Guy van Melle

Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide

Purpose: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy. Experimental Design: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR. Results: Inactivation of the MGMT gene by promoter methylation was associated with longer survival (P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation (P = 0.002; Fisher’s exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor (P = 0.017; Cox regression). Conclusions: This prospective clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O-6-benzylguanine, a noncytotoxic substrate of this enzyme.

PREVENTION OF GRAM-NEGATIVE SHOCK AND DEATH IN SURGICAL PATIENTS BY ANTIBODY TO ENDOTOXIN CORE GLYCOLIPID

The prophylactic effect of antibody to endotoxin core glycolipid was studied in surgical patients at high risk of gram-negative infection. At randomisation (on admission to intensive care unit), every 5 days thereafter, and at onset of septic shock, patients received plasma taken from donors before (control) or after immunisation with Escherichia coli J5, a mutant with only core determinants in its endotoxin. Gram-negative shock occurred in 15 of 136 controls and 6 of 126 J5 antibody recipients and related deaths in 9 of 136 and 2 of 126, respectively. J5 antibody was most effective in abdominal surgery patients, in whom shock occurred in 13 of 83 controls and 2 of 71 antibody recipients. Although antibody prophylaxis did not lower the infection rate, it prevented the serious consequences of gram-negative infections and thus improved the overall prognosis.

Adjusted versus Fixed-Dose Subcutaneous Heparin in the Prevention of Deep-Vein Thrombosis after Total Hip Replacement

Venous thromboembolism after total hip replacement continues to be a serious problem. We conducted a study to determine whether adjustment of the dose of subcutaneous heparin to yield partial thromboplastin times in the high-normal range results in a greater reduction of postoperative deep-vein thrombosis than fixed doses of heparin. Seventy-nine patients undergoing elective hip arthroplasty were randomly divided into two groups two days before surgery. Group 1 (41 patients) received a fixed dose of 3500 IU of heparin subcutaneously ever eight hours; 16 of the 41 (39 per cent) had deep-vein thrombosis diagnosed by venography. Group 2 (38 patients) was started on the same dose, which was then adjusted to keep the activated partial thromboplastin time between 31.5 and 36 seconds. From the day of operation to the eighth postoperative day these patients needed progressively more heparin to maintain the activated partial thromboplastin time in the prescribed range. Only 5 of the 38 (13 per cent) had deep-vein thrombosis (P less than 0.01), and the number of thrombi in proximal veins was also lower in this group (P = 0.003). The number of units of blood transfused, the frequency of postoperative wound hematomas, and the drop in hemoglobin levels were identical in the two groups. Adjusted low-dose heparin prophylaxis appears to be a safe and efficacious method to reduce the frequency of deep-vein thrombosis in patients undergoing total hip replacement.

A Vaccine against Nicotine for Smoking Cessation: A Randomized Controlled Trial

Background Tobacco dependence is the leading cause of preventable death and disabilities worldwide and nicotine is the main substance responsible for the addiction to tobacco. A vaccine against nicotine was tested in a 6-month randomized, double blind phase II smoking cessation study in 341 smokers with a subsequent 6-month follow-up period. Methodology/Principal Findings 229 subjects were randomized to receive five intramuscular injections of the nicotine vaccine and 112 to receive placebo at monthly intervals. All subjects received individual behavioral smoking cessation counseling. The vaccine was safe, generally well tolerated and highly immunogenic, inducing a 100% antibody responder rate after the first injection. Point prevalence of abstinence at month 2 showed a statistically significant difference between subjects treated with Nicotine-Qβ (47.2%) and placebo (35.1%) (P = 0.036), but continuous abstinence between months 2 and 6 was not significantly different. However, in subgroup analysis of the per-protocol population, the third of subjects with highest antibody levels showed higher continuous abstinence from month 2 until month 6 (56.6%) than placebo treated participants (31.3%) (OR 2.9; P = 0.004) while medium and low antibody levels did not increase abstinence rates. After 12 month, the difference in continuous abstinence rate between subjects on placebo and those with high antibody response was maintained (difference 20.2%, P = 0.012). Conclusions Whereas Nicotine-Qβ did not significantly increase continuous abstinence rates in the intention-to-treat population, subgroup analyses of the per-protocol population suggest that such a vaccination against nicotine can significantly increase continuous abstinence rates in smokers when sufficiently high antibody levels are achieved. Immunotherapy might open a new avenue to the treatment of nicotine addiction. Trial Registration Swiss Medical Registry 2003DR2327; ClinicalTrials.gov NCT00369616

Ischemic stroke and active migraine

To the Editor: An important factor was not mentioned in the recent study by Milhaud et al.1 We know that migraine is frequently associated with other types of headaches, mostly tension-type headaches. These patients and migraine patients in general use over-the-counter medications. This includes aspirin (ASA)-containing drugs and ASA may influence the outcome of cases in which thrombotic events are considered. The usage of ASA was not mentioned in the different groups analyzed. Furthermore, the use of triptans also may have an influence in the outcome. Triptans are frequently being used in migraine treatment. Although potentially confusing, it would be interesting to review the same cases under another set of variables. It is sometimes preferable to be puzzled rather than mistaken. # Ischemic stroke and active migraine {#article-title-2} To the Editor: We appreciate the study on ischemic stroke and active migraine by Milhaud et al.1 They concluded that migraine is frequent in young stroke patients and infrequent in older patients and is related to age. In the Results section (table 2), they report on the age of the migraineurs whose mean age ± SD was 57.6 ± 9 years. Unfortunately, …Objective: To determine the characteristics of acute ischemic stroke (IS) in patients with active migraine in a prospective stroke registry. Methods: The authors studied the characteristics of patients admitted to a population-based primary-care center with IS and active migraine. The diagnosis of previous migraine was made based on replies to International Headache Society–based questions. Patients with migraine were divided into two age groups, one below 45 years of age and one 45 years or older, and compared by univariate and multivariate analysis with age-matched control subjects with IS, but without migraine. Results: Of the 3,502 patients with acute IS, 130 (3.7%) had active migraine; 66 of these were younger than 45 years and 64 were 45 years or older (15.8% and 2.1% of the total for the corresponding age group). The proportion of women was significantly higher in both groups of patients with migraine (74% and 63% in the younger and older groups) than in control subjects. In young migraineurs, the posterior circulation involvement and the presence of patent foramen ovale were characteristic. In the younger migraine group, nine patients developed IS during a typical attack of migraine with aura, and 15 during migraine attack without aura in the absence of any other determined cause. In the older group, surprisingly, absence of vascular risk factors (previous hypertension, ischemic heart disease, and cigarette smoking) was characteristic. Conclusions: Migraine is frequent in young patients with IS and infrequent in older patients with IS. Patients with IS and migraine are mainly women with stroke features that are age dependent.

Risk of falls for hospitalized patients: A predictive model based on routinely available data

The incidence rate of falls is often used as an indicator of nursing care outcome. Comparing outcome between different settings should, however, make allowance for case mix. To measure the incidence of falls, describe their circumstances and develop a prediction model based on routinely collected data to allow comparison between hospital settings with different case mix. A dynamic population of patients hospitalized over a year in which a case was defined as any accidental fall systematically reported on an ad hoc form. A Swiss university hospital of 800 beds; 634 falls were reported for 26,643 hospitalizations over 236,307 hospitalization days. First fall rates were analyzed using a Poisson regression model with routinely computerized discharge data as independent variables. The incidence rate of first falls was 2.2 per 1000 patient-days. For subsequent falls the rates of incidence increased with the number of falls. Five independent variables played a significant role: age, gender, morbidity predisposition, surgical procedure and length of stay. Two of the interactions between these variables were significant and remained in the model (length of stay with age, morbidity with age). The model offers good medical plausibility and satisfactory predictive performance. The proposed model can be used by national health agencies to compute expected first fall rates accounting for case mix. Hospitals can use these rates for evaluation. Recommendations for measuring, monitoring and assessing fall rates are also given.

Measuring potentially avoidable hospital readmissions

The objectives of this study were to develop a computerized method to screen for potentially avoidable hospital readmissions using routinely collected data and a prediction model to adjust rates for case mix. We studied hospital information system data of a random sample of 3,474 inpatients discharged alive in 1997 from a university hospital and medical records of those (1,115) readmitted within 1 year. The gold standard was set on the basis of the hospital data and medical records: all readmissions were classified as foreseen readmissions, unforeseen readmissions for a new affection, or unforeseen readmissions for a previously known affection. The latter category was submitted to a systematic medical record review to identify the main cause of readmission. Potentially avoidable readmissions were defined as a subgroup of unforeseen readmissions for a previously known affection occurring within an appropriate interval, set to maximize the chance of detecting avoidable readmissions. The computerized screening algorithm was strictly based on routine statistics: diagnosis and procedures coding and admission mode. The prediction was based on a Poisson regression model. There were 454 (13.1%) unforeseen readmissions for a previously known affection within 1 year. Fifty-nine readmissions (1.7%) were judged avoidable, most of them occurring within 1 month, which was the interval used to define potentially avoidable readmissions (n = 174, 5.0%). The intra-sample sensitivity and specificity of the screening algorithm both reached approximately 96%. Higher risk for potentially avoidable readmission was associated with previous hospitalizations, high comorbidity index, and long length of stay; lower risk was associated with surgery and delivery. The model offers satisfactory predictive performance and a good medical plausibility. The proposed measure could be used as an indicator of inpatient care outcome. However, the instrument should be validated using other sets of data from various hospitals.

Pathogenesis of anterior circulation stroke in patients with nonvalvular atrial fibrillation The Lausanne Stroke Registry

We studied coexisting potential arterial and cardiac causes of stroke in 159 patients with nonvalvular atrial fibrillation (AF), who were admitted to a population-based primary care center for an anterior circulation infarct. Systematic investigations included brain CT, carotid Doppler ultrasounds with frequency analysis and echotomography, and mono- and bidimensional echocardiography. Lacunar infarction due to small-artery disease was at least as likely as an AF-related stroke in 13% of the patients who had hypertension and a small deep infarct. In 67% of the patients, internal carotid artery disease ipsilateral to infarct was present, but it was severe (≥50% stenosis or occlusion) in only 11%. There was a potential cardiac source of embolism other than AF in 14%. Overall, although only 18% of the patients had AF as the only potential cause of stroke, embolism from the heart remained the most likely etiology of infarct in 76%. Our findings emphasize the role of AF-related hemodynamic disturbances, which were often associated with embolie phenomena, and a rather low early risk of recurring embolism (4%) within the 1st month after stroke.

Prediction of Hip Fracture Risk by Quantitative Ultrasound in More Than 7000 Swiss Women ≥70 Years of Age: Comparison of Three Technologically Different Bone Ultrasound Devices in the SEMOF Study†‡

To compare the prediction of hip fracture risk of several bone ultrasounds (QUS), 7062 Swiss women ≥70 years of age were measured with three QUSs (two of the heel, one of the phalanges). Heel QUSs were both predictive of hip fracture risk, whereas the phalanges QUS was not.

Clinical and prognostic features in unilateral femoral neuropathies

We have examined the clinical features of patients with femoral neuropathy and the factors that influence the prognosis. Of 80 consecutive patients referred for neurophysiological evaluations of proximal lower limb weakness, 32 fulfilled strict inclusion criteria and had adequate information, including estimates of axon loss (AxL) by stimulation of the bilateral femoral nerve. In 31, the Kaplan‐Meier method was used to describe the time course of the outcome, while logistic regression was employed to determine the contributing factors. Excellent, satisfactory, and poor outcomes were seen in 10 (31%), 11 (34%), and 10 (31%) patients, respectively. Logistic regression analysis of seven factors demonstrated that the estimate of AxL was the only significant variable. The best prognostic factor was an estimate of AxL ≤ 50%, with all patients fulfilling this criterion showing improvement within 1 year; fewer than half the patients with AxL >50% should be expected to improve. This study clearly shows that, irrespective of the cause of femoral neuropathy, functional improvement is seen in 2 out of 3 patients within 2 years and that the estimate of AxL is the only factor influencing prognosis.