The aim of this work was to investigate white-matter microstructural changes within and outside the corticospinal tract in classical amyotrophic lateral sclerosis (ALS) and in lower motor neuron (LMN) ALS variants by means of diffusion tensor imaging (DTI). We investigated 22 ALS patients and 21 age-matched controls utilizing a whole-brain approach with a 1.5-T scanner for DTI. The patient group was comprised of 15 classical ALS- and seven LMN ALS-variant patients (progressive muscular atrophy, flail arm and flail leg syndrome). Disease severity was measured by the revised version of the functional rating scale. White matter fractional anisotropy (FA) was assessed using tract-based spatial statistics (TBSS) and a region of interest (ROI) approach. We found significant FA reductions in motor and extra-motor cerebral fiber tracts in classical ALS and in the LMN ALS-variant patients compared to controls. The voxel-based TBSS results were confirmed by the ROI findings. The white matter damage correlated with the disease severity in the patient group and was found in a similar distribution, but to a lesser extent, among the LMN ALS-variant subgroup. ALS and LMN ALS variants are multisystem degenerations. DTI shows the potential to determine an earlier diagnosis, particularly in LMN ALS variants. The statistically identical findings of white matter lesions in classical ALS and LMN variants as ascertained by DTI further underline that these variants should be regarded as part of the ALS spectrum.

BACKGROUND Inhibition of signal transduction pathways has been successfully introduced into cancer treatment. The dual phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 has antitumor activity in vitro against solid tumors. Here, we examined the activity of NVP-BEZ235 in acute lymphoblastic leukemia (ALL) cells and the best modalities for combination approaches. MATERIALS AND METHODS ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were treated with NVP-BEZ235 alone, or in combination with cytarabine (AraC), doxorubicin (Doxo) or dexamethasone (Dexa). RESULTS NVP-BEZ235 potently inhibited the proliferation and metabolic activity of ALL cells. Antiproliferative effects were associated with G(0)/G(1) arrest and reduced levels of cyclin-dependent kinase 4 (CDK4) and cyclin D3. Inhibition of PI3K and mTOR activity was detected at 10 and 100 nM. NVP-BEZ235 combined with AraC, Doxo or Dexa synergistically enhanced the cytotoxicity compared to single-drug treatment, even in glucocorticoid-resistant cells. CONCLUSION NVP-BEZ235 displays pronounced antiproliferative effects in ALL cells and might therefore be a useful drug in the treatment of ALL.

AIMS/HYPOTHESIS: The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). METHODS: Participants with type 2 diabetes (HbA(1c) 6.7-10.0%[50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n = 30) or placebo (n = 30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. RESULTS: Compared with placebo, colesevelam improved HbA(1c)(mean change from baseline of 0.3 [SD 1.1]% for placebo [n = 28] and -0.3 [1.1]% for colesevelam [n = 26]), glucose concentrations, fasting plasma glucose clearance and glycolytic disposal of oral glucose. Colesevelam did not affect gluconeogenesis or appearance rate (absorption) of oral glucose. Fasting endogenous glucose production and glycogenolysis significantly increased with placebo but were unchanged with colesevelam (treatment effect did not reach statistical significance). Compared with placebo, colesevelam increased total GLP-1 and GIP concentrations and improved HOMA-beta cell function while insulin, glucagon and HOMA-insulin resistance were unchanged. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis. CONCLUSIONS/INTERPRETATION: Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents. TRIAL REGISTRATION: ClinicalTrials.gov NCT00596427 FUNDING: The study was funded by Daiichi Sankyo.

PHI in HMORN medical records must be systematically removed prior to use and sharing data with co-investigators at other institutions. The problem is particularly acute when one needs to link clinical and follow-up data with pathologic specimens from cancer patients in studies of prognostic and predictive tumor markers. Natural language processing (NLP) can be customized to identify and remove PHI in selected clinical records by substituting nonsense characters. Such a process of deidentification can proceed largely without human intervention and, if successful, can allow efficient linkage of clinical notes with similarly deidentified specimens for laboratory investigators at other institutions. The Shared Pathology Informatics Network (SPIN) was funded by the Cancer Diagnosis Program of the National Cancer Institute to develop a computerized program that would search pathology department text files and reports from several institutions and retrieve, in a database, all records that met search criteria. SPIN was designed to access information from each institution's electronic records without affecting the records and collating data from several sites into a single report. Our current project, the Specimen Retrieval System, requires the identification of large numbers of cancer specimens of specific types from Kaiser Permanente Northwest (KPNW) and, subsequently, other Cancer Research Network sites, retrieval of those specimens and linkage with clinical annotations that describe staging, treatment and outcome. We have used the existing databases of the KPNW Tumor Registry and Department of Pathology to identify cases. The EPIC electronic medical record and several other computerized text files provided the clinical notes for these patients. Using SPIN technology we then processed text files to 'scrub' them of PHI. All records were then manually inspected to assess the completeness of the process, which elements of PHI persisted and which had been successfully 'scrubbed' of PHI. We processed several hundred files from more than 100 patients and will report detailed statistical analysis. This technology has demonstrated significant capability to facilitate searches for pathologic specimens and clinical annotations using conventional reports from pathology departments. It is a valuable tool to remove PHI, deidentify medical records and ease sharing of clinical information with investigators at other sites.

BACKGROUND To characterize healthcare resource utilization and costs in patients with metastatic lung cancer receiving chemotherapy in the US. METHODS Using data from a large private multi-payer health insurance claims database (2000-2006), we identified all patients beginning chemotherapy for metastatic lung cancer. Healthcare resource use (inpatient, outpatient, medications) and costs were tallied over time from date of therapy initiation ("index date") to date of disenrollment from the health plan (in most instances, presumably due to death) or the end of the study period, whichever occurred first. Healthcare utilization and costs were characterized using Kaplan-Meier sample average methods. RESULTS The study population consisted of 4068 patients; mean (SD) age was 65 (11) years. Over a median follow-up of 334 days, study subjects averaged 1.5 hospital admissions, 8.9 total inpatient days, and 69 physician office and hospital outpatient visits. Mean (95% CI) cumulative total healthcare costs were $125,849 ($120,228,$131,231). Costs of outpatient medical services and inpatient care constituted 34% and 20% of total healthcare costs, respectively; corresponding estimates for outpatient chemotherapy and other medication were 22% and 24%. CONCLUSION Our study sheds additional light on the burden of metastatic lung cancer among patients receiving chemotherapy, in terms of total cost thru end of life as well as component costs by setting and type of service, and may be useful in informing medical resource allocation in this patient population.

OBJECTIVES If in a clinical trial prognostic factors are known in advance, it is often recommended that randomization of patients should be stratified. The best-known method is permuted-block randomization within strata. But it suffers from the disadvantage that imbalance still occurs in the trial as a whole if there are a large number of strata, or/and the block sizes are too large for the number of patients. The results of Hallstrom and Davis are appropriate for evaluating the risk of such a troubled situation by using two special cases of their general variance formula. But it is merely generally argued for whichever practical situations these special cases are valid. Consequently, additional investigations are required to reveal the conditions for correct application. METHODS We investigated the range of validity of special cases by performing computer simulations, varying a number of trial characteristics, and discuss the application of results for practical situations. RESULTS The validity of special cases is not given in each situation. Depending on block size, a binomial distribution model is valid for a permitted average maximum number of patients per stratum between 36% and 57% of considered block sizes, whereas the uniform distribution model works adequately from at least 70%. In an intermediate range of invalidity, implementation of a simulation study is necessary to compute the probability distribution of differences. CONCLUSIONS Our results are important if choosing the stratified permuted-block randomization to estimate the risk for an intolerable overall imbalance when planning a trial.

The economic costs of treating patients with metastatic breast cancer have been examined in several studies, but available estimates of economic burden are at least a decade old. In this study, we characterize healthcare utilization and costs in the US among women with metastatic breast cancer receiving chemotherapy as their principal treatment modality. Using a large private health insurance claims database (2000-2006), we identified all women initiating chemotherapy for metastatic breast cancer with no evidence of receipt of concomitant or subsequent hormonal therapy, or receipt of trastuzumab at anytime. Healthcare utilization and costs (inpatient, outpatient, medication) were estimated on a cumulative basis from date of chemotherapy initiation ("index date") to date of disenrollment from the health plan or the end of the study period, whichever occurred first. Study measures were cumulated over time using the Kaplan-Meier Sample Average (KMSA) method; 95% CIs were generated using nonparametric bootstrapping. Findings also were examined among the subgroup of patients with uncensored data. The study population consisted of 1444 women; mean (SD) age was 59.1 (12.1) years. Over a mean follow-up of 532 days (range: 3 to 2412), study subjects averaged 1.7 hospital admissions, 10.7 inpatient days, and 83.6 physician office and hospital outpatient visits. Mean (95% CI) cumulative total healthcare costs were $128,556 ($118,409,$137,644) per patient. Outpatient services accounted for 29% of total costs, followed by medication other than chemotherapy (26%), chemotherapy (25%), and inpatient care (20%). Healthcare costs-especially in the outpatient setting--are substantial among women with metastatic breast cancer for whom treatment options other than chemotherapy are limited.

OBJECTIVE: Our objective was to elucidate long-term clinical and functional effects of intramyocardial stem cell transplant and to identify patients who will show sustained benefit. METHODS: Long-term outcomes of 35 patients after intramyocardial CD133(+) bone marrow stem cell transplant during coronary artery bypass grafting were compared with those of a control group of 20 patients after coronary artery bypass grafting alone. Clinical effects were assessed with the New York Heart Association classification system and the Minnesota Living With Heart Failure questionnaire. Electrocardiography, 24-hour Holter monitoring, echocardiography, myocardial perfusion scanning, magnetic resonance imaging, and computed tomography were performed. Logistic regression analyses were used to identify prognostic factors for improvement in long-term left ventricular ejection fraction after stem cell treatment. RESULTS: The stem cell group revealed similar New York Heart Association and life quality scores to the control group. Myocardial perfusion score at the area of risk was significantly increased in the stem cell group after 36-month follow-up (P = .024 vs control). Multivariate logistic regression analysis revealed a 44-fold higher probability of at least 5% improvement in left ventricular ejection fraction for patients with preoperative left ventricular ejection fraction not greater than 40% than for patients with preoperative ejection fraction greater than 40%(P = .018). Furthermore, patients operated on between 7 and 12 weeks after myocardial infarction had a 56-fold higher chance of at least 5% improvement in left ventricular ejection fraction than patients treated later than 12 weeks after infarction (P = .023). CONCLUSIONS: Intramyocardial stem cell therapy was safe but lacked significant lasting benefits beyond 6 months in our study cohort with a limited number of patients. Preoperative left ventricular ejection fraction and time since myocardial infarction may be critical parameters for selection of patients who can benefit most from intramyocardial stem cell treatment during coronary artery bypass grafting.

Although the effectiveness of cervical cancer screening, by means of the Pap smear, has been firmly established in reproductive-age women, the usefulness of cytologic screening in older women is unclear. We sought to assess the degree to which such screening in older women can reduce the incidence of cervical cancer. We conducted a case-control study to evaluate the efficacy of cervical cancer screening in older women enrolled in one of two large health maintenance organizations in the northwestern United States. Cases (n = 69) consisted of those women, 55 to 79 years of age, who were diagnosed with invasive cervical cancer during 1980 to 1999 as enumerated by regional cancer registries. Controls (n = 208) were women sampled from among enrollees who had not previously had a hysterectomy and were similar to cases in terms of age and length of enrollment in the health plan. We reviewed medical records to ascertain demographic, reproductive, and cervical screening history information during the 7 years before the reference date. Only tests which occurred during the presumed detectable preinvasive phase (DPP) of the disease, when screening could be beneficial, were considered and we evaluated results for a series of plausible estimates of this interval. Compared to cases, controls were more likely to have had a Pap test during the DPP, regardless of the estimate used. After adjustment for age and current smoking status, screening was associated with a substantial reduction in the risk of invasive cervical cancer (DPP = 72 months: OR, 0.23; 95% CI, 0.11-0.44). We observed only small differences in the odds ratio across the various estimates of the DPP that were employed. Analysis of the relative incidence of invasive cervical cancer in relation to the time following a negative screening test suggested a large reduction during the first year (OR, 0.09; 95% CI, 0.03-0.24). The incidence remained low for several years thereafter, returning to the incidence among unscreened women after 5 to 7 years. Cervical cancer screening is highly efficacious in older women. This needs to be explicitly considered in weighing the benefits and costs of such screening beyond the reproductive years.

OBJECTIVE: Experimental and clinical studies have suggested that intramyocardial bone marrow stem cell transplantation combined with coronary artery bypass grafting might improve left ventricular function in the setting of chronic ischemic heart disease. We therefore conducted a systematic review and meta-analysis of available publications regarding the efficacy and safety of intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting. METHODS: The databases PUBMED, MEDLINE, Cochrane Controlled Trials Register, and ClinicalTrials.gov (all from their inception to May 2009) were searched for randomized controlled trials and cohort studies of intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting to treat ischemic heart disease. Six studies were included. RESULTS: Compared with control groups, the bone marrow stem cell transplantation group showed a significant improvement of left ventricular ejection fraction from baseline to follow-up (5.40%; 95% confidence interval, 1.36-9.44; P = .009). Moreover, the overall change of left ventricular end-diastolic volume from baseline to follow-up favored the bone marrow stem cell therapy group (9.55 mL; 95% confidence interval,-2.82 to 21.92; P = .13). Major adverse cardiovascular events, including ventricular arrhythmia and the composite of other cardiovascular events, were not significantly different between the bone marrow stem cell therapy group and controls (relative risk for ventricular arrhythmia = 0.951; 95% confidence interval, 0.389-2.325; P = .913; relative risk for cardiovascular event = 1.134; 95% confidence interval, 0.28-4.6; P = .86). CONCLUSIONS: Clinical evidence suggests that intramyocardial bone marrow stem cell transplantation in combination with coronary artery bypass grafting is associated with improvements of functional parameters in patients with chronic ischemic heart disease. Furthermore, surgical intramyocardial bone marrow stem cell transplantation seems to be safe.