Patterns of primary care and mortality among patients with schizophrenia or diabetes: a cluster analysis approach to the retrospective study of healthcare utilization

Abstract Background Patients with schizophrenia have difficulty managing their medical healthcare needs, possibly resulting in delayed treatment and poor outcomes. We analyzed whether patients reduced primary care use over time, differentially by diagnosis with schizophrenia, diabetes, or both schizophrenia and diabetes. We also assessed whether such patterns of primary care use were a significant predictor of mortality over a 4-year period. Methods The Veterans Healthcare Administration (VA) is the largest integrated healthcare system in the United States. Administrative extracts of the VA's all-electronic medical records were studied. Patients over age 50 and diagnosed with schizophrenia in 2002 were age-matched 1:4 to diabetes patients. All patients were followed through 2005. Cluster analysis explored trajectories of primary care use. Proportional hazards regression modelled the impact of these primary care utilization trajectories on survival, controlling for demographic and clinical covariates. Results Patients comprised three diagnostic groups: diabetes only (n = 188,332), schizophrenia only (n = 40,109), and schizophrenia with diabetes (Scz-DM, n = 13,025). Cluster analysis revealed four distinct trajectories of primary care use: consistent over time, increasing over time, high and decreasing, low and decreasing. Patients with schizophrenia only were likely to have low-decreasing use (73% schizophrenia-only vs 54% Scz-DM vs 52% diabetes). Increasing use was least common among schizophrenia patients (4% vs 8% Scz-DM vs 7% diabetes) and was associated with improved survival. Low-decreasing primary care, compared to consistent use, was associated with shorter survival controlling for demographics and case-mix. The observational study was limited by reliance on administrative data. Conclusion Regular primary care and high levels of primary care were associated with better survival for patients with chronic illness, whether psychiatric or medical. For schizophrenia patients, with or without comorbid diabetes, primary care offers a survival benefit, suggesting that innovations in treatment retention targeting at-risk groups can offer significant promise of improving outcomes.http://deepblue.lib.umich.edu/bitstream/2027.42/78274/1/1472-6963-9-127.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78274/2/1472-6963-9-127.pdfPeer Reviewe

HS1, a Lyn Kinase Substrate, Is Abnormally Expressed in B-Chronic Lymphocytic Leukemia and Correlates with Response to Fludarabine-Based Regimen

In B-Chronic Lymphocytic Leukemia (B-CLL) kinase Lyn is overexpressed, active, abnormally distributed, and part of a cytosolic complex involving hematopoietic lineage cell-specific protein 1 (HS1). These aberrant properties of Lyn could partially explain leukemic cells’ defective apoptosis, directly or through its substrates, for example, HS1 that has been associated to apoptosis in different cell types. To verify the hypothesis of HS1 involvement in Lyn-mediated leukemic cell survival, we investigated HS1 protein in 71 untreated B-CLL patients and 26 healthy controls. We found HS1 overexpressed in leukemic as compared to normal B lymphocytes (1.38±0.54 vs 0.86±0.29, p<0.01), and when HS1 levels were correlated to clinical parameters we found a higher expression of HS1 in poor-prognosis patients. Moreover, HS1 levels significantly decreased in ex vivo leukemic cells of patients responding to a fludarabine-containing regimen. We also observed that HS1 is partially localized in the nucleus of neoplastic B cells. All these data add new information on HS1 study, hypothesizing a pivotal role of HS1 in Lyn-mediated modulation of leukemic cells’ survival and focusing, one more time, the attention on the BCR-Lyn axis as a putative target for new therapeutic strategies in this disorder

Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis.United States. National Institutes of Health (R01GM107536)Alex's Lemonade Stand FoundationHoward Hughes Medical InstituteBoston Children's Hospital. Manton Center for Orphan Disease ResearchNational Institute of General Medical Sciences (U.S.) (T32GM007753

Copy Number and Loss of Heterozygosity Detected by SNP Array of Formalin-Fixed Tissues Using Whole-Genome Amplification

The requirement for large amounts of good quality DNA for whole-genome applications prohibits their use for small, laser capture micro-dissected (LCM), and/or rare clinical samples, which are also often formalin-fixed and paraffin-embedded (FFPE). Whole-genome amplification of DNA from these samples could, potentially, overcome these limitations. However, little is known about the artefacts introduced by amplification of FFPE-derived DNA with regard to genotyping, and subsequent copy number and loss of heterozygosity (LOH) analyses. Using a ligation adaptor amplification method, we present data from a total of 22 Affymetrix SNP 6.0 experiments, using matched paired amplified and non-amplified DNA from 10 LCM FFPE normal and dysplastic oral epithelial tissues, and an internal method control. An average of 76.5% of SNPs were called in both matched amplified and non-amplified DNA samples, and concordance was a promising 82.4%. Paired analysis for copy number, LOH, and both combined, showed that copy number changes were reduced in amplified DNA, but were 99.5% concordant when detected, amplifications were the changes most likely to be ‘missed’, only 30% of non-amplified LOH changes were identified in amplified pairs, and when copy number and LOH are combined ∼50% of gene changes detected in the unamplified DNA were also detected in the amplified DNA and within these changes, 86.5% were concordant for both copy number and LOH status. However, there are also changes introduced as ∼20% of changes in the amplified DNA are not detected in the non-amplified DNA. An integrative network biology approach revealed that changes in amplified DNA of dysplastic oral epithelium localize to topologically critical regions of the human protein-protein interaction network, suggesting their functional implication in the pathobiology of this disease. Taken together, our results support the use of amplification of FFPE-derived DNA, provided sufficient samples are used to increase power and compensate for increased error rates

Clinical Evaluation of Targeted Arterial Infusion of Verapamil in the Interventional Chemotherapy of Primary Hepatocellular Carcinoma

This study evaluates the clinical effectiveness of targeted arterial infusion of verapamil in interventional treatment of primary hepatocellular carcinoma. For this purpose, in 273 patients with middle- or late-stage primary hepatocellular carcinoma, verapamil, IL-2, and chemotherapeutic agents were infused into the target tumor vasculature through femoral artery using Seldinger technique. The medications were infused as serial dilutions, and effectiveness was evaluated after two treatment cycles. Among these 273 patients, 76 cases showed clinical cure or significant improvement, 119 cases improved, 64 cases stabilized, while 14 cases progressed or deteriorated. In 238 patients, KPS score and body weights were stabilized. Regarding side effects, 99 patients (36.3%) developed leukopenia; 160 patients had gastrointestinal reactions (58.6%); 80 patients (29.3%) presented with elevated ALT/AST profile; and 65 cases (23.8%) had pyrexia; however, these side effects abated quickly. No elevations in BUN/Cr and/or allergic reactions were observed. Pre- and post-intervention cardiac function did not change in all the patients. No significant change was observed in ECG. Liver function was also improved after two cycles of treatment. It was concluded that verapamil management via targeted arterial infusion could effectively reverse the multidrug resistance in cancer cells in primary hepatocellular carcinoma patients and therefore enhanced the efficacy of chemotherapy

The Association between ATM IVS 22-77 T>C and Cancer Risk: A Meta-Analysis

BACKGROUND AND OBJECTIVES: It has become increasingly clear that ATM (ataxia-telangiectasia-mutated) safeguards genome stability, which is a cornerstone of cellular homeostasis, and ATM IVS 22-77 T>C affects the normal activity of ATM proteins. However, the association between the ATM IVS 22-77 T>C genetic variant and cancer risk is controversial. Therefore, we conducted a systematic meta-analysis to estimate the overall cancer risk associated with the polymorphism and to quantify any potential between-study heterogeneity. METHODS: A total of nine studies including 4,470 cases and 4,862 controls were analyzed for ATM IVS 22-77 T>C association with cancer risk in this meta-analysis. Heterogeneity among articles and their publication bias were also tested. RESULTS: Our results showed that no association reached the level of statistical significance in the overall risk. Interestingly, in the stratified analyses, we observed an inverse relationship in lung and breast cancer. CONCLUSION: Further functional research on the ATM mechanism should be performed to explain the inconsistent results in different cancer types

Correlations of EGFR mutations and increases in EGFR and HER2 copy number to gefitinib response in a retrospective analysis of lung cancer patients

<p>Abstract</p> <p>Background</p> <p>Gefitinib, a small molecule tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (<it>EGFR</it>), has shown limited efficacy in the treatment of lung cancer. Recognized clinical predictors of response to this drug, specifically female, non-smoker, Asian descent, and adenocarcinoma, together suggest a genetic basis for drug response. Recent studies have addressed the relationship between response and either sequence mutations or increased copy number of specific receptor tyrosine kinases. We set out to examine the relationship between response and the molecular status of two such kinases, <it>EGFR </it>and <it>HER2</it>, in 39 patients treated with gefitinib at the BC Cancer Agency.</p> <p>Methods</p> <p>Archival patient material was reviewed by a pathologist and malignant cells were selectively isolated by laser microdissection or manual recovery of cells from microscope slides. Genomic DNA was extracted from 37 such patient samples and exons 18–24, coding for the tyrosine kinase domain of <it>EGFR</it>, were amplified by PCR and sequenced. <it>EGFR </it>and <it>HER2 </it>copy number status were also assessed using FISH in 26 samples. Correlations between molecular features and drug response were assessed using the two-sided Fisher's exact test.</p> <p>Results</p> <p>Mutations previously correlated with response were detected in five tumours, four with exon 19 deletions and one with an exon 21 missense L858R point mutation. Increased gene copy number was observed in thirteen tumours, seven with <it>EGFR </it>amplification, three with <it>HER2 </it>amplification, and three with amplification of both genes. In our study cohort, a correlation was not observed between response and <it>EGFR </it>mutations (exon 19 deletion p = 0.0889, we observed a single exon 21 mutation in a non-responder) or increases in <it>EGFR </it>or <it>HER2 </it>copy number (p = 0.552 and 0.437, respectively).</p> <p>Conclusion</p> <p>Neither mutation of <it>EGFR </it>nor increased copy number of <it>EGFR </it>or <it>HER2 </it>was diagnostic of response to gefitinib in this cohort. However, validation of these features in a larger sample set is appropriate. Identification of additional predictive biomarkers beyond <it>EGFR </it>status may be necessary to accurately predict treatment outcome.</p