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.

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.

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.

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.

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.

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.

Synergistic shortening of the bleeding time by desmopressin and ethamsylate in patients with various constitutional bleeding disorders.

Desmopressin and ethamsylate were evaluated for possible synergistic effects on the bleeding time. The drugs were administered individually and together to 12 patients with markedly prolonged bleeding times known to be relatively or absolutely unresponsive to desmopressin alone. The bleeding disorders studied included Glanzmann's thrombasthenia (one), other disorders of platelet function (four), pseudo-von Willebrand disease (one), and von Willebrand disease type I (three), type II (two), and type III (one). Desmopressin alone shortened the bleeding time from 23.9 +/- 1.5 to 19.5 +/- 2.3 min (p = 0.03). Ethamsylate alone was without effect. Desmopressin and ethamsylate together shortened the bleeding time to 11.2 +/- 1.4 min (p less than 0.01 compared to baseline, p = 0.02 compared to desmopressin alone). The combination was ineffective in three patients, with Glanzmann's thrombasthenia (one), and von Willebrand disease type I (one) and type III (one). Toxic effects of the drugs were not observed. Five patients received desmopressin and ethamsylate prior to dental work with mandibular block (one), heart surgery requiring cardiopulmonary bypass (two), and adenotonsillectomy surgery (two). Normal hemostasis was achieved in each case. A synergistic shortening of the bleeding time was observed with the combination of desmopressin and ethamsylate in a wide range of bleeding disorders.

Anthracycline cardiomyopathy.

Life-threatening irreversible cardiomyopathy is a major complication of anthracycline therapy, particularly in the pediatric population. The pediatric cardiologist, in concert with the primary oncologist, should therefore play a major role in the care of patients receiving these agents and in clinical trials involving their use. Many risk factors and their relationships to drug pharmacokinetics, mechanisms of action, and toxicity have been identified. These data provide a rational basis for present-day recommendations regarding anthracycline administration and dosage scheduling. They furthermore provide potential avenues for clinical investigation aimed at improving the therapeutic index of these agents: alpha-tocopherol, cytochrome Q10, and other free radical scavengers may decrease the deleterious effects of free radical generation on the myocardium without apparent interference with tumoricidal effect. The cardiac glycosides may decrease cardiac toxicity by specific myocardial exclusion. Anthracycline analogs have been designed to specifically inhibit myocardial binding and/or free radical generation. Clinical trials involving these agents are difficult to interpret because of variability in front end risk factors and dosage schedules in the study population. Furthermore, the relatively low (5 to 10%) incidence of affected patients implies the need for large numbers to demonstrate a statistically significant benefit. Pediatric protocols addressing these issues are urgently needed. Guidelines for present-day management and future studies are outlined.

Excretion of mutagens following chemotherapy.

The mutagenic activity of urine was evaluated in children receiving single and multiple agent chemotherapy to determine the duration of carcinogenic risk to health care personnel and family contacts. Urine samples from 21 children were evaluated before and daily for 5 days after chemotherapy administration. Mutagenic activity, a sensitive though not specific indicator of carcinogenic risk, was assayed using mutant strains of Salmonella typhimurium (the "Ames test"). Validity of the assay was confirmed by demonstrating mutagenic activity in urine samples from 17 adult cigarette smokers but not from 21 adult nonsmokers (24/24 versus 0/37, p less than 0.001). None of the 21 children tested demonstrated mutagenic activity before chemotherapy administration. Following single agent dactinomycin, cyclophosphamide, daunorubicin, doxorubicin, methotrexate, or vincristine, mutagenic activity was demonstrated for 2 days (5/5 at 1 and 2 days and 0/5 at 3 days). Following multiple agent chemotherapy using two or three of the latter drugs on a single day, mutagenic activity was demonstrated for 4 or 5 days (16/16 at 1, 2, 3, and 4 days, and 4/16 at 5 days). Based on these observations with urine, and presumably other body fluids, precautions are recommended for 2 days following single agent and at least 5 days following multiple agent chemotherapy.

In vitro stability and compatibility of daunorubicin, cytarabine, and etoposide.

The continuous infusion of cytarabine, daunorubicin, and etoposide offers several theoretical advantages over bolus infusion in the treatment of acute nonlymphocytic leukemia. To date, this approach has been limited by the need for three separate iv lines. The in vitro stability and compatibility of these three agents were therefore evaluated. Solutions of 200 mg of cytarabine, 25 mg of daunorubicin, and 300 mg of etoposide per 750 ml of 5% dextrose and 0.45% saline were prepared alone and in combination. The solutions were evaluated visually, spectrophotometrically, and by high-pressure liquid chromatography (HPLC) twice daily for 72 hours. Precipitates or color changes were not noted. Changes in the patterns of the spectral scans and chromatographs were not observed. Concentrations of the drugs as assessed by HPLC were stable over the 72-hour period of observation for both individual and combined drug preparations. In conclusion, cytarabine, daunorubicin, and etoposide are stable and compatible in vitro for at least 72 hours. These drugs can therefore be administered together by continuous infusion using a single iv line.

Improved hemophilia A carrier detection by DDAVP stimulation of factor VIII.

We studied the differential increase in FVIIIc and FVIII R:Ag after the intravenous infusion of 0.30 micrograms/kg DDAVP in 20 obligate hemophilia A carriers and in 20 female controls. FVIIIc increased in carriers (59.5 +/- 23.1 to 137.5 +/- 45.9) and in controls (98.0 +/- 20.7 to 259.9 +/- 57.4) (P less than 0.001), but the magnitude of the FVIIIc increase in carriers was less than that in controls by 51.9% (P less than 0.001). FVIII R:Ag increased comparably in carriers (105.2 +/- 30.4 to 171.9 +/- 25.4) and controls (92.1 +/- 33.0 to 165.2 +/- 20.6). Using the post-DDAVP instead of the standard FVIIIc/FVIII R:Ag ratio, hemophilia carrier detection was increased from 85% (with 10% false positive and 20% false negative assignments) to 95% (with 5% false positive and 5% false negative assignments). Toxicity associated with DDAVP infusion correlated linearly with doses greater than 10.5 +/- 1.3 micrograms/m2 (P less than 0.02) and with total doses greater than 17.0 +/- 4.5 micrograms (P less than 0.02). The use of DDAVP improves carrier detection in factor VIII-deficient hemophilia.

The unstable Hb Hammersmith or alpha 2 beta 2(42)(CD1)Phe----Ser observed in an Indian child; identification by HPLC and by sequence analysis of amplified DNA.

We have identified the unstable hemoglobin variant present in a Chipewayan Indian patient with severe hemolytic anemia as Hb Hammersmith or alpha 2 beta 2(42)(CD1)Phe----Ser. Her parents were normal. Identification was greatly facilitated by the use of reversed phase high performance liquid chromatography for the isolation of the beta X chain and its tryptic fragments, and of sequence analysis of amplified DNA which readily identified a TTT(Phe)----TCT(Ser) mutation at codon 42.

Increased nausea and vomiting induced by naloxone in patients receiving cancer chemotherapy.

To evaluate the role of endogenous opiates in chemo-therapy-induced nausea and vomiting, the narcotic-antagonist naloxone was administered to six pediatric patients receiving cancer chemotherapy. Naloxone was administered by continuous intravenous (i.v.) infusion after randomized, double-blind controlled assignment at a dose of 0, 10 or 40 micrograms/kg/h for 12 h. Each patient was studied for four consecutive and identical courses of chemotherapy (eight courses for each naloxone dose or 24 courses in all). A dose-related increase in nausea (nausea score 2.5 +/- 2.24, 3.83 +/- 2.73, and 5.75 +/- 2.86/12 h, p = 0.003), vomiting (emetic events 6.0 +/- 7.50, 8.08 +/- 6.71, and 10.3 +/- 8.91/12 h, p = 0.035), and patient aversion (course preference rank 1.5 +/- 0.45, 2.83 +/- 1.17, and 3.25 +/- 0.42/4 courses, p = 0.014) was observed. The infusion of naloxone in the absence of chemotherapy was without effect. These results support a role for endogenous opiates in regulating chemotherapy-induced nausea and vomiting, and further suggest that narcotic agents may be effective antiemetics in this setting.