Patient- and caregiver-reported bleeding symptoms and reasons for starting and stopping treatment with recombinant factor VIIa: analysis of the Dosing Observational Study in Haemophilia (DOSE).

Acute haemorrhage treatment in patients with congenital haemophilia with inhibitors (CHwI) has transitioned to home. Patient/caregiver perceptions of bleeding symptoms and reasons for starting/stopping treatment were investigated. Frequently bleeding CHwI patients (≥ 4 episodes in 3 months) prescribed recombinant factor VIIa (rFVIIa) as first-line therapy, or their caregivers, completed daily diaries for 3-6 months capturing bleeding symptoms and treatment decisions. Thirty-eight patients reported 131 joint, 19 muscle and 44 other bleeding events. Symptoms (all/joint/muscle haemorrhages) included pain (78.9%/90.1%/89.5%), joint swelling (44.8%/65.6%/5.3%), decreased mobility (41.2%/48.9%/68.4%), local warmth (21.1%/26.0%/15.8%), other swelling (16.0%/6.9%/47.4%), irritability (14.9%/16.8%/10.5%), visible bleeding (12.4%/7.6%/5.3%) and redness (10.3%/6.1%/10.5%). Most patients/caregivers recognized when bleeds started (58.4%/58.0%), but were less clear when bleeds stopped (43.5%/33.3%). Medication was commonly started by patients/caregivers when bleeds were identified (73.7%/47.4%) or when concerned bleeds might start (32.9%/27.6%). Common reasons for delays in starting medication by patients included 'I thought it might not be a bleed' (48.9%), 'I wanted to see if the bleed progressed' (46.8%) and 'I thought it was just joint pain' (44.7%). Common reasons for caregivers were: 'I wanted to see if it progressed' (37.9%), 'I didn't have medication' (20.7%) and 'I thought it might not be a bleed' (17.2%). Reasons for stopping medication for patients/caregivers were pain cessation/stabilization (93.9%/54.7%), arrest of swelling progression (60.6%/46.9%) and improved mobility (50.0%/35.9%). Patients/caregivers have difficulty in determining bleed onset and particularly resolution, both quite necessary for treatment decisions and clinical trials. Caregivers' inability to assess resolution in children may lead to longer treatment duration seen in the Dosing Observational Study in Haemophilia (DOSE).

Clinical perspectives in lymphoma.

The classification of both Hodgkin's and non-Hodgkin's lymphomas continues to evolve. The current World Health Organization classification incorporates data derived from advances in our understanding of the pathogenesis of these disorders together with their distinguishing immunophenotypic, genotypic, clinical and histopathological characteristics. As outcomes have improved, the main emphasis of treatment has been to incorporate a risk-adapted approach to reduce long-term toxicity without sacrificing efficacy through the use of varying combinations of chemotherapy, radiotherapy and immunotherapy.

Patterns of failure with increasing intensification of induction chemotherapy for acute myeloid leukaemia.

Patterns of failure were studied in two consecutive randomized trials of intensified induction therapy carried out by the Australian Leukaemia Study Group (ALSG) between 1984 and 1991 to determine the impact of dose intensification. Patients received standard dose cytarabine and daunorubicin (7-3), 7-3 plus etoposide (7-3-7) or 7-3 plus high-dose cytarabine (HIDAC-3-7) chemotherapy. Patients with FAB M3 morphology were excluded. Time to failure (TTF) was defined as the time from randomization to induction death or removal from study for non-responders, or to relapse or death in complete response (CR) for complete responders. An estimated 86% of 470 de novo patients with acute myeloid leukaemia failed within 10 years of randomization, as a result of death in induction in 17% of the randomized patients, failure to achieve CR in a further 17%, relapse in 44% and death in CR in 8% of patients. An estimated 66% of patients failed as a result of refractory disease or relapse within that period (disease-related failures). Multifactor analysis identified age and peripheral blast count as the most significant pretreatment factors associated with overall TTF. These factors, together with cytogenetics, were significantly associated with disease-related failures. High-dose cytarabine in induction significantly decreased the disease-related failure rate as did allogeneic transplantation in first CR. The impact of high-dose cytarabine did not depend on the cytogenetic risk group.

Lymphoma at uncommon sites.

Lymphoma can often present in unusual situations. This article provides a comprehensive review of the literature in which both non-Hodgkin's lymphoma and Hodgkin's disease are discussed.

A phase I/II study of intensive dose escalation of cytarabine in combination with idarubicin and etoposide in induction and consolidation treatment of adult acute myeloid leukemia. Australian Leukaemia Study Group (ALSG).

To determine the safety and efficacy of the combination of idarubicin, cytarabine and etoposide ("ICE") for induction and consolidation treatment of acute myeloid leukemia (AML), and of dose-intensification of cytarabine in this setting, 54 previously untreated patients in three cohorts were studied by sequential dose escalation of cytarabine, in combination with standard doses of idarubicin and etoposide. Cytarabine was given to Cohort 1 at the conventional dosage of 100 mg/m2 per day by continuous infusion for 7 days in induction and 5 days in consolidation; to Cohort 2 at high-dose (HiDAC) (3 g/m2 intravenously twice daily on days 1, 3, 5 and 7) during induction with conventional dosage during consolidation; to Cohort 3 HiDAC was given for both induction and consolidation. In addition, Cohort 3 patients received lenograstim (Granocyte; rHuG-CSF) after both induction and consolidation courses. We found that there was no significant difference between the three cohorts in hematological toxicity in induction, but that HiDAC was associated with a greater incidence of gastro-intestinal toxicities. There was no difference in induction mortality between the three cohorts, which was 11% overall. Consolidation with HiDAC led to a significant increase in hematological toxicity. Overall, the complete remission (CR) rate was 80% with no significant difference between the three regimens. The estimated disease free survival at 3 years was 28%, 67% and 54% respectively for Cohorts 1, 2 and 3 with an estimated overall survival of 38%, 63% and 47%. We conclude that cytarabine dosage can be escalated safely in combination with idarubicin and etoposide in both induction and consolidation. The combination is effective for induction treatment of AML and its side-effects appear similar to those of standard regimens. Whether its use offers long-term benefits compared with standard regimens is the subject of ongoing controlled randomized studies.

A double-blind comparison of fluconazole and nystatin in the prevention of candidiasis in patients with leukaemia. Antifungal Prophylaxis Study Group.

In this multicentre, randomised, double-blind study, the safety and efficacy of oral fluconazole (200 micrograms/day) and nystatin suspension (6,000,000 IU/day) for the prevention of fungal infections were compared in patients with leukaemia undergoing remission induction chemotherapy. Antifungal prophylaxis was initiated at the time chemotherapy was started and continued throughout the hospital stay or the period of neutropenia to a maximum of 42 days. Prophylaxis was successful (no evidence of fungal infection or fever of unknown origin unresponsive to antibiotics) in 38 of 56 (68%) fluconazole-treated and 25 of 53 (47%) nystatin-treated patients (P = 0.03). 2 patients (4%) in the fluconazole group and 6 (11%) patients in the nystatin group developed systemic fungal infections (P = 0.15). The overall frequency of adverse events was similar among fluconazole-treated (29%) and nystatin-treated (32%); most events in both treatment groups involved the gastrointestinal tract. These results indicated fluconazole was more effective than nystatin in preventing Candida infections in patients with leukaemia; fluconazole was well tolerated.

Characterisation of erythrocyte shapes and sizes by NMR diffusion-diffraction of water: correlations with electron micrographs.

The utility of 1H nuclear magnetic resonance (NMR) diffusion-diffraction of water as a tool for characterising red cell shape was investigated. Experiments were conducted on various cell suspensions which contained different shapes/forms of erythrocytes prepared by manipulating the conditions of the suspension medium, such as osmolality, and altering metabolism to affect the adenosine triphosphate concentration. Abnormal red cells from patients with hereditary stomatocytosis and megaloblastic anemia were also studied in order to assess the practical application of this "new" technique. The results clearly show that NMR diffusion-diffraction is sensitive to very small changes in mean cell dimensions and that a "characteristic" q-space plot/profile can be ascribed to each erythrocyte form. It was also found that the homogeneity of the cell shape and/or size is an important factor that affects the intensity of the diffusion-diffraction peaks. This study demonstrates the potential of the NMR diffusion-diffraction technique as a diagnostic tool in hematology.

Intensified induction chemotherapy with high dose cytarabine and etoposide for acute myeloid leukemia: a review and updated results of the Australian Leukemia Study Group.

Induction therapy of acute myeloid leukemia (AML) with standard dose chemotherapy will result in approximately 55-75% of patients achieving a complete remission (CR). Intensification of induction treatment with etoposide and high dose cytarabine does not alter the CR rate but appears to significantly improve the subsequent outcome. Updated results of the comparison of high dose cytarabine with daunorubicin and etoposide in induction (HIDAC-3-7) versus a standard dose combination (7-3-7) demonstrated a highly significant increase in relapse free survival, (RFS) on the high dose arm (p = 0.007) with RFS of 48% at 5 years with HIDAC-3-7 and 25% on 7-3-7. The high dose arm had a more modest survival advantage at 5 years of 33% compared with 25% on standard treatment, possibly because of a higher initial death rate with HIDAC-3-7. The improvement seen in patients with CR after high dose induction appear to parallel results obtained with post-remission therapies intensified with high dose cytarabine. These studies provide clinical evidence that a dose-response effect is present for cytarabine in AML. Intensified treatment is more toxic, gives more profound myelosuppression post-remission and has been shown to benefit younger patients only. Issues of patient selection and the optimal placement of intensification in the treatment sequence require further study. In the future, it is likely that remission duration may be a useful clinical tool to study the influence of new induction therapies on residual resistant leukemia.

Increased plasma leptin/fat ratio in patients with chronic renal failure: a cause of malnutrition?

BACKGROUND: Protein-energy malnutrition occurs in patients with chronic renal failure primarily due to loss of appetite. The ob gene protein, leptin, which is secreted by adipocytes, regulates body composition by lowering food intake. We have measured plasma leptin in undialysed and dialysed patients and in controls and the concentrations have been related to body composition, dietary intake, and biochemistry. METHODS: Plasma leptin was measured by radioimmunoassay in 93 individuals in groups of undialysed, peritoneal dialysed, and haemodialysed patients and controls. Body composition was determined by DEXA. RESULTS: Protein-energy malnutrition was evident in non-dialysed and dialysed patients from low lean or fat tissues, plasma albumin and transferrin. A third of the dialysis patients were eating less than prescribed intakes. Leptin relative to total fat mass (ng/ml/kg) was significantly greater for patients than for controls, particularly the dialysed patients. Leptin was highly correlated with total, arm, leg, and all other fat measurements, e.g. r for leptin vsm % total fat was: undialysed 0.88, PD 0.81, HD 0.93, and controls 0.83 (P < 0.0001 for all). Dialysis patients with the highest leptin/fat mass ratio had low protein intakes and significantly lower lean tissue mass. Leptin/fat ratio correlated inversely with dietary intake e.g. with protein intake in g/day and marginally in g/kg of ideal weight/day. Leptin concentration was unrelated to plasma creatinine or residual renal function or to the protein 'nutritional indices', albumin and transferrin. CONCLUSIONS: Our data suggests that leptin is markedly increased in some patients with chronic renal failure. The association of increased leptin with low protein intake and loss of lean tissue is consistent with leptin contributing to malnutrition but a definitive role cannot be substantiated by this study.

The narrative skills of primary school children with a unilateral hearing impairment.

The discourse skills of four boys with a unilateral hearing impairment (UHI), aged 7·2-10·7 years, were appraised over a 2-year period by examining their oral narrative use. All subjects exhibited delayed narrative skills, including features typical of children with a language disorder. These findings of language difficulties within this population were at variance with previous findings showing that children with UHI do not experience language problems. The subjects' language skills were discussed in relation to their academic performance. The implications of the findings for the process of narrative assessment were also discussed.

Effects of cytosine arabinoside on human leukemia cells.

Cytosine arabinoside (Ara-C) is used to treat leukemias, with complete remission induced by combination chemotherapy in approximately 70% of cases of acute myelogenous leukemia (AML). Ara-CTP acts as a competitive inhibitor of DNA polymerase and may also be incorporated into DNA. Accumulation of deoxyribonucleoside triphosphates (dNTPs) induced by Ara-C may indicate disruption of DNA synthesis in susceptible leukemia cells. A procedure has been developed for the quantification of Ara-CTP and dNTPs from small samples of leukaemia cells from patients (4 x 10(7) cells) activated with concanavalin A (10 micrograms/ml, 48 hr) and grown in the presence of [32P]orthophosphate (1.1 microM, 9 x 10(6) Ci/mol, 16 hr). The susceptibilities to Ara-C of the human leukemia cell lines CCRF-CEM (IC50 = 6.30 nM), CCRF-HSB-2 (IC50 = 10.4 nM) and MOLT-4 (IC50 = 10.0 nM) may be correlated with their abilities to accumulate high concentrations of Ara-CTP (> 1000 amol/cell) with increases of between 1.3- and 3.4-fold in dATP, dGTP and dTTP for the four cell lines, while dCTP decreased between 0.23- and 0.78-fold. By contrast, an Ara-C-resistant derivative of HL-60 cells (IC50 = 400 nM) accumulated only low concentrations of Ara-CTP (71 amol/cell) without significant changes in dNTPs. High concentrations of Ara-CTP in leukemia cells induce accumulations of dATP, dGTP and dTTP due to inhibition of DNA synthesis, and depletion of dCTP. This imbalance in the pools of the four dNTPs could lead to genetic miscoding and cell death.

A randomized study of high-dose cytarabine in induction in acute myeloid leukemia.

High-dose cytarabine (ara-c) may overcome cytarabine resistance in leukemic blasts. It has been used as a successful salvage and in postremission therapy but not as initial induction treatment. Patients aged 15 to 60 years, presenting with newly diagnosed acute myeloid leukemia (AML) were randomized to receive either high-dose cytarabine, 3 g/m2 12 hourly on days 1, 3, 5, and 7 for 8 doses, daunorubicin 50 mg/m2 days 1 to 3, etoposide 75 mg/m2 days 1 to 7, (HIDAC-3-7) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above (7-3-7). Patients could receive a second or third induction course if complete remission (CR) was not achieved. All patients received the same postinduction consolidation therapy (5-2-5) for 2 courses. Eligible patients had no prior chemotherapy or myelodysplastic disease. Patients have been followed for a median of 4.5 years. Of 301 patients treated, complete response (CR) was achieved in 71% with HIDAC-3-7 and 74% with 7-3-7. For patients in CR, the estimated median remission duration was 45 months with HIDAC-3-7 and 12 months with 7-3-7 (P = .0005 univariate analysis, P = .0004 multivariate analysis). The estimated percentage of patients relapse free 5 years after achieving a CR was 49% on HIDAC-3-7 and 24% on 7-3-7. Patients in CR tended to survive longer with HIDAC-3-7 but there were no overall survival differences between the two arms. HIDAC-3-7 was associated with significantly more toxicity in induction with more leukopenia, thrombocytopenia, nausea, and vomiting and eye toxicity (all P < .001) but a similar incidence of severe central nervous system and cerebellar toxicity compared to 7-3-7. The consolidation treatment was the same in both arms but caused significantly more leukopenia and thrombocytopenia in patients previously treated with HIDAC-3-7 induction (P < .0001). We conclude that a dose-effect exists for cytarabine in AML and that HIDAC-3-7 prolongs remission duration and disease-free survival and is tolerable when used as initial induction therapy in patients with de novo AML.

Thalidomide responsive chronic pulmonary GVHD.

A 29-year-old male underwent allogeneic bone marrow transplantation for progressive multiple myeloma. His post-transplant course was complicated by severe chronic pulmonary graft-versus-host disease (GVHD) resistant to cyclosporin A, corticosteroids and azathioprine. The introduction of thalidomide resulted in a dramatic improvement in his lung function which has been maintained even after cessation of thalidomide. He remains well 40 months after transplantation.

Acute interactive effects of MK-801 and morphine on cortical EEG and EEG power spectra in rats.

The interaction between MK-801 and morphine-induced effects on cortical electroencephalography (EEG) was investigated. Rats were administered one of five MK-801 doses (IP) prior to morphine (IV). MK-801 dose-dependently increased morphine-induced global spectral power, duration of morphine-induced EEG bursts and latency to sleep onset, and decreased morphine-induced mean frequency, mobility, complexity, and edge frequency. MK-801 pretreatment shifted the relative distribution of total power to the left. Significant interaction effects were found for all spectral parameters except peak frequency. A second group of rats was administered MK-801 prior to an increasing cumulative morphine dose. MK-801 increased maximal morphine effects on all spectral parameters except peak frequency. The results are in agreement with those of recent analgesia and in vitro studies in spinal neurons, and support observations of a synergistic interaction between effects of NMDA antagonism and morphine. These data further suggest that the component of cortical EEG that is produced by mu-opioid- and NMDA-receptor interactive effects may be dominated by an inhibitory effect of morphine on NMDA receptor activity.

Interactive effects of MK-801 and morphine on EEG, EEG power spectra and behavior in rats: I. Morphine tolerance development.

This study investigated a potential interaction between MK-801 and morphine tolerance using electroencephalography (EEG), EEG spectral parameters and behavior in the rat. Rats were treated for 7 days with morphine alone or with morphine and MK-801. Control groups received chronic MK-801 alone or saline. On day 8 all rats received morphine alone. Co-treatment significantly accelerated the development of tolerance to morphine-induced total power and latency to sleep onset. Co-treatment, but not morphine alone, produced tolerance to morphine-induced complexity and edge frequency, and produced tolerance equal to that from morphine alone in duration of EEG bursting. MK-801 co-treatment decreased, where chronic morphine alone increased, the excitatory response to morphine. Our results support recent reports that chronic morphine treatment produces supersensitivity to glutamate in the rat cortex and alteration in mesolimbic dopamine levels that are modulated by glutamatergic activity.

Interactive effects of MK-801 and morphine on EEG, EEG power spectra and behavior in rats: II. Morphine dependence.

A potential interaction between MK-801 and the cortical electroencephalographic (EEG) and behavioral expressions of morphine dependence in female Sprague-Dawley rats was assessed. Rats were treated chronically (7 days) with either morphine alone, morphine and MK-801, MK-801 alone or saline vehicle alone. On day 8 all rats received morphine alone followed by naloxone. An additional group received chronic (7 days) morphine alone, followed by MK-801 on day 8 prior to morphine and naloxone. Naloxone-induced EEG complexity in morphine-dependent rats was significantly lower than in chronic saline-treated rats. Total power, mobility, mean frequency, complexity and edge frequency in response to naloxone-induced withdrawal in morphine-dependent rats were significantly altered from those in chronically MK-801 alone-treated rats. No differences were found in the EEG and behavioral responses to naloxone between rats that received chronic MK-801 and those that didn't during chronic morphine treatment. Acute MK-801 prior to naloxone in morphine-dependent rats attenuated the behavioral, but not the EEG response to naloxone-induced withdrawal.

Dynorphin A-(1-13)-morphine interactions: quantitative and qualitative EEG properties differ in morphine-naive vs. morphine-tolerant rats.

The effects of dynorphin A-(1-13) on cumulative IV morphine-induced EEG and EEG power spectra were studied in naive and morphine-tolerant rats. Adult female Sprague-Dawley rats were implanted with cortical EEG electrodes and permanent indwelling ICV and IV cannulae. In naive rats, dynorphin A-(1-13) quantitatively decreased cumulative IV morphine-induced EEG spectral power as well as qualitatively shifting the relative distribution of spectral power to predominantly faster frequencies. In morphine-tolerant rats, the quantitative and qualitative EEG properties were identical to those in dynorphin A-(1-13) pretreated morphine-naive rats. Thus, dynorphin A-(1-13) pretreatment apparently produced instantaneous acute morphine tolerance. Furthermore, in morphine-tolerant rats, dynorphin A-(1-13) pretreatment quantitatively increased morphine-induced EEG power without qualitatively changing the relative distribution of EEG spectral power. This latter effect may be due to a summation of increased endogenous levels of dynorphin A-(1-13) associated with the development of morphine tolerance and the experimentally administered dynorphin A-(1-13). These results indicate that dynorphin-induced quantitative and qualitative EEG changes of morphine may reflect different underlying processes. That is, quantitative changes may reflect the number of receptors that are activated, while qualitative changes may reflect the nature of the receptor-effector coupling.

D-Amino acids in chronic renal failure and the effects of dialysis and urinary losses.

Total D-amino acids were measured in plasma for 20 non-dialysed patients (creatinine clearance < 12 ml/minute), 20 on CAPD, 20 on haemodialysis and 20 normals. Plasma D-tyrosine and D-phenylalanine were measured in 8 of each group by HPLC. Total D-amino acids, D-tyrosine and D-phenylalanine were significantly greater for patients than normals. D-amino acids and D-tyrosine correlated with creatinine and were decreased during HD. During dialysis, the mean losses for D-tyrosine and D-phenylalanine were similar, about 0.2 mg/CAPD exchange and 3 mg/4 hour haemodialysis (i.e. 2% of the total amino acid, as in plasma). Clearance was unaffected by stereochemical configuration. Urinary losses/24 hour in the non-dialysed patients were 0.35 mg D-tyrosine and 0.25 mg D-phenylalanine. Clearance for D-phenylalanine was greater than for the L-enantiomer. Increases in D-amino acids in renal failure are probably due to depletion of D-amino acid oxidase, but may be enhanced by a D-amino acid rich diet, peptide antibiotics and D-amino acid oxidase inhibiting drugs and metabolites. Possible toxic effects need further investigation.