Disease risk score as a confounder summary method: systematic review and recommendations: DRS AS A CONFOUNDER SUMMARY METHOD

To systematically examine trends and applications of the disease risk score (DRS) as a confounder summary method

Quantification of crypt and stem cell evolution in the normal and neoplastic human colon.

Human intestinal stem cell and crypt dynamics remain poorly characterized because transgenic lineage-tracing methods are impractical in humans. Here, we have circumvented this problem by quantitatively using somatic mtDNA mutations to trace clonal lineages. By analyzing clonal imprints on the walls of colonic crypts, we show that human intestinal stem cells conform to one-dimensional neutral drift dynamics with a "functional" stem cell number of five to six in both normal patients and individuals with familial adenomatous polyposis (germline APC(-/+)). Furthermore, we show that, in adenomatous crypts (APC(-/-)), there is a proportionate increase in both functional stem cell number and the loss/replacement rate. Finally, by analyzing fields of mtDNA mutant crypts, we show that a normal colon crypt divides around once every 30-40 years, and the division rate is increased in adenomas by at least an order of magnitude. These data provide in vivo quantification of human intestinal stem cell and crypt dynamics.This study was supported by Cancer Research UK (to A.-M.B. and N.A.W.), the Medical Research Council (to B.C. and S.A.C.M.), the Engineering and Physical Sciences Research Council (to A.G.F.), Microsoft Research (to A.G.F.), the National Institute for Health Research University College London Hospitals Biomedical Research Centre (to M.R.J.), the Dutch Cancer Research Foundation (to M.J.), the Wellcome Trust (to B.D.S.), and Higher Education Funding Council for England (to T.A.G.)

Toward the clinical application of time-domain fluorescence lifetime imaging

High-speed (video-rate) fluorescence lifetime imaging (FLIM) through a flexible endoscope is reported based on gated optical image intensifier technology. The optimization and potential application of FLIM to tissue autofluorescence for clinical applications are discussed. (c) 2005 Society of Photo-Optical Instrumentation Engineers

Interventions for reducing anticholinergic medication burden in older adults – a systematic review and meta-analysis

Introduction Anticholinergic medications block the neurotransmitter acetylcholine in the brain and peripheral nervous system. Many medications have anticholinergic properties, and the cumulative effect of these medications is termed anticholinergic burden. Increased anticholinergic burden can have short-term side effects such as dry mouth, blurred vision and urinary retention as well as long-term effects including dementia, worsening physical function and falls. Methods We carried out a systematic review (SR) with meta-analysis (MA) looking at randomised controlled trials addressing interventions to reduce anticholinergic burden in older adults. Results We identified seven papers suitable for inclusion in our SR and MA. Interventions included multi-disciplinary involvement in medication reviews and deprescribing of AC medications. Pooled data revealed no significant difference in outcomes between control and intervention group for falls (OR = 0.76, 95% CI: 0.52–1.11, n = 647), cognition (mean difference = 1.54, 95% CI: −0.04 to 3.13, n = 405), anticholinergic burden (mean difference = 0.04, 95% CI: −0.11 to 0.18, n = 710) or quality of life (mean difference = 0.04, 95% CI: −0.04 to 0.12, n = 461). Discussion Overall, there was no significant difference with interventions to reduce anticholinergic burden. As we did not see a significant change in anticholinergic burden scores following interventions, it is likely other outcomes would not change. Short follow-up time and lack of training and support surrounding successful deprescribing may have contributed

Membrane connectivity estimated by digital image analysis of HER2 immunohistochemistry is concordant with visual scoring and fluorescence in situ hybridization results: algorithm evaluation on breast cancer tissue microarrays

<p>Abstract</p> <p>Introduction</p> <p>The human epidermal growth factor receptor 2 (HER2) is an established biomarker for management of patients with breast cancer. While conventional testing of HER2 protein expression is based on semi-quantitative visual scoring of the immunohistochemistry (IHC) result, efforts to reduce inter-observer variation and to produce continuous estimates of the IHC data are potentiated by digital image analysis technologies.</p> <p>Methods</p> <p>HER2 IHC was performed on the tissue microarrays (TMAs) of 195 patients with an early ductal carcinoma of the breast. Digital images of the IHC slides were obtained by Aperio ScanScope GL Slide Scanner. Membrane connectivity algorithm (HER2-CONNECT™, Visiopharm) was used for digital image analysis (DA). A pathologist evaluated the images on the screen twice (visual evaluations: VE1 and VE2). HER2 fluorescence <it>in situ </it>hybridization (FISH) was performed on the corresponding sections of the TMAs. The agreement between the IHC HER2 scores, obtained by VE1, VE2, and DA was tested for individual TMA spots and patient's maximum TMA spot values (VE1max, VE2max, DAmax). The latter were compared with the FISH data. Correlation of the continuous variable of the membrane connectivity estimate with the FISH data was tested.</p> <p>Results</p> <p>The pathologist intra-observer agreement (VE1 and VE2) on HER2 IHC score was almost perfect: kappa 0.91 (by spot) and 0.88 (by patient). The agreement between visual evaluation and digital image analysis was almost perfect at the spot level (kappa 0.86 and 0.87, with VE1 and VE2 respectively) and at the patient level (kappa 0.80 and 0.86, with VE1max and VE2max, respectively). The DA was more accurate than VE in detection of FISH-positive patients by recruiting 3 or 2 additional FISH-positive patients to the IHC score 2+ category from the IHC 0/1+ category by VE1max or VE2max, respectively. The DA continuous variable of the membrane connectivity correlated with the FISH data (HER2 and CEP17 copy numbers, and HER2/CEP17 ratio).</p> <p>Conclusion</p> <p>HER2 IHC digital image analysis based on membrane connectivity estimate was in almost perfect agreement with the visual evaluation of the pathologist and more accurate in detection of HER2 FISH-positive patients. Most immediate benefit of integrating the DA algorithm into the routine pathology HER2 testing may be obtained by alerting/reassuring pathologists of potentially misinterpreted IHC 0/1+ versus 2+ cases.</p

Immunohistochemistry profiles of breast ductal carcinoma: factor analysis of digital image analysis data

<p>Abstract</p> <p>Background</p> <p>Molecular studies of breast cancer revealed biological heterogeneity of the disease and opened new perspectives for personalized therapy. While multiple gene expression-based systems have been developed, current clinical practice is largely based upon conventional clinical and pathologic criteria. This gap may be filled by development of combined multi-IHC indices to characterize biological and clinical behaviour of the tumours. Digital image analysis (DA) with multivariate statistics of the data opens new opportunities in this field.</p> <p>Methods</p> <p>Tissue microarrays of 109 patients with breast ductal carcinoma were stained for a set of 10 IHC markers (ER, PR, HER2, Ki67, AR, BCL2, HIF-1α, SATB1, p53, and p16). Aperio imaging platform with the Genie, Nuclear and Membrane algorithms were used for the DA. Factor analysis of the DA data was performed in the whole group and hormone receptor (HR) positive subgroup of the patients (n = 85).</p> <p>Results</p> <p>Major factor potentially reflecting aggressive disease behaviour (i-Grade) was extracted, characterized by opposite loadings of ER/PR/AR/BCL2 and Ki67/HIF-1α. The i-Grade factor scores revealed bimodal distribution and were strongly associated with higher Nottingham histological grade (G) and more aggressive intrinsic subtypes. In HR-positive tumours, the aggressiveness of the tumour was best defined by positive Ki67 and negative ER loadings. High Ki67/ER factor scores were strongly associated with the higher G and Luminal B types, but also were detected in a set of G1 and Luminal A cases, potentially indicating high risk patients in these categories. Inverse relation between HER2 and PR expression was found in the HR-positive tumours pointing at differential information conveyed by the ER and PR expression. SATB1 along with HIF-1α reflected the second major factor of variation in our patients; in the HR-positive group they were inversely associated with the HR and BCL2 expression and represented the major factor of variation. Finally, we confirmed high expression levels of p16 in Triple-negative tumours.</p> <p>Conclusion</p> <p>Factor analysis of multiple IHC biomarkers measured by automated DA is an efficient exploratory tool clarifying complex interdependencies in the breast ductal carcinoma IHC profiles and informative value of single IHC markers. Integrated IHC indices may provide additional risk stratifications for the currently used grading systems and prove to be useful in clinical outcome studies.</p> <p>Virtual Slides</p> <p>The virtual slide(s) for this article can be found here: <url>http://www.diagnosticpathology.diagnomx.eu/vs/1512077125668949</url></p