significantly (P less than 0.05) below the prevasectomy level; over-all levels of LH, T, and FTI did not change. We speculate that this decline in mean FSH levels is compatible with the existence of an as yet unidentified T-independent testicular factor influencing FSH production.

Does iron deficiency raise the seizure threshold?

To determine the effect of iron status on the seizure threshold, measures of iron sufficiency were prospectively evaluated in 51 children presenting to a pediatric emergency department with a febrile illness with (26) or without (25) an associated febrile seizure. A higher proportion of children from the febrile seizure group had a family history of mental retardation (5/26 versus 0/25, P = .02) or of previous febrile seizures (10/26 versus 2/23, P = .01). The two groups were otherwise comparable for age, sex, race, family history of afebrile seizures, temperature at presentation, white blood cell count, differential, and vitamin and antibiotic use. Patients with febrile seizures were less frequently iron deficient as defined by a free erythrocyte protoporphyrin level above 0.80 ng/L (2/23 versus 10/25, P < .01), hemoglobin concentration less than 110 g/L (1/26 versus 6/25, P < .03), hematocrit less than 0.30 L/L (0/22 versus 4/25, P < .02), mean corpuscular hemoglobin less than 20 pg (0/25 versus 3/24, P < .04), mean corpuscular volume less than 65 fL (0/26 versus 4/24, P < .02), and platelet count higher than 550 x 10(9)/L (0/26 versus 3/25, P < .04). This association was even stronger when adjusted for differences in family history. None of the patients in the febrile seizure group was being treated for iron deficiency at presentation, whereas three of 25 controls used an iron supplement (P < .04). Iron deficiency may protect against the development of febrile seizures.

Acute nonlymphocytic leukemia.

The discovery of cytosine arabinoside, and then the anthrocycline antibiotics, 6-thioguanine, vincristine, cyclophosphamide, and other drugs, has added to the armamentarium of known effective agents. The use of combination chemotherapy, the recognition of the need during induction for virtual marrow aplasia to obtain a remission, and recognition of the predilection of the disease for the central nervous system requiring prophylaxis constitute major advances. The impediment to long-term survival is the lack of effective maintenance therapy.

Histiocytosis X (Langerhans' cell histiocytosis). Prognostic role of histopathology.

Histiocytosis X (HX) follows a variable course from the self-limited eosinophilic granuloma (EG) to the aggressive disseminated disease in infants. Some classifications place EG in a well-differentiated category and the disseminated infantile form in a morphologically atypical group. However, criteria for determining prognosis from biopsy material have not received widespread acceptance. We retrospectively reviewed 51 cases of HX, emphasizing the cytological atypia and mitotic activity of the Langerhans' histiocytes, as well as the presence of other parameters. Ten patients died. We were unable to predict clinical outcome from the histopathological findings. Some cases of EG showed mild atypia and high proliferative rates while some fatal disseminated cases had a bland appearance. The prognosis is best predicted by clinical parameters. The findings favor HX being a reactive, nonneoplastic proliferation of the Langerhans' cells.

Malignant rhabdoid tumor of the central nervous system with subarachnoid dissemination.

A case of primary central nervous system malignant rhabdoid tumor is presented. Clinical, radiological, and histopathological findings are described in detail. Because of a relatively long clinical course after presentation, it was possible to assess the clinical and radiological response to different treatment modalities: surgery, chemotherapy, and radiotherapy. Despite the complete clinical and radiological response that was achieved after subtotal excision, two cycles of chemotherapy, and high-dose radiotherapy, the tumor recurred within 4 months of completion of the treatment, with wide subarachnoid dissemination. Radiotherapy treatment of whole cranial axis is recommended.

Regulation of nausea and vomiting in cancer chemotherapy. A review with emphasis on opiate mediators.

Chemotherapy-induced nausea and vomiting are primarily regulated by chemoreceptor trigger zone (CTZ)-vomiting center (VC) pathways. Dopaminergic (D2), histaminic (H1), and muscarinic cholinergic (Ach) receptors are present in these sites, and specific receptor antagonists are potent but not "universal" antiemetics when used alone or in combination. Recently, neurons containing the endogenous opiate enkephalin were also identified near the CTZ and the VC. Furthermore, opiates stimulate vomiting at the CTZ and inhibit vomiting at the VC in dogs and in cats. A dose-related increase in nausea and vomiting in response to the opiate antagonist naloxone has also been demonstrated in patients receiving cancer chemotherapy. These observations support a role for endogenous opiates in regulating chemotherapy-induced nausea and vomiting; further, they suggest that narcotic agents may be effective antiemetics in this setting.

Perioperative management of patients with von Willebrand's disease.

This review focuses on the pathophysiology of the Factor VIII molecule as it relates to Von Willebrand's disease. Three major categories of Von Willebrand's disease are identified. The perioperative diagnosis and management of all categories are reviewed. 1-Deamino-8-D-arginine vasopressin (DDAVP) is presented as an alternative to the transfusion of blood and blood products for the management of a bleeding diathesis.

Autosomal recessive muscular dystrophy in Manitoba Hutterites.

A slowly progressive type of muscular dystrophy affecting 11 known members of several Southern Manitoba Hutterite colonies is described. Though encompassing the facial characteristics of the facio-scapulo-humeral type and the proximal distribution of the limb-girdle type, it was felt that this disease represents a distinct type of muscular dystrophy with autosomal recessive inheritance. Since all "affected" colonies can be traced to one founding colony in South Dakota, the disease may have been introduced from Europe between 1874 and 1879. Furthermore, normal fertility and a high degree of inbreeding in a genetically isolated population have contributed to the maintenance of the disease in the population.

Endothelial cells suppress granulocyte clusters and stimulate large granulocyte colonies in culture.

Endothelial cells have been shown to produce granulopoietic colony stimulating activity (CSA) under the regulatory control of a humoral factor, MRA produced by blood monocytes. An endothelial cell-derived granulopoietic inhibitory factor has also been described. To further define these apparently paradoxical observations, human bone marrow mononuclear cells were co-cultured with umbilical cord derived endothelial cells in a plasma clot system in vitro. To enhance the sensitivity of the assay for growth effects attributable to the endothelial cells (or their products) alone, an exogenous source of CSA (e.g. a peripheral blood leukocyte feeder layer) was not used. On day ten of culture, less than or equal to 1% endothelial cells markedly stimulated the growth of early granulocyte progenitors (large diaminofluorine positive (DAF+) GM-CFUc) (p less than .01) and a linear dose response relationship was confirmed (p less than .001). Late granulocyte progenitors (DAF+ clusters) were coincidently suppressed by less than or equal to 2% endothelial cells (p less than .01). No effect of endothelial cells on intermediate progenitors (small GM-CFUc) was demonstrated at any concentration. Similar effects were observed with the addition of 5% to 30% endothelial conditioned medium (ECM) (p less than .01). When cohort cultures were evaluated serially, suppression of clusters was observed by day four and stimulation of large GM-CFUcs by day six. These varied effects on different stages of granulocyte differentiation suggest that endothelial cell derived CSA(S) may be of biological relevance in the regulation of granulopoiesis.