Autologous stem cell transplantation for non-Hodgkin's lymphoma: comparison of radiation-based and chemotherapy-only preparative regimens

The aim of this study was to compare toxicity and efficacy of total body irradiation (TBI), cyclophosphamide (CY) and etoposide (E) (TBI/CY/E) vs busulfan, melphalan and thiotepa (Bu/Mel/T) in patients receiving autologous stem cell infusion (ASCI) for malignant lymphoma (NHL). Between September 1990 and July 1998, 351 patients with NHL were treated with TBI/CY/E (n = 221) or Bu/Mel/T (n = 130) followed by ASCI. Patients in first, or second remission, first responding or untreated relapse were defined as having less advanced disease before transplantation. The median follow-up was 5 years (range 1-9) and 3.5 years (1-6) for patients receiving TBI/CY/E and Bu/Mel/T, respectively. The cumulative probabilities of survival, event-free survival (EFS) and relapse at 5 years were 44%, 32%, 49% following TBI/CY/E and 42%, 34% and 42% following Bu/Mel/T. The probability of EFS at 5 years for patients who had prior dose-limiting radiation (n = 59) was 32% after Bu/Mel/T therapy. Transplant-related mortality was 16% for TBI/CY/E and 21% for Bu/Mel/T. In univariate and multivariate analyses, more advanced disease status was associated with poor outcome (TBI/CY/E: RR 0.70, CI 0.50 to 0.97 P = 0.04; Bu/Mel/T: RR 0.61, CI 0.39 to 0.97 P = 0.03). No significant differences in toxicities and outcomes were observed between these two regimens despite the inclusion of patients who had received dose-limiting irradiation in the Bu/Mel/T regimen.     

Decreased Capacity to Metabolize Diphenylhydantoin in a Patient with Hypersensitivity to Warfarin

Summary: Decreased capacity to metabolize diphenylhydantoin in a patient with hypersensitivity to warfarin. F. Bochner, W. D. Hooper, M. J. Eadie and J. H. Tyrer, Aust. N.Z. J. Med. , 1975, 5, pp. 462–466.     

The Effect of Certain Drugs on the Plasma Protein Binding of Phenytoin

Summary: Most of the phenytoin in plasma is protein bound. Anti-convulsants are often prescribed in combination and it is important to know if other anticonvulsants displace phenytoin from its plasma-protein binding sites. If this happened, the biological effect of phenytoin could be altered without much change in its total concentration in plasma. The binding of phenytoin to serum albumin and plasma protein in vitro has been studied by ultrafiltration techniques and equilibrium dialysis at a variety of temperatures and in the presence of "therapeutic" concentrations of other anticonvulsants and aspirin. Equilibrium dialysis and ultrafiltration yielded comparable results. Phenytoin binding de-creased with increasing temperature (92% bound at 3 °C, 80% bound at 37 °C). With the possible exception of sulthiame, the other anticonvulsants tested (phenobarbitone, ethosuximide, diazepam and carbamazepine), and also aspirin, did not displace phenytoin from its plasma protein binding sites. These findings may be helpful in interpreting plasma phenytoin concentrations when other anticonvulsants are prescribed simultaneously.     

Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers

Bcl-2 family proteins play a critical role in the regulation of apoptosis in chronic lymphocytic leukemia (CLL). However, their association with established prognostic markers is unknown. In this study, we analyzed the expression of Bcl-2, Bax, and Mcl-1 in 185 CLL patients and evaluated their relationship with other prognostic markers, in vitro sensitivity to fludarabine, and clinical outcome. Mcl-1 expression was significantly correlated with stage of disease (P < .001), lymphocyte doubling time (P = .01), V(H) gene mutation status (P < .001), CD38 expression (P < .001), and ZAP-70 expression (P = .003). In addition, Mcl-1 and Mcl-1/Bax ratios showed strong correlations with in vitro resistance to fludarabine (P = .005 and P < .001, respectively). Furthermore, elevated Mcl-1 expression and Mcl-1/Bax ratios were predictive of time to first treatment in the whole cohort (P < .001 and P < .001, respectively) and in stage A patients only (P = .002 and P = .001, respectively). Taken together, our data show that Mcl-1 is a key controller of in vitro drug resistance and is an important regulator of disease progression and outcome in CLL. It therefore represents a promising therapeutic target in this incurable condition. The close correlation between Mcl-1 expression and V(H) gene mutation status, CD38 expression, and ZAP-70 expression offers a biologic explanation for their association with adverse prognosis.     

Safety and potential efficacy of low-dose methotrexate for treatment of chronic graft-versus-host disease

Low-dose methotrexate (MTX) is widely used in autoimmune diseases because of its anti-inflammatory activity. We report here the results of a retrospective study to review the outcomes of low-dose MTX used for treatment of refractory chronic graft-versus-host disease GVHD, with the goal of reducing the amount of prednisone needed to control the disease. In all, 14 patients with refractory chronic GVHD received MTX at a dose of 7.5 mg/m(2)/weekly for 3--0 weeks. Also, 11 patients had skin involvement, often with scleroderma or fasciitis. The median duration of chronic GVHD at the start of MTX was 38 (range 1--35) months. In this retrospective review, we found no grade 3-- toxicities, and none of the patients needed blood transfusion or growth factors. In 10 patients (71%), GVHD could be adequately controlled with prednisone at doses below 1 mg/kg every other day without the addition of other agents. Four patients decreased the amount of concomitant immunosuppressive treatment, five continued with the same regimen, four required an increase in immunosuppressive treatment, and one decided to discontinue all treatment. From this preliminary analysis, MTX appears to be a well-tolerated, inexpensive and possibly steroid-sparing agent that is worthy of further evaluation in prospective trials for treatment of chronic GVHD.     

Assessment of right ventricular function at rest and during exercise in patients with coronary heart disease: A new approach using equilibrium radionuclide angiography

To evaluate a new method of calculating right ventricular ejection fraction by equilibrium radionuclide angiography and to assess its response during supine bicycle exercise, 20 normal persons and 50 patients with angiographically documented coronary artery disease were studied. Each subject underwent a resting equilibrium and first pass right ventricular study as well as symptom-limited graded bicycle exercise while supine. The correlation between the two methods in all 70 cases was good (r = 0.81). Inter- and intraobserver variability was small (3.9 ejection fraction units or less) and serial reproducibility (two studies performed 2 weeks apart) was also good (4 ejection fraction units or less). There was no difference in the right ventricular ejection fraction at rest when normal subjects and patients with coronary disease were compared (0.49 ± 0.10 versus 0.46 ± 0.08). Ejection fraction increased with exercise in normal subjects (0.49 ± 0.10 to 0.64 ± 0.12, p < 0.005). As a group, patients with right coronary stenosis (alone or in combination with other lesions) showed no change in ejection fraction with exercise (0.46 ± 0.13 to 0.45 ± 0.12); and ejection fraction increased with exercise in patients with coronary disease without right coronary stenosis (0.46 ± 0.08 to 0.53 ± 0.11, p < 0.05). Among patients with both significant right and left coronary artery disease more severe right ventricular dysfunction during exercise was seen in the presence of more severe left ventricular dysfunction. It is concluded that during exercise the right ventricle shows dysfunction caused in part by local ischemia as well as by altered loading conditions due to left ventricular dysfunction. Equilibrium angiography is a useful and reliable method for evaluating right ventricular function in man.     

Effect of orlistat on cardiovascular disease risk in obese adults

AIM: The aim of this study is to compare the effect of orlistat vs. placebo on the predicted 10-year cardiovascular disease (CVD) risk in obese people with one or more cardiovascular risk factors treated for 12 months, in conjunction with a fat-reduced, but otherwise ad libitum, diet. METHODS: A double-blind, randomized, placebo-controlled, parallel study was performed in conjunction with a fat-reduced diet and physical activity advice for 1 year. Participants (n = 339) from eight centres in Australia and New Zealand were randomized to either orlistat (120 mg) three times daily (n = 104 women, 66 men; mean +/- s.d. age = 52.0 +/- 7.5 years, body mass index (BMI) = 37.6 +/- 5.1 kg/m(2)) or placebo three times daily (n = 89 women, 80 men; age = 52.5 +/- 7.4 years, BMI = 38.0 +/- 4.9 kg/m(2)). The primary efficacy criterion was the 10-year risk of developing CVD calculated from the Framingham equation. Secondary efficacy criteria were body weight, waist circumference, blood pressure and serum concentrations of triglycerides, cholesterol (total, LDL and HDL), glucose, insulin and glycated haemoglobin and quality of life. RESULTS: There was no difference in the change in 10-year CVD risk between orlistat and placebo groups over 1 year. The orlistat group, however, had significant favourable changes in many of the individual CVD risk factors (total cholesterol, LDL-cholesterol, glucose, glycated haemoglobin, insulin, body weight and waist circumference) and one of the domains of quality of life measured by means of the SF-36 questionnaire (vitality), compared to the placebo group. Significant reductions in medication use for hypertension and diabetes were observed in the orlistat group, compared to those in placebo, but there were no significant differences in medication use for blood lipids. CONCLUSIONS: Orlistat may have reduced CVD risk, as judged by the favourable changes in individual risk factors and reductions in medication use, but the method used in order to measure absolute CVD risk in this study (Framingham CVD equation) was not sensitive enough to detect the changes in this relatively low-risk group (approximately 10% of risk of a CVD event over 10 years).     

Tidal breathing parameters in young children: comparison of measurement by respiratory inductance plethysmography to a facemask pneumotachograph system

The ratio of expiratory time at tidal peak flow to total expiratory time (t(ptef)/t(e)) correlates with conventional measures of airway obstruction. It is usually assessed using a facemask and pneumotachograph system which may be poorly tolerated in young children and hence limits the usefulness of this technique. We therefore determined in young asthmatic children the accuracy of t(ptef)/t(e), using an uncalibrated respiratory inductance plethysmograph (RIP), and compared the results with those from a facemask-pneumotachograph system. We also assessed whether age influenced the agreement between measurements using the two devices. Forty-seven children aged between 1 month and 12 years were recruited: 39 were inpatients recovering from an acute wheezy episode, and 8 were recruited from the asthma clinic. All were receiving bronchodilators. Tidal breathing parameters t(ptef)/t(e), the duty cycle (t(i)/t(tot)), and respiratory rate were initially measured using the Respitrace alone and then simultaneously with both the Respitrace and the facemask-pneumotachograph system. Eight children did not tolerate the facemask, and in two others it was impossible to analyze the Respitrace trace due to artefacts. In the remaining 37 children, the reliability coefficients and coefficients of variation of the two techniques were similar. Similar values of t(i)/t(tot) and respiratory rate were obtained using the two devices. The mean t(ptef)/t(e) obtained using the Respitrace was lower than with the facemask-pneumotachograph system (P < 0.01), although this was age group-dependent (P < 0.05), as the difference was less apparent in the 1 to 2-year-old children than in other age groups. Application of the facemask-pneumotachograph system did not significantly influence the results obtained using the Respitrace. We conclude that uncalibrated respiratory inductance plethysmography can measure tidal breathing parameters as reliably as a facemask-pneumotachograph system in young asthmatic children, and is better tolerated than the pneumotachograph system. The results obtained using the two devices are not interchangeable.