Methotrexate pharmacokinetics in childhood acute lymphoblastic leukaemia: a prognostic value?

WHAT IS KNOWN AND OBJECTIVE: In industrialized countries, acute lymphoblastic leukaemia (ALL) is the most frequent cancer in children aged less than 15 years. High-dose methotrexate is a common component of many chemotherapeutic protocols for childhood with ALL. Our objective was to retrospectively evaluate the pharmacokinetics and plasma levels of high-dose methotrexate as it relates to event-free survival (EFS) in children with ALL. METHODS: Relapsed patients and subjects in EFS were compared for MTX serum concentrations 24, 36, 48 and 72 h after the start of 24 h infusion. Clearance (Cl), area under the curve (AUC) and volume of distribution (V(d) ) of the drug were estimated by the NONMEM computer program and also compared between both groups. RESULTS AND DISCUSSION: Among 69 children included, 54 (78·3%) were still in EFS, whereas 15 (21·7%) relapsed. The difference between relapsed and EFS patients for the pharmacokinetic parameters studied was not significant. On the contrary, the cohort studied was representative and known prognostic factors for relapse in ALL were significantly associated with relapse. WHAT IS NEW AND CONCLUSION: Serum concentrations and pharmacokinetic parameters of MTX are not associated with outcome in ALL. Prognoses based on single-drug pharmacokinetic estimates within a complex multiple-agent protocol appear to be unreliable. However, therapeutic drug monitoring of high-dose methotrexate remains a useful tool for early detection of impaired elimination and for avoiding systemic toxicity.

Volumetric thoracic growth in children with moderate and severe scoliosis compared to subjects without spinal deformity.

Idiopathic scoliosis leads to a three-dimensional thoracic deformity. The purpose of this study is to measure thoracic dimensions and volume related to growth and to verify the influence of moderate and severe scoliosis. 176 children (36 boys, 140 girls; 4-16 years) with scoliosis <45 degrees and 17 patients (2 boys, 15 girls) with scoliosis >65 degrees were compared to 239 children without spinal deformity (97 boys, 142 girls) using an optical system. Thoracic volume, perimeter, anterior-posterior and transversal diameters, T1-T12 and sternal lengths were calculated. These measurements were related to age and sitting height. Thoracic volume (3-16 dm(3)) did not differ significantly over growth between reference and moderate scoliosis groups. At 4 years, it represents 33%, at 10 years it represents 55% of its volume compared with age 16. It triples from 4-16 years and doubles during puberty. In severe scoliosis, the age related thoracic volume was always lower than volumes in reference and moderate scoliosis groups. During growth, the transversal diameter corresponds to 30%, the anterior-posterior diameter represents 20% and the thoracic perimeter 100% of sitting height. In severe lordoscoliosis the anterior-posterior diameter represents less than 20%. Scoliosis <45 degrees does not influence thoracic volume significantly. Severe deformities seem to inhibit volumetric growth. Thoracic parameters should be related to growth parameters such as sitting height rather than age because of possible height variations in one age section. The established relationships offer a reliable orientation of thoracic proportions. They help to understand the global deformity and represent a baseline for surgical treatment using vertical expandable prosthetic titanium ribs.

Quality of life and comorbidity score as prognostic determinants in non-small-cell lung cancer patients.

BACKGROUND: Both quality of life (QoL) and comorbidity influence therapy and prognosis of non-small-cell lung cancer (NSCLC). We previously developed a lung cancer disease-specific simplified comorbidity score (SCS) and demonstrated the prognostic impact of this disease-specific instrument. This study aimed at validating the SCS in a prospective bicentric NSCLC population by measuring its relative prognostic determinant impact taking into account well-established variables such as QoL, performance status (PS), Charlson comorbidity index (CCI) and disease stage. PATIENTS AND METHODS: Prognostic values of different pretherapeutic features were tested in univariate and multivariate analyses in a population of 301 NSCLC. RESULTS: Median survival was 17 months. One-third of patients reporting difficulties in their normal daily activities and an overall poor QoL. The following pretreament variables were independent determinants of a shorter overall survival: advanced disease, SCS, Lung Cancer Symptoms Scale global symptoms score, anaemia, hyponatremia, serum alkaline phosphatases level, serum CYFRA 21-1 and serum neuron-specific enolase. CONCLUSION: In this extended validation population, the SCS is more informative than the CCI in predicting NSCLC patient outcome as the former is also more disease specific. Combination of both SCS comorbidity score and LSCC QoL yields a more accurate information that conventional analysis of PS.

The diagnosis of asthma using a self-questionnaire in those suffering from allergic rhinitis: a pharmaco-epidemiological survey in everyday practice in France.

BACKGROUND: All recent guidelines recommend a search for asthma utilizing both specific interrogation and pulmonary function tests in patients suffering from allergic rhinitis. Although the mandatory place of spirometry has not been confirmed, a self-questionnaire containing nine specific questions on asthma symptoms in different daily life situations was found to be capable of discriminating asthmatics from nonasthmatics in a rhinitic population. OBJECTIVE: We addressed the questions of prevalence of asthma using a validated self-questionnaire and what might be the risk factors of being asthmatic according to that specific self-questionnaire. METHODS: Between April 2003 and September 2004, nearly 12,000 rhinitis patients were enrolled by more than 2300 physicians (78% general practitioners, 22% ear nose and throat specialists). Patients were consulting for an exacerbation of chronic rhinitis and did not have a previous diagnosis of asthma. Both doctors and patients filled out a specific questionnaire on rhinitis and asthma. RESULTS: Almost 30% of the patients had at least three positive answers to the self-questionnaire and could possibly be considered as asthmatics. We found five independent clinical risk factors for having >or=3 positive answers to the self-questionnaire. Severity of rhinitis (moderate-severe vs mild, OR=1.84; 95% CI=1.68-2.00), diagnosis of allergy (yes vs no) (OR=1.86; 95% CI=1.68-2.00), body mass index (30) (OR=0.51; 95% CI=0.39-0.66), type of rhinitis (persistent vs intermittent) (OR=1.25; 95% CI=1.15-1.37), and patient age (47) (OR=0.73; 95% CI=0.65-0.80). CONCLUSION: Asthma symptoms are frequent in rhinitics without a prior history of asthma. Several variables were shown to be predictive of asthma in these patients.

A new simplified comorbidity score as a prognostic factor in non-small-cell lung cancer patients: description and comparison with the Charlson's index.

Treatment of non-small-cell lung cancer (NSCLC) might take into account comorbidities as an important variable. The aim of this study was to generate a new simplified comorbidity score (SCS) and to determine whether or not it improves the possibility of predicting prognosis of NSCLC patients. A two-step methodology was used. Step 1: An SCS was developed and its prognostic value was compared with classical prognostic determinants in the outcome of 735 previously untreated NSCLC patients. Step 2: the SCS reliability as a prognostic determinant was tested in a different population of 136 prospectively accrued NSCLC patients with a formal comparison between SCS and the classical Charlson comorbidity index (CCI). Prognosis was analysed using both univariate and multivariate (Cox model) statistics. The SCS summarised the following variables: tobacco consumption, diabetes mellitus and renal insufficiency (respective weightings 7, 5 and 4), respiratory, neoplastic and cardiovascular comorbidities and alcoholism (weighting=1 for each item). In step 1, aside from classical variables such as age, stage of the disease and performance status, SCS was a statistically significant prognostic variable in univariate analyses. In the Cox model weight loss, stage grouping, performance status and SCS were independent determinants of a poor outcome. There was a trend towards statistical significance for age (P=0.08) and leucocytes count (P=0.06). In Step 2, both SCS and well-known prognostic variables were found as significant determinants in univariate analyses. There was a trend towards a negative prognostic effect for CCI. In multivariate analysis, stage grouping, performance status, histology, leucocytes, lymphocytes, lactate dehydrogenase, CYFRA 21-1 and SCS were independent determinants of a poor prognosis. CCI was removed from the Cox model. In conclusion, the SCS, constructed as an independent prognostic factor in a large NSCLC patient population, is validated in another prospective population and appears more informative than the CCI in predicting NSCLC patient outcome.

Optimizing the use of anti-interleukin-6 monoclonal antibody with dexamethasone and 140 mg/m2 of melphalan in multiple myeloma: results of a pilot study including biological aspects.

Interleukin-6 (IL-6) is a major survival factor for multiple myeloma (MM) cells preventing apoptosis induced by dexamethasone (DEX) or chemotherapy. In all, 24 consecutive patients with MM in first-line therapy received DEX for 4 days, followed by melphalan (HDM: 140 mg/m2) and autologous stem cell transplantation (ASCT). The anti-IL-6 monoclonal antibody (mAb) (B-E8) was given till haematological recovery, starting 1 day before DEX. Results were historically compared to MM patients treated with HDM 140 and 200 mg/m2. Our results show (1) that B-E8 was able to fully neutralize IL-6 activity in vivo before and after HDM as shown by inhibition of C reactive protein (CRP) production; (2) no haematological toxicity; (3) a significant reduction of mucositis and fever; (4) a median event-free survival of 35 months and an overall survival of 68.2% at 5 years with a median follow-up of 72 months; and (5) the overall daily IL-6 production progressively increased on and after 7 days post-HDM, with the increased serum CRP levels. In the 5/24 patients with uncontrolled CRP production, a large IL-6 production was detected (320 microg/day) that could not possibly be neutralized by B-E8. These data show the feasibility to neutralize IL-6 in vivo with anti-IL-6 mAb in the context of HDM.

Variable virological outcomes according to the center providing antiretroviral therapy within the PharmAdapt clinical trial.

PURPOSE: Differences in virological response between HIV-infected patients at different study centers were analyzed as a substudy of PharmAdapt, a multicenter prospective randomized study to evaluate the utility of therapeutic drug monitoring after a genotypic-based treatment adaptation. RESULTS: After 12 weeks, the percentage of patients participating in PharmAdapt with HIV RNA < 200 copies/mL ranged from 17% to 69% between centers providing antiretroviral care. In a multivariate analysis, independent factors predictive of viral load <200 HIV RNA copies/mL at Week 12 included: lower baseline viral load, lower nonnucleoside reverse transcriptase inhibitor resistance, lower protease inhibitor resistance, and the center providing antiretroviral therapy. To evaluate the final factor, study sites were divided into two groups based on Week 12 HIV RNA values above or below the median. CONCLUSION: Using this definition, observed differences between centers included the use of stavudine, abacavir-, and/or efavirenz-based regimens and use of online expert advice.

Financial costs of alcoholism treatment programs: a longitudinal and comparative evaluation among four specialized centers.

BACKGROUND: Alcoholism is a worldwide problem. Many strategies for alcohol detoxification and relapse prevention exist, but each alcohol treatment center has its own program. The objective of this study was to analyze and compare the financial cost and effectiveness of alcohol treatment programs from inpatient stay to follow-up 1 year later. This was a prospective, open, nonrandomized study of 4 specialized alcohol treatment centers and 267 patients admitted for alcohol detoxification. METHODS: We recorded all medical and nonmedical interventions related to the program during patient stay in the hospital and every 3 months after discharge for 1 year and recorded the occurrence of alcohol relapse. Financial evaluation was based on the prices of refund from the French national health insurance service. RESULTS: The mean cost of hospitalization ranged from 1326 euros to 1917 euros(p = 0.001), a variation mainly due to the difference in the length of hospital stay but also to the cost of the inpatient program, routine medical checkups, and drugs administered. The mean cost of 1 year of follow-up per patient ranged from 419 euros to 1704 euros (p = 0.001). The efficiency, corresponding to the money spent to prevent the relapse of one patient during 1 month, was approximately 500 euros/month in three centers and 658 euros in the fourth. However, for a similar efficiency, the effectiveness, assessed by the mean time without relapse, was significantly (p = 0.001) different; center 1, which had the highest total cost, had an effectiveness 1.56 times higher than center 3, which had the lowest cost. CONCLUSIONS: This work emphasizes the heterogeneity of the costs and effectiveness of alcoholism treatment programs and suggests that research should be conducted to determine which program is the most rational, cost-efficient, and beneficial for patients and the public health office economy.

[Validation of an asthma knowledge questionnaire]. / Validation d'un questionnaire de connaissances sur l'asthme.

INTRODUCTION: A patient's knowledge of his disease and its treatment is an essential part of the evaluation of an educational process. It is useful therefore to use a rapid, easy and valid means of collecting the information necessary to produce an educational programme adapted to the needs of the patient. METHODS: Following a review of the literature an initial questionnaire was constructed. It included four domains: biomedical, signs and symptoms of severity, general knowledge and treatment. The questionnaire was administered to 73 asthmatics in order to assess its clarity and comprehensibility. It was then reviewed and modified in both format and content by 10 French experts. The revised questionnaire was completed by 108 asthmatics distributed throughout 10 French respiratory centres, a group of 83 non-asthmatic subjects and 203 sixth year medical students at the Bordeaux University School of Medicine. RESULTS: The mean scores were: 19 for the non-asthmatics (range 2-36), 25.7 for the asthmatics (range 4-38) and 32.9 for the students (range 17-40), p 0.0001. The questionnaire was shown to be discriminating with good reliability and reproducibility: alpha Cronbach coefficient=0.82; intra-class correlation coefficient=0.70. CONCLUSIONS: This study has validated a French language asthma knowledge questionnaire.

Preliminary evaluation of medical outcomes (including quality of life) and costs in incident RA cases receiving hospital-based multidisciplinary management.

A six-month, prospective descriptive study of medical outcomes (including quality of life) and costs was conducted in 20 incident cases of rheumatoid arthritis (RA). Multidisciplinary management was started during an inpatient stay at the beginning of the study. Patients were evaluated on a day-hospital basis three and six months later. The following parameters were studied: quality-of-life scores on a generic scale (the Nottingham Health Profile [NHP]) and two specific scales (Health Assessment Questionnaire [HAQ] and the short-form Arthritis Impact Measurement Scale [AIMS]), pain severity, disease activity assessed by the patient and physician, painful and swollen joint counts, erythrocyte sedimentation rate, and C-reactive protein level. The following costs were evaluated: laboratory tests, plain radiographs, other investigations, physician care (by rheumatologists or other specialists), second-line drug therapy and monitoring for its side effects, care by nurses, physical therapy, and occupational therapy. All patients showed significant improvement three months after initiation of multidisciplinary management. This effect was sustained through the sixth month. Quality-of-life scores improved, with the exceptions of the social isolation subscore on the NHP and the psychological impact, social activity, and occupational activity subscores on the short-form AIMS. Mean total cost for the six-month period was 3429 +/- 880 euros (1 euro = 6.6 FF). Laboratory tests contributed the largest portion of the total cost (39%), followed by rheumatologist care (16%); the other costs accounted for 7.6 to 9.2% of the total cost. This prospective medical and economic study is preliminary. Comparative studies are needed.