Ballman, Karla V.

ABSTRACTOBJECTIVE:To describe the quality of life (QOL) over time for adults with newly diagnosed high-grade gliomas and to examine the relationship between QOL and outcome data collected in three prospective cooperative group clinical trials.METHODS:The QOL study was a companion protocol for three Phase II high-grade glioma protocols. Five self-administered forms were completed by patients to assess QOL at study entry, 2 months, and 4 months after enrollment.RESULTS:QOL data were available for baseline, first, and second subsequent follow-up evaluations for 89%, 71%, and 69% of patients, respectively. A significant proportion of patients (47.1%) experienced impaired QOL (QOL ≤ 50) in at least one measure at subsequent evaluations, whereas most patients (88%) with impaired QOL at baseline continued to have impaired QOL at subsequent evaluations. On multivariable analyses, baseline QOL measures were predictive of QOL at the time of follow-up. In addition, patients who underwent a gross total resection were much less likely to have impaired QOL (P = 0.006), were less likely to experience worsening depression (P = 0.0008), and were more likely to have improved QOL (P = 0.003) at their first follow-up evaluation. Changes in QOL measures over time were not found to be associated with survival in multivariable analyses that adjusted for known prognostic variables; variables that were independently associated with improved survival were better performance status (P < 0.001), younger age (P < 0.001), and greater extent of resection (P < 0.001).CONCLUSION:Baseline QOL was predictive of QOL over time. Gross total resection was associated with longer survival and improved QOL over time for patients with high-grade gliomas.

Background Temsirolimus (CCI-779) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) and represents a rational therapeutic target against glioblastoma multiforme (GBM). Methods Recurrent GBM patients with ≤ 1 chemotherapy regimen for progressive disease were eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly. Results Sixty-five patients were treated. The incidence of grade 3 or higher nonhematologic toxicity was 51%, and consisted mostly of hypercholesterolemia (11%), hypertriglyceridemia (8%), and hyperglycemia (8%). Grade 3 hematologic toxicity was observed in 11% of patients. Temsirolimus peak concentration (Cmax), and sirolimus Cmax and area under the concentration-time curve were decreased in patients receiving p450 enzyme–inducing anticonvulsants (EIACs) by 73%, 47%, and 50%, respectively, but were still within the therapeutic range of preclinical models. Twenty patients (36%) had evidence of improvement in neuroimaging, consisting of decrease in T2 signal abnormality +/− decrease in T1 gadolinium enhancement, on stable or reduced steroid doses. Progression-free survival at 6 months was 7.8% and median overall survival was 4.4 months. Median time to progression (TTP) for all patients was 2.3 months and was significantly longer for responders (5.4 months) versus nonresponders (1.9 months). Development of grade 2 or higher hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response (71% v 31%; P = .04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P = .04). Conclusion Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on temsirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was observed in 36% of temsirolimus–treated patients, and was associated with significantly longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These findings should be validated in other studies of mTOR inhibitors.

Background— The incidence, determinants, and outcome of postoperative atrial fibrillation (AF) after surgery for mitral regurgitation (MR) are poorly defined but may have important implications for timing of mitral valve surgery. Methods and Results— In 762 patients in sinus rhythm with no AF history undergoing MR surgical correction, we examined the rates and prognostic implications of postoperative AF for early AF (within 2 weeks postoperatively) and late AF (>2 weeks after surgery). During postoperative follow-up, 180 patients (24%) experienced new AF (early AF in 136 and late AF in 111). Isolated early AF without recurrence was observed in 69 patients characterized by high angina class and lower left ventricular ejection fraction but no significant left atrial (LA) enlargement. However, overall early AF predicted late AF: 62±5% of patients with early AF had late AF at 10 years compared with 9±1% of patients without early AF ( P <0.0001). Large LA size strongly and independently predicted early AF ( P =0.01) and late AF ( P =0.003). For late AF, the predictive value of an enlarged LA was cumulative to that of early AF. Postoperative AF was associated with an increased subsequently higher risk of stroke or congestive heart failure (adjusted risk ratio=1.46 [1.04 to 2.05], P =0.03). Conclusions— Postoperative AF is common after surgical correction of MR in patients with no prior history of AF and is associated with increased subsequent morbidity. LA enlargement is independently predictive of postoperative AF and as such, should be integrated into the clinical decision-making process in patients with MR.

AbstractImmunoglobulin light chain amyloidosis (AL) is characterized by a clonal expansion of plasma cells within the bone marrow. Gene expression analysis was used to identify a unique molecular profile for AL using enriched plasma cells (CD138+) from the bone marrow of 24 patients with AL and 28 patients with multiple myeloma (MM) and 6 healthy controls. Class prediction analysis (PAM) revealed a subset of 12 genes, which included TNFRSF7 (CD27), SDF-1, and PSMA2, that distinguished between these 2 groups with an estimated and observed accuracy of classification of 92%. This model was validated with an independent dataset of 11 patients with AL and 12 patients with MM with 87% accuracy. Differential expression for the most discriminant genes in the 12-gene subset was validated using quantitative real-time polymerase chain reaction and protein expression analysis, which upheld the observations from the micro-array expression data. Functional analyses using a novel network mapping software revealed a number of potentially significant pathways that were dysregulated in patients with AL, with those regulating proliferation, apoptosis, cell signaling, chemotaxis, and migration being substantially represented. This study provides new insight into the molecular profile of clonal plasma cells and its functional relevance in the pathogenesis of light chain amyloidosis.

Abstract Motivation: Our goal was to develop a normalization technique that yields results similar to cyclic loess normalization and with speed comparable to quantile normalization. Results: Fastlo yields normalized values similar to cyclic loess and quantile normalization and is fast; it is at least an order of magnitude faster than cyclic loess and approaches the speed of quantile normalization. Furthermore, fastlo is more versatile than both cyclic loess and quantile normalization because it is model-based. Availability: The Splus/R function for fastlo normalization is available from the authors.

Early-onset peripheral lower extremity arterial occlusive disease (PAD) is an uncommon, poorly characterized manifestation of atherosclerotic vascular disease. We studied the clinical presentation and correlates of disease severity and location in patients with early-onset PAD identifi ed at non-invasive arterial evaluation. We identifi ed a series of 159 patients who were younger than 50 years and had an abnormal resting or postexercise ankle brachial index (ABI) (<0.9) or, if arteries were noncompressible, monophasic arterial Doppler signals. Disease severity and location were determined based on results of noninvasive vascular laboratory testing. Presence of coexisting atherosclerosis in other arterial beds was ascertained by review of patient records. Multivariable logistic regression analyses were used to identify risk factors associated with disease severity and location. Mean age of the patients was 42.7 6 4.2 years and 55% were women. Prevalence of risk factors was 76% for current or past smoking; 71%, dyslipidemia; 53%, hypertension; 35%, diabetes; and 53%, family history. Claudication was present in 50%, rest pain in 3%, ulceration in 31% and the remaining 16% did not have symptoms from PAD. Low high-density lipoprotein (HDL)-cholesterol and female sex were associated with severity. Of 102 patients in whom disease location could be determined noninvasively, 65% had aortoiliac disease. Female sex, low HDL-cholesterol, and absence of diabetes were associated with aortoiliac disease. Atherosclerosis in other arterial beds was identifi ed in 53% of the patients. Conclusion: In this study population of early-onset atherosclerotic PAD, men and women were equally represented. The disease involved predominantly the aortoiliac location. Low HDL-cholesterol and female sex were associated with disease severity. An aggressive approach to diagnosis and treatment may be warranted as atherosclerosis in other arterial beds was prevalent in half of the patients.

Background— We tested the hypothesis that patients with untreated obstructive sleep apnea (OSA) would be at increased risk for recurrence of atrial fibrillation (AF) after cardioversion. Methods and Results— We prospectively obtained data on history, echocardiogram, ECG, body mass index, hypertension, diabetes, NYHA functional class, ejection fraction, left atrial appendage velocity, and medications in patients with AF/atrial flutter referred for DC cardioversion. Forty-three individuals were identified as having OSA on the basis of a previous sleep study. Data regarding the use of continuous positive airway pressure (CPAP) and recurrence of AF were obtained for 39 of these patients. Follow-up data were also obtained in 79 randomly selected postcardioversion patients (controls) who did not have any previous sleep study. Twenty-seven of the 39 OSA patients either were not receiving any CPAP therapy (n=25) or were using CPAP inappropriately (n=2). Recurrence of AF at 12 months in these 27 patients was 82%, higher than the 42% recurrence in the treated OSA group (n=12, P =0.013) and the 53% recurrence (n=79, P =0.009) in the 79 control patients. Of the 25 OSA patients who had not been treated at all, the nocturnal fall in oxygen saturation was greater ( P =0.034) in those who had recurrence of AF (n=20) than in those without recurrence (n=5). Conclusions— Patients with untreated OSA have a higher recurrence of AF after cardioversion than patients without a polysomnographic diagnosis of sleep apnea. Appropriate treatment with CPAP in OSA patients is associated with lower recurrence of AF.