High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.     

Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients

Sixty-five multiply transfused patients with severe aplastic anemia were given cyclophosphamide followed by grafts anemia were given cyclophosphamide followed by grafts from HLA-identical siblings. The effect of the administration of viable donor buffy coat cells following the marrow inoculum was evaluated with regard to graft rejection and survival. Results in 43 patients so treated are presented along with those in 22 concurrent patients given marrow alone. Most patients given buffy coat had positive in vitro tests of sensitization indicating a high risk for graft rejection, while all but one of the patients given marrow alone had negative tests. Thirty of the 43 (70%) patients given marrow and buffy coat are alive between 10 and 61 mo (median 36) after grafting; 4 died after graft rejection and 6 with acute or chronic graft-versus-host disease (GVHD). Eleven of the 22 (50%) patients given marrow alone are alive between 29 and 65 mo (median 52); 7 died after graft rejection and 3 with GVHD. The addition of buffy coat cell infusions to the marrow inoculum reduced the risk of rejection and increased survival in the currently reported transfused patients when compared to patients grafted before 1976. However, there was an increased risk of chronic GVHD. Recipients of marrow from female donors survived slightly better (73%) than recipients of male marrow (58%).     

Early changes in phosphatidylcholine metabolism in human acute promyelocytic leukemia cells stimulated to differentiate by phorbol ester

The HL-60 leukemia cell line derived from a human acute promyelocytic leukemia is stimulated to differentiate into macrophages within 24-28 hr after exposure to the phorbol ester, 12-O-tetradecanoylphorbol-13- acetate (TPA). We studied early alterations (within 90 min of exposure to TPA) in phosphatidylcholine metabolism in HL-60 cells and found that phosphatidylcholine synthesis by methylation is phosphatidylethanolamine was inhibited in a dose-dependent fashion. In contrast, synthesis of phosphatidylcholine from endogenous choline was enhanced and correlated inversely with the degree of inhibition of the methylation pathway. Phorbol ester congeners of TPA caused similar alterations in phosphatidylcholine metabolism in direct relationship to their capacity to induce differentiation in HL-60 cells. Perturbation of phosphatidylcholine metabolism is an early membrane even in TPA- induced HL-60 cell differentiation.     

Exploring the utility of whole‐exome sequencing as a diagnostic tool in a child with atypical episodic muscle weakness

The advent of whole‐exome next‐generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½‐year old female patient with a 2‐year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work‐up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di‐deoxy sequencing. WES revealed a de novo non‐synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future.     

The prevalence and burden of recurrent headache in Australian adolescents: findings from the longitudinal study of Australian children

BackgroundHeadache disorders are highly prevalent worldwide, but not well investigated in adolescents. Few studies have included representative nationwide samples. This study aimed to present the prevalence and burden of recurrent headache in Australian adolescents.MethodsThe prevalence of recurrent headache, headache characteristics (severity and frequency) and burden on health-related quality of life in Australian children aged 10–17 years were presented, using nationally representative data from the Longitudinal Study of Australian children (LSAC). The LSAC, commencing in 2004, collects data every 2 years from a sample of Australian children of two different age cohorts: B ‘baby’ cohort, aged 0–1 years and K ‘kindergarten’ cohort, aged 4–5 years at the commencement of the study. Face-to-face interviews and self-complete questionnaires have been conducted with the study child and parents of the study child (carer-reported data) at each data collection wave, with seven waves of data available at the time of the current study. Wave 7 of the LSAC was conducted in 2016, with B cohort children aged 12–13 years and K cohort children aged 16–17 years. For the current study, data were accessed for four out of seven waves of available data (Wave 4–7) and presented cross-sectionally for the two cohorts of Australian children, for the included age groups (10–11 years, 12–13 years, 14–15 years and 16–17 years). All available carer-reported questionnaire data pertaining to headache prevalence, severity and frequency, general health and health-related quality of life, for the two cohorts, were included in the study, and presented for male and female adolescents. Carer-reported general health status of the study child and health-related quality of life scores, using the parent proxy-report of the Paediatric Quality of Life Inventory™ 4.0, were compared for male and female adolescents with recurrent headache and compared with a healthy group. Finally, health-related quality of life scores were compared based on headache frequency and severity.ResultsThe LSAC study initially recruited 10,090 Australian children (B cohort n = 5107, K cohort n = 4983), and 64.1% of the initial sample responded at wave 7. Attrition rates across the included waves ranged from 26.3% to 33.8% (wave 6 and 7) for the B cohort, and 16.3% to 38.0% (wave 4–7) for the K cohort. Recurrent headache was more common in females, increasing from 6.6% in 10–11 years old females to 13.2% in 16–17 years old females. The prevalence of headache in males ranged from 4.3% to 6.4% across the age groups. Health-related quality of life scores were lower for all functional domains in adolescents with recurrent headache, for both sexes. Headache frequency, but not severity, was significantly associated with lower health-related quality of life scores, in both males and females.ConclusionsRecurrent headache was common among Australian adolescents and increased in prevalence for females, across the age groups. Frequent recurrent headache is burdensome for both male and female adolescents. This study provides information regarding the prevalence and burden of recurrent headache in the adolescent population based on findings from the Longitudinal Study of Australian Children.     

An alternative extrinsic pathway of human blood coagulation

To study the interrelationships of the major human coagulation pathways, factor X activation in normal and various deficient human plasmas was evaluated when clotting was triggered by dilute rabbit or human thromboplastin. Various dilutions of thromboplastin were added to plasma samples containing 3H-labeled factor X, and the time course of factor X activation was determined. At a 1/250 dilution of rabbit brain thromboplastin the rate of factor X activation in factor VIII or factor IX deficient plasma was only 10% of the activation rate seen for normal or factor XI deficient plasma. Reconstitution of the deficient plasmas with factors VIII or IX, respectively, restored normal factor X activation. Similar results were obtained when various dilutions of human thromboplastin replaced the rabbit thromboplastin. From these experiments, it is inferred that normal activation of factor X in plasma due to dilute thromboplastin requires factors VII, IX and VIII. An alternative extrinsic pathway that involves factors VII, IX, and VIII may be a major physiologic extrinsic pathway, and this pathway may help to explain the clinical observations of bleeding diatheses in patients deficient in factors IX or VIII.