The Chronic CARe for diAbeTes study (CARAT): a cluster randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Diabetes is a major challenge for the health care system and especially for the primary care provider. The Chronic Care Model represents an evidence-based framework for the care for chronically ill. An increasing number of studies showed that implementing elements of the Chronic Care Model improves patient relevant outcomes and process parameters. However, most of these findings have been performed in settings different from the Swiss health care system which is dominated by single handed practices.</p> <p>Methods/Design</p> <p>CARAT is a cluster randomized controlled trial with general practitioners as the unit of randomization (trial registration: ISRCTN05947538). The study challenges the hypothesis that implementing several elements of the Chronic Care Model via a specially trained practice nurse improves the HbA1c level of diabetes type II patients significantly after one year (primary outcome). Furthermore, we assume that the intervention increases the proportion of patients who achieve the recommended targets regarding blood pressure (<130/80), HbA1c (=<6.5%) and low-density lipoprotein-cholesterol (<2.6 mmol/l), increases patients' quality of life (SF-36) and several evidence-based quality indicators for diabetes care. These improvements in care will be experienced by the patients (PACIC-5A) as well as by the practice team (ACIC). According to the power calculation, 28 general practitioners will be randomized either to the intervention group or to the control group. Each general practitioner will include 12 patients suffering from diabetes type II. In the intervention group the general practitioner as well as the practice nurse will be trained to perform care for diabetes patients according to the Chronic Care Model in teamwork. In the control group no intervention will be applied at all and patients will be treated as usual. Measurements (pre-data-collection) will take place in months II-IV, starting in February 2010. Follow-up data will be collected after 1 year.</p> <p>Discussion</p> <p>This study challenges the hypothesis that the Chronic Care Model can be easily implemented by a practice nurse focused approach. If our results will confirm this hypothesis the suggestion arises whether this approach should be implemented in other chronic diseases and multimorbid patients and how to redesign care in Switzerland.</p

Cavernous malformation hemorrhage due to trans-mural pressure alterations after cerebrospinal fluid diversion: a case report

Background Cavernous malformations are rare cerebral pseudo-vascular lesions with annualized bleeding rates of 0.5–3% in most studies. Of the various explored risk factors for bleeding to date, only prior hemorrhage has shown significant correlation. Case presentation In this case, we describe a 65-year old man with a peri-ventricular atrial cavernous malformation that hemorrhaged after CSF diversion via ventriculoperitoneal shunting. Serial imaging showed that bleeding continued until the shunt was revised with a programmable valve set at maximum resistance with the addition of a gravitational unit, thereby lowering the trans-mural pressure differential across the cavernous malformation. Conclusions Given that other vascular lesions are subject to hemorrhage from alterations in trans-mural pressure dynamics, we hypothesize that cavernous malformations are similarly affected by trans-mural pressure gradients as they are composed of primitive vascular elements. This hypothesis is corroborated by the temporal correlation of interventions, imaging, and exam findings in the present case, and suggests a potentially important risk factor for hemorrhage in CM patients that affects prognostication and management

Gene expression profiling of solitary fibrous tumors.

Solitary fibrous tumors (SFTs) are rare spindle-cell tumors. Their cell-of-origin and molecular basis are poorly known. They raise several clinical problems. Differential diagnosis may be difficult, prognosis is poorly apprehended by histoclinical features, and no effective therapy exists for advanced stages.We profiled 16 SFT samples using whole-genome DNA microarrays and analyzed their expression profiles with publicly available profiles of 36 additional SFTs and 212 soft tissue sarcomas (STSs). Immunohistochemistry was applied to validate the expression of some discriminating genes.SFTs displayed whole-genome expression profiles more homogeneous and different from STSs, but closer to genetically-simple than genetically-complex STSs. The SFTs/STSs comparison identified a high percentage (∼30%) of genes as differentially expressed, most of them without any DNA copy number alteration. One of the genes most overexpressed in SFTs encoded the ALDH1 stem cell marker. Several upregulated genes and associated ontologies were also related to progenitor/stem cells. SFTs also overexpressed genes encoding therapeutic targets such as kinases (EGFR, ERBB2, FGFR1, JAK2), histone deacetylases, or retinoic acid receptors. Their overexpression was found in all SFTs, regardless the anatomical location. Finally, we identified a 31-gene signature associated with the mitotic count, containing many genes related to cell cycle/mitosis, including AURKA.We established a robust repertoire of genes differentially expressed in SFTs. Certain overexpressed genes could provide new diagnostic (ALDH1A1), prognostic (AURKA) and/or therapeutic targets

Comprehensive genome characterization of solitary fibrous tumors using high‐resolution array‐based comparative genomic hybridization

International audienceSolitary fibrous tumors (SFTs) are rare spindle cell tumors with limited therapeutic options. Their molecular basis is poorly known. No consistent cytogenetic abnormality has been reported. We used high-resolution whole-genome array-based comparative genomic hybridization (Agilent 244K oligonucleotide chips) to profile 47 samples, meningeal in >75% of cases. Few copy number aberrations (CNAs) were observed. Sixty-eight percent of samples did not show any gene CNA after exclusion of probes located in regions with referenced copy number variation (CNV). Only low-level CNAs were observed. The genomic profiles were very homogeneous among samples. No molecular class was revealed by clustering of DNA copy numbers. All cases displayed a "simplex" profile. No recurrent CNA was identified. Imbalances occurring in >20%, such as the gain of 8p11.23-11.22 region, contained known CNVs. The 13q14.11-13q31.1 region (lost in 4% of cases) was the largest altered region and contained the lowest percentage of genes with referenced CNVs. A total of 425 genes without CNV showed copy number transition in at least one sample, but only but only 1 in at least 10% of samples. The genomic profiles of meningeal and extra-meningeal cases did not show any differences

ALDH1 is an immunohistochemical diagnostic marker for solitary fibrous tumours and haemangiopericytomas of the meninges emerging from gene profiling study

International audienceBackgroundSolitary Fibrous Tumours (SFT) and haemangiopericytomas (HPC) are rare meningeal tumours that have to be distinguished from meningiomas and more rarely from synovial sarcomas. We recently found that ALDH1A1 was overexpressed in SFT and HPC as compared to soft tissue sarcomas. Using whole-genome DNA microarrays, we defined the gene expression profiles of 16 SFT/HPC (9 HPC and 7 SFT). Expression profiles were compared to publicly available expression profiles of additional SFT or HPC, meningiomas and synovial sarcomas. We also performed an immunohistochemical (IHC) study with anti-ALDH1 and anti-CD34 antibodies on Tissue Micro-Arrays including 38 SFT (25 meningeal and 13 extrameningeal), 55 meningeal haemangiopericytomas (24 grade II, 31 grade III), 163 meningiomas (86 grade I, 62 grade II, 15 grade III) and 98 genetically confirmed synovial sarcomas.Results ALDH1A1 gene was overexpressed in SFT/HPC, as compared to meningiomas and synovial sarcomas. These findings were confirmed at the protein level. 84% of the SFT and 85.4% of the HPC were positive with anti-ALDH1 antibody, while only 7.1% of synovial sarcomas and 1.2% of meningiomas showed consistent expression. Positivity was usually more diffuse in SFT/HPC compared to other tumours with more than 50% of tumour cells immunostained in 32% of SFT and 50.8% of HPC. ALDH1 was a sensitive and specific marker for the diagnosis of SFT (SE = 84%, SP = 98.8%) and HPC (SE = 84.5%, SP = 98.7%) of the meninges. In association with CD34, ALDH1 expression had a specificity and positive predictive value of 100%.ConclusionWe show that ALDH1, a stem cell marker, is an accurate diagnostic marker for SFT and HPC, which improves the diagnostic value of CD34. ALDH1 could also be a new therapeutic target for these tumours which are not sensitive to conventional chemotherapy

TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT

International audienceIn some types of cancer, telomere length is maintained by the alternative lengthening of telomeres (ALT) mechanism. In many ALT cancers, the a-thalassemia/mental retardation syndrome X-linked (ATRX) gene is mutated leading to the conclusion that the ATRX complex represses ALT. Here, we report that most high-grade pediatric osteosarcomas maintain their telomeres by ALT, and that the majority of these ALT tumors are ATRX wild-type (wt) and instead carry an amplified 17p11.2 chromosomal region containing TOP3A. We found that TOP3A was overexpressed in the ALTpositive ATRX-wt tumors consistent with its amplification. We demonstrated the functional significance of these results by showing that TOP3A overexpression in ALT cancer cells countered ATRXmediated ALT inhibition and that TOP3A knockdown disrupted the ALT phenotype in ATRX-wt cells. Moreover, we report that TOP3A is required for proper BLM localization and promotes ALT DNA synthesis in ALT cell lines. Collectively, our results identify TOP3A as a major ALT player and potential therapeutic target

Microscopic aspects and ALDH1 expression using IHC.

<p><b><i>A.</i></b> Microscopic features (HES) of a glioblastoma used as positive control for ALDH1 immunostaining. <b><i>B.</i></b> ALDH1 expression in the cytoplasm of few astrocytic tumor cells. <b><i>C–D.</i></b> Microscopic features (HES) of an SFT in a collagenic area (C) and of an SFT in a cellular area with an “hemangiopericytoma” vascular pattern (D). <b><i>E–F.</i></b> ALDH1 immunostaining in a collagenic area (E) and in a cellular area (F): note the strong and diffuse expression in the cytoplasm of tumor cells. For all images, magnification is ×25.</p

Supervised analyses of SFTs based on the location and mitotic count.

<p><b><i>A.</i></b> Legend similar to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064497#pone-0064497-g002" target="_blank">Figure 2</a>, but applied to 16 SFT samples (12 meningeal M and 4 extra-meningeal Extra-M). The signature includes 573 genes. Samples are ordered from left to right according to the decreasing correlation coefficient of their expression profile with the mean profile of the meningeal samples. The solid vertical line indicates the threshold of 50% (equiprobability according to PAM model) that separates the two signature-predicted classes of samples. The genes are ordered form top to bottom according to their decreasing SAM statistics of meningeal SFT association. <b><i>B.</i></b> Similar to A, but applied to the 23 samples from the independent validation set (8 meningeal M and 15 extra-meningeal Extra-M). <b><i>C.</i></b> Similar to A, but applied to 16 SFT samples (10 with low mitotic count MC and 6 with high count). The signature includes 31 genes. Samples are ordered from left to right according to the decreasing metagene score. The solid vertical line indicates the optimal cut-point (0.33) defined using ROC analysis that separates the two signature-predicted classes of samples. <b><i>D.</i></b> Similar to C, but applied to the 13 samples from the independent validation set (all with low mitotic count).</p