Citations

Background— Spontaneous coronary artery dissection (SCAD) is an acute coronary event of uncertain origin. Clinical features and prognosis remain insufficiently characterized. Methods and Results— A retrospective single-center cohort study identified 87 patients with angiographically confirmed SCAD. Incidence, clinical characteristics, treatment modalities, in-hospital outcomes, and long-term risk of SCAD recurrence or major adverse cardiac events were evaluated. Mean age was 42.6 years; 82% were female. Extreme exertion at SCAD onset was more frequent in men (7 of 16 versus 2 of 71; P <0.001), and postpartum status was observed in 13 of 71 women (18%). Presentation was ST-elevation myocardial infarction in 49%. Multivessel SCAD was found in 23%. Initial conservative management (31 of 87) and coronary artery bypass grafting (7 of 87) were associated with an uncomplicated in-hospital course, whereas percutaneous coronary intervention was complicated by technical failure in 15 of 43 patients (35%) and 1 death. During a median follow-up of 47 months (interquartile range, 18–106 months), SCAD recurred in 15 patients, all female. Estimated 10-year rate of major adverse cardiac events (death, heart failure, myocardial infarction, and SCAD recurrence) was 47%. Fibromuscular dysplasia of the iliac artery was identified incidentally in 8 of 16 femoral angiograms (50%) undertaken before closure device placement and in the carotid arteries of 2 others with carotid dissection. Conclusions— SCAD affects a young, predominantly female population, frequently presenting as ST-elevation myocardial infarction. Although in-hospital mortality is low regardless of initial treatment, percutaneous coronary intervention is associated with high rates of complication. Risks of SCAD recurrence and major adverse cardiac events in the long term emphasize the need for close follow-up. Fibromuscular dysplasia is a novel association and potentially causative factor.

Context.— Original surgical pathology materials from external sources are reviewed by our pathologists for referred patients before their clinical evaluation and treatment. Objective.— To identify the rate of major disagreements with diagnoses from external institutions and to characterize the nature and impact of discordant diagnoses on patient care. Design.— We identified and reviewed all surgical pathology cases, except for medical liver, medical renal, and cardiac pathology cases, for the period between January 1, 2005, and December 31, 2010, to determine the overall frequency of major disagreements, defined as any change in diagnosis having a substantial impact on patient management. Results.— Our review of 71 811 cases initially examined between 2005 and 2010 identified 457 major disagreements (0.6%). The most frequent areas of disagreement were gastrointestinal (80 cases; 17.5%), lymph node (73; 16.0%), bone/soft tissue (47; 10.3%), and genitourinary (43; 9.4%). For a subset of 166 cases reviewed between July 1, 2009, and December 31, 2010, follow-up data were available for 140 (84.3%). Treatment was affected by a changed diagnosis in 126 cases (90.0%), and prognosis was affected in 129 cases (92.1%). For 86 (51.8%) of the 166 cases, additional tissue was obtained. Revised diagnoses concurred with follow-up tissue diagnosis in 84.9% (73 cases), whereas they differed from follow-up tissue diagnosis in 15.1% (13 cases). Conclusions.— Our findings demonstrate the value of outside case review of pathology materials for referred patients, and suggest that it decreases the likelihood of diagnostic errors and provides better protection for patients.

Neural cells derived from induced pluripotent stem cells from patients with genetic forms of Parkinson’s disease provide insights into disease pathogenesis.

Abstract Mesenchymal Stem Cells (MSCs) have the ability to migrate specifically to tumours in vivo, and coupled with their capacity to bypass immune surveillance, are potentially attractive vehicles for tumor-targeted delivery of therapeutic agents. The aim of this study was to determine the potential of MSC-mediated expression of the sodium iodide symporter (NIS) for in vivo imaging and therapy of breast tumours. Expression of NIS allows cells to concentrate radionuclides including technetium-99m (Tc-99m) and 131-Iodine (131-I). This could potentially support imaging of NIS-expressing MSCs following engraftment, and 131-I therapy of surrounding tumour tissue based on the bystander effect of the radionuclide. Methods: Tumor bearing animals (MDA-MB-231 flank) were given an intravenous or intratumoral injection of NIS expressing human MSCs (MSC-NIS), followed by imaging 3, 7, 10 or 14 days later. Imaging was performed using a Bazooka SPECT γ-camera, following intraperitoneal injection of 2mCi/74MBq Tc-99m. Following imaging, animals were sacrificed and organs harvested for analysis of hNIS expression by RQ-PCR. A second group of animals received an intraperitoneal injection of 1mCi/37MBq 131-I or saline (controls) 14 days following intratumoral or intravenous injection of MSC-NIS, and tumour volume was tracked for 8 weeks. Results: Bazooka SPECT imaging of animals revealed uptake of tracer (Tc-99m) in the mouse thyroid/salivary glands and stomach, representing native NIS expression. Following injection of MSC-NIS, an image of animal intestines was also observed at D3, with a weak image of the tumour also visible. By Day14, uptake of tracer was visible at the site of the tumour with no significant image of non-target tissue observed. Expression of hNIS in harvested organs supported the imaging data, with hNIS detected in the intestines, heart, lungs and tumour at early timepoints. While NIS expression depleted in non-target tissues by D7, gene expression persisted at the tumour site. Based on imaging/biodistribution data, animals were given a therapeutic dose of 131-I 14 days following MSC-NIS injection to avoid toxicity to non-target organs. No adverse effect of injection of MSC-NIS or radionuclide was observed. Tracking of tumour volume revealed a significant reduction in tumour growth in animals that had received an intravenous injection of 131-I 14days following MSC-NIS injection (Mean ± SEM, 236 ± 62mm3 versus 665 ± 204 mm3 in controls). Following intratumoral injection of MSC-NIS + 131-I, although tumour size was reduced compared to controls (472 ± 80 mm3), the difference in volume was not significant. Conclusion: The ability to non-invasively track MSC migration and transgene expression in real time prior to therapy is a major advantage to this strategy. This promising data supports the viability of this approach as a novel therapy for metastatic breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5392. doi:10.1158/1538-7445.AM2011-5392

Abstract Variation in drug response results from a combination of factors that include differences in gender, ethnicity, and environment, as well as genetic variation that may result in differences in mRNA and protein expression. This article presents two integrative analytic approaches that make use of both genome-wide SNP and mRNA expression data available on the same set of subjects: a step-wise integrative approach and a comprehensive analysis using sparse canonical correlation analysis (SCCA). In addition to applying standard SCCA, we present a novel modification of SCCA which allows different weighting for the various pair-wise relationships in the SCCA. These integrative approaches are illustrated with both simulated data and data from a pharmacogenomic study of the drug gemcitabine. Results from these analyses found little overlap in terms of genes detected, possibly detecting different biological mechanisms. In addition, we found the proposed weighted SCCA to outperform its unweighted counterpart in detecting associations between the genomic features and phenotype. Further research is needed to develop and assess new integrative methods for pharmacogenomic studies, as these types of analyses may uncover novel insights into the relationship between genomic variation and drug response.

Abstract Purpose/Background: The first-line chemotherapeutic temozolomide (TMZ) does not offer any therapeutic benefit in some cases of glioblastoma (GBM) and emergence of resistance leads to tumor progression in almost all patients. While the expression of O-6-methylguanine-DNA-methyltransferase (MGMT) correlates well with TMZ resistance, its expression varies among GBM tumors. The goal of this study is to identify additional genes with potential roles in TMZ resistance. Materials and Methods: Five primary GBM xenografts were generated from patient samples, and subsequent secondary models for resistance were developed by subjecting tumor-bearing mice to escalating doses of TMZ. Triplicate samples from parental and TMZ-resistant xenografts were analyzed for gene expression using the Illumina BeadChip microarray platform. The top 100 differentially expressed genes for each line were considered candidates. Genes were selected for qRT-PCR validation after ontological and pathway analysis. A lentivirus-mediated shRNA knockdown was performed to validate the role of several candidate genes in TMZ resistance in U87 and primary GBM12 cell lines. Knockdown was confirmed with qRT-PCR and western blots. TMZ responsiveness was assessed using CyQUANT and Neurosphere assays. Results: Upregulated MGMT expression was found in 3 of the 5 xenografts (GBM12TMZ, GBM14TMZ and GBM28TMZ) and was mechanistically linked with TMZ resistance in these lines using O6-benzylguanine to reverse the resistance phenotype. Differential expression of other DNA damage response genes included CCND2, CDKN1A, GADD45B, UBB as well as apoptosis regulators NFKB2 and BIRC3. In lines with unchanged MGMT expression (GBM22TMZ and GBM39TMZ), changes in anti-apoptosis genes NFKB2 and MAP3K1, transcription factor SRF and signal transduction gene PRKCDBP were validated by qRT-PCR. In GBM12TMZ, in addition to MGMT upregulation, expression of Ubiquitin B (UBB) was found to be the most significantly down-regulated gene both on microarray (Log2FC = −4.55, Fold change = 0.043) and qRT-PCR (Log2RQ =-4.04, RQ = 0.061). To test a possible role of UBB in TMZ resistance, knockdown was achieved in U87 (knockdown efficiency=91.2%) and in primary xenograft line GBM12 (knockdown efficiency=84.4%). The CyQUANT assay for U87UBB-KD and U87NT treated with escalating doses of TMZ revealed no significant difference in cell survival (10 M TMZ relative survival= 89.7% for U87UBB-KD and 79.2% for U87NT; p-value=0.53). Similarly, a neurosphere assay for GBM12UBB-KD and GBM12NT also yielded no significant difference in cell survival (10 M TMZ relative survival= 25.13% for GBM12UBB-KD and 23.35% for GBM12NT; p-value=0.83). Conclusions: We have used a TMZ resistance xenograft model to identify candidate TMZ resistance genes. The current data provides evidence on the role of MGMT in the development of acquired TMZ resistance while ruling out UBB as potential TMZ resistance gene in GBM. Additional studies are underway to assess the functional significance of other candidate genes, particularly those with differential expression in the setting of constant MGMT expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B68.