tbuckley/cabot-search huggingface dataset:
PWE-188 Using a “conversion factor” to estimate adenoma detection rate
Authors: P T Rajasekhar, T J Lee, M D Rutter, M G Bramble, D W Wilson, J E East, B P Saunders, P Hungin, C J Rees
Journal: Gut (2012)

<h3>Introduction</h3> Adenoma detection rate (ADR) is the recommended surrogate marker for a thorough colonoscopic examination. Collecting histology makes its calculation arduous so polyp detection rate (PDR) is often used instead. It has been proposed that the ADR:PDR ratio can be used as a "conversion factor" to accurately estimate ADR. Work from the Bowel Cancer Screening Programme (BCSP) has shown that adenomas are more prevalent in this population suggesting the ratio may be different. We aimed to assess the feasibility of using a "conversion factor" to estimate ADR from PDR in different UK populations. <h3>Methods</h3> Colonoscopy performance data from the symptomatic services were collected over a 3-month period from 12 units in the northern region of England. Data from all procedures performed by BCSP accredited colonoscopists were excluded from this group. National colonoscopy performance data were extracted from the BCSP database from a 12-month period. Colonoscopists detecting polyps in ≥10 patients were included. Data collected included colonoscopist, PDR and ADR. The conversion factor was calculated separately for each group. The ADR:PDR ratio was calculated at the level of the colonoscopist and the group mean used as the conversion factor. The estimated ADR was calculated using: PDR × conversion factor. The relationship between the actual and estimated ADR was evaluated using Pearson9s correlation coefficient. <h3>Results</h3> In the symptomatic services 3219 colonoscopies were performed by 55 colonoscopists. In the BCSP 31 017 procedures were performed by 147 colonoscopists. The PDR and ADR respectively for the symptomatic group were 30.7%, IQR 24.8–40.0 and 18.0%, IQR 14.0–24.0, and for the BCSP group were 59.3%, IQR 53.8–65.0 and 46.0%, IQR 43.0–51.3. The ADR:PDR ratio in the symptomatic and BCSP groups were 0.59 (IQR 0.47–0.69) and 0.78 (IQR 0.74–0.81). The correlation between the estimated and actual ADR was 0.68 (p&lt;0.001) and 0.83 (p&lt;0.001) for the symptomatic and BCSP groups respectively. <h3>Conclusion</h3> We demonstrate using estimated ADR, when calculation of ADR is not feasible, may be an acceptable marker of quality in colonoscopy. The difference in the conversion factors between the groups studied here is likely to be due to the selected population colonoscoped within the BCSP but suggests it will need to be adjusted for different patient populations. Studies to further validate this concept and ensure that conversion factors remain consistent over time are ongoing. <h3>Competing interests</h3> None declared.
Abstract 1505: Stroma-mediated DNA damage resistance of human breast cancer
Authors: Mirjam C. Boelens, Tony J. Wu, Taewon Yoon, Diana Azzam, Joyce M. Slingerland, Andy J. Minn
Journal: Cancer Research (2012)

Abstract Chemotherapy and radiation are often employed to decrease breast cancer deaths. However, patients with metastatic disease invariably manifest resistance to chemotherapy and/or radiation, ultimately causing breast cancer deaths due to ineffective treatment. We have defined a gene expression signature, the interferon-related DNA damage resistance signature (IRDS), that is highly associated with radiation and chemotherapy resistance of breast cancer in both cell lines and patients. Interestingly, IRDS-mediated resistance in experimental models appears to be much greater in vivo than in vitro, suggesting a potential contribution of the tumor microenvironment. To address the question of whether the tumor microenvironment plays a role in IRDS-mediated radioresistance, we investigated the influence of heterotypic interactions between breast cancer and stromal cells on IRDS expression. We found that breast cancer cell lines primarily of the basal subtype increase IRDS expression after tumor-stroma interaction, resulting in enhanced resistance to radiation and chemotherapy. This increase in IRDS and DNA damage resistance depends on STAT1, a member and transcriptional regulator of the IRDS. Tumor-stroma interaction also leads to induction of a population of breast cancer cells with properties of breast cancer stem-like cells (BCSC). Evaluation of a tumor-stroma extracellular interactome revealed that a stroma-directed NOTCH signaling pathway can cooperate with STAT1 signaling to regulate common target genes. STAT1 and NOTCH signaling direct the expansion and/or survival of BCSC, an inherently DNA damage resistant population. Using available primary breast cancer data sets, a similar activation of NOTCH signaling is observed, as well as transcriptomic activation of the NOTCH pathway in breast cancer. Importantly, a marker for NOTCH signaling cooperates with the IRDS to identify breast cancer patients likely to fail adjuvant chemotherapy. The ability of gamma secretase inhibitors to inhibit both stroma-mediated expansion of BCSC and DNA damage resistance highlights the therapeutic potential of this class of targeted agents for breast cancers that express the IRDS. In conclusion, our data suggests that stroma can regulate DNA damage resistant BCSC populations in a subset of basal breast cancers through STAT1 and NOTCH signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1505. doi:1538-7445.AM2012-1505
Preexposure Prophylaxis for HIV Infection
Authors: Reed A Siemieniuk, Isaac I Bogoch
Journal: New England Journal of Medicine (2015)

We appreciate the acknowledgment by Xydakis et al. of our efforts to avoid potential sources of bias while conducting a very large, complex, multinational clinical trial of TBI.We relied on the Glasgow Coma Scale score as the primary entry criterion and the Glasgow Outcome Scale score as the primary end point, because these instruments have been shown to be robust over several decades.We agree that they have their limitations, and we support the concept of multidimensional approaches to classification of initial severity and of outcome. 1 However, how exactly these new pieces of information may best be used to improve TBI trial design and sensitivity remains to be determined.Xydakis et al. raise an important point regarding the need to evaluate patient subgroups on the basis of relevant criteria, whether biomarkers or imaging components.Indeed, we performed extensive prespecified subgroup analyses (see Table 2 of our article) and post hoc subgroup analyses.We found no hint of a trend toward efficacy in any of these analyses, in patients with diffuse injury, mass lesions, or traumatic subarachnoid hemorrhage or in those undergoing surgery.It would therefore seem unlikely that progesterone had any benefit in these subpopulations.It is of interest that Xydakis et al. suggest a potential role for characterizing patients on the basis of pathoanatomical findings from neuro-
CD44v6 expression in squamous cell carcinomas of the lung
Authors: R. Lopez, J. Rodriguez, J. Barandela, L. Leon, A. Ruibal
Journal: Journal of Clinical Oncology (2004)

9688 Background: CD44v6 is a variant isoform of CD44 involved in the metastatic process of some malignant tumors. We want to study its expression in squamous cell carcinomas of the lung and its correlations with other clinical and biological parameters. Methods: The study group included 95 patients having squamous cell carcinomas of the lung. CD44v6 levels were dossified using an EIA (Bender Diagnostics. Austria) in the cell surfaces. The cut off for positivity was established in 5 ng/mg prot. Likewise we determined the concentrations of EGFR and erbB2/neu oncoprotein in cell surfaces. All results were expressed per mg of protein. Clinical stage, histological grade, ploidy and S-phase were taken into account. Results: In squamous cell carcinomas CD44v6 positivity was observed in 76 cases (80%) and it was similar to that noted in 38 normal lung tissues obtained from the same patients (86.8%).Nevertheless, CD44v6 concentrations were higher (p<0.001) than those observed in normal lung tissues (r: 5.1–1305, median 68.2 vs r: 8.6–100; median 32.3 ng/mg prot.) from the same patients. CD44v6-positive tumors had higher concentrations of EGFR (r: 3.1–325, median 38,7 vs r: 1–394, median 21.3 fmol/mg prot,; p:0,007), erbB2 oncoprotein (r: 219–77895, median 1868 vs r: 246-7848, median 1532 NHI/mg prot.; p:0,056) and global values of S-phase (r: 1.2–51.8, median 16 vs r: 1.8–28.9, median 9.9%; p:0,011) than CD44v6-negative tumors. Likewise, they were more frequently (p: 0,041) S-phase positive (>15.4%, which corresponds to the median for the entire tumor group studied). Conclusions: Our results led us to the following conclusions: 1) In squamous cell lung cancers CD44v6 expression is high and similar to that observed in normal pulmonary tissue obtained from the same patients; nevertheless, the CD44v6 concentrations are higher in those tumors than in normal lung tissues from the same patients 2) Its association with high EGFR and erbB2 oncoprotein levels, as well as, with high S-phase values suggests that it could be an indicator of a poorer outcome and progression in this subtype of lung carcinomas. No significant financial relationships to disclose.
FRI0538 Gender-specific effort-reward imbalance in patients with systemic lupus erythematosus?
Authors: J. Richter, T. Muth, R. Brinks, T. Koch, J. Siegrist, P. Angerer, M. Schneider
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Working life factors influence patients' (life) satisfaction and well being. Effort at work is part of a social contract that reciprocates effort by adequate reward. Components of work-related rewards matter for health. Research on effort-reward imbalance (ERI) might contribute to the understanding of factors related to the well-being of patients (pts) with systemic lupus erythematosus (SLE). We studied the ERI model in SLE with respect to gender-specific aspects. <h3>Objectives</h3> We studied the ERI model in SLE with respect to gender-specific aspects. <h3>Methods</h3> A cross-sectional study applied a set of standardized self-reported questionnaires to SLE pts capable for work. Effort- reward ratio (ERR) &gt; 1 reflects ERI, overcommitment scores (OCS) in the upper tertile (UT) indicate relevant values. Data were compared to controls (c) not suffering from rheumatic diseases. Ethical approval was obtained. <h3>Results</h3> 252 pts (95.6% female (f)) and 177 c (90.3% f) contributed data. Pts mean age was 40.1±9.4 (c 42.8±9.8) years, mean disease duration 10.5±7.3 years, mean HAQ 0.8±0.4 (c 0.4±0.1). In pts 86.0% self-reported at least one comorbidity (range 0-10), c 45.2% (range 0-4). 77.4% took at least one immunosuppressive drug (DMARD, range 0-3). 40.5% steroids ≤7.5mg, 16.3% steroids &gt;7.5mg, 34.0% NSAIDS. For (gender-specific) ERI and OCS results see table 1. 13.8% showed relevant effort-reward imbalance (ERR&gt;1). ERR&gt;1 pts scored significantly worse in all ERI subscales (p-values&lt;0.01). Except marital status the above mentioned personal and disease related factors did not differ significantly in ERR&gt;1 and ERR≤1 pts, none of the factors differed significantly in pts with OCS in the lower tertiles compared to pts with OCS in UT. Compared to c pts differed significantly in the OCS, effort, reward and esteem scale as well as in ERR&gt;1 and proportions of OCS in UT. Although the same was found for female pts, male (m) pts did not differ significantly to male c. <h3>Conclusions</h3> In this first study investigating the ERI in SLE pts a high proportion had effort reward imbalance (ERR&gt;1). ERI values and OCS were significantly different between female pts and c. Further study analysis will address pts satisfaction with their family situation and other (gender) specific factors to develop appropriate support strategies. <h3>Acknowledgements</h3> Unrestricted grants Ministry of Innovation, Science, Research and Technology of the German State North Rhine-Westphalia, Deutsche Rheuma-Liga e.V., German LE Self-Help Community, Abbott Immunology Germany, Hiller Foundation. <h3>Disclosure of Interest</h3> None Declared
Abstract 4637: Mini-chromosome maintenance protein 7 as a potential theranostic biomarker in epithelial ovarian cancer
Authors: Takayo Ota, Amy C. Clayton, Douglas M. Minot, Lynn C. Hartmann, Viji Shridhar, Blake Gilks, Jeremy R. Chien
Journal: Cancer Research (2010)

Abstract Mini-Chromosome Maintenance protein 7 (MCM7) is involved in replicative licensing and synthesis of DNA. It is previously identified as over-expressed gene in high-grade serous carcinomas compared to serous borderline tumors of the ovary in cDNA microarray studies. In this study, we sought to validate MCM7 expression in ovarian tumors by applying immunohistochemical analysis on tissue microarrays consisting of 445 ovarian tumors. MCM7 expression was quantified as MCM7 labeling index by determining the tumor nuclei positive for MCM7 staining as a percentage of total tumor nuclei. The labeling index scores were independently generated by two methods: PATH score provided by a manual review of each samples by a pathologist and ACIS score provided by Automated Cell Imaging System. Analyses of both scores indicated high degree of concordance in score distribution between PATH and ACIS. MCM7 expression is significantly higher in high-grade serous carcinomas compared to serous borderline tumors, confirming our previous cDNA microarray studies. In both PATH and ACIS analysis, MCM7 expression is also significantly higher in high-grade serous carcinomas compared to other histology subtypes of ovarian cancer. Finally, to identify the clinical significance of MCM7 expression, we determined the association between MCM7 expression and disease-free survival. MCM7 labeling index was dichotomized into two groups (high and low) using median labeling index as cut-off. For both PATH or ACIS-derived scores, univariate analyses indicate significant association of high MCM7 labeling index with better disease-free survival in high-grade serous carcinomas. These results suggest the clinical significance of MCM7 expression in high-grade serous carcinomas of the ovary and the need for further evaluation of MCM7 as a potential theranostic biomarker. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4637.
Abstract 540: The pro-inflammatory protein S100A9 promotes pancreatic cancer cell growth
Authors: Joseph Markowitz, Bethany Mundy, Alena C. Jaime-Ramirez, Bonnie Paul, Tanios Bekaii-Saab, William E. Carson
Journal: Cancer Research (2011)

Abstract S100A9 is a pro-inflammatory protein originally found in macrophages which is felt to be important in promoting inflammatory responses and cancer cell growth. The protein is found in cancer cells of gastric, colon, breast cervical and thyroid cancer. Generally, S100A9 is a cytoplasmic, cell surface and secreted protein that promotes cancer cell growth via inflammatory mechanisms and migration of immune cells (e.g. PBMCs) to the cancer microenvironment via non-covalent interactions with glycosaminoglycans on endothelial surfaces. Previously, this protein was reported in the stroma of pancreatic cancers but not in pancreatic cancer cells themselves. This report iilustrates S100A9 up-regulation on the surface of p53 mutant pancreatic cancer cell lines BxPC3 and AsPC1 as determined by immunoblot analysis and flow cytometry. In this study, pentamidine a known inhibitor of S100B, inhibited S100A9 dependent cell growth in BxPC3 cell lines (IC50 = 20.1 +/- 10.3 μM). Pentamidine treated BxPC3 cells (20 μM for 96 hrs) exhibited 30.1% apoptotic cell death as measured by Annexin/PI statining vs less than 3% for control treated cells. Given that S100A9 was found in other cancer models to promote recruitment of pro-infammatory cells (e.g. PBMCs) and subsequent support of cancer cell growth, we studied the effect of pentamidine on PBMC migration. Pentamidine also blocked the migration of PBMC from a metastatic pancreatic cancer patient (67%) to a similar degree as an Anti-s100A9 (68%) Ab or an anti-s100A8/A9 (65%) antibody. S100A8/A9 antibody is known to bind to helix 1 of S100A8 and helix 4 of S100A9, areas of the protein considered important for target interactions. It is likely that pentamidine indiscriminately binds to both the S100A8/A9 heterodimer as well as the homodimer in addition to other S100 proteins. S100A9 levels in BxPC3 cells as detected via Western analysis also increase with 20 μM pentamidine treatment, but not 10 fold as reported in the literature for S100B. As p53 was also shown previously to bind to the S100A9 promoter and S100A9 is not as robustly expressed in mutant p53 cell lines, p53 independent pathways are clearly important for cancer cell survival. This study suggests that S100A9 is up-regulated in pancreatic cancer and that inhibition causes pancreatic cancer cell death. 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 540. doi:10.1158/1538-7445.AM2011-540
Abstract 522: CXCR4 inhibition sensitizes prostate cancer cells to conventional chemotherapy in an <i>in vitro</i> co-culture model
Authors: Urszula M. Domanska, Roeliene C. Kruizinga, Wouter B. Nagengast, Hetty Timmer – Bosscha, Elisabeth G.E. de Vries, Gerwin A. Huls, Annemiek M.E. Walenkamp
Journal: Cancer Research (2011)

Abstract Background: Chemokine receptor 4 (CXCR4) mediates homing of hematopoietic stem cells to niches, where stromal cells express CXCL12, the CXCR4 ligand. Indeed, in clinical practice the CXCR4 inhibitor AMD3100 is used to mobilize hematopoietic stem cells. Also in several solid cancer types, including prostate cancer, tumor cells show CXCR4 overexpression. In solid cancers this receptor is involved in tumor metastasis, invasiveness and primary tumor growth. It is postulated that in these tumors, the stromal microenvironment expressing CXCL12, protects tumor cells from chemotherapy. We therefore aimed to study whether inhibition of the CXCR4/CXCL12 axis, with the specific CXCR4 inhibitor AMD3100, sensitizes prostate cancer cells for conventional chemotherapy and improves treatment outcome. Methods: A co – culture model of murine stroma (MS5) and human prostate cancer cells (PC3-luc) has been developed. To assess the effect of stromal cells on sensitivity to chemotherapy, PC3-luc cells labeled with fluorescent DiI dye were cultured with or without MS5 cells and treated with 1 μM docetaxel for 40 hours. To determine whether observed effect can be reversed by CXCR4 inhibition, experiments were repeated with addition of 25μg/ml AMD3100. After 40 hours treatment, the percentage of viable PC3-luc cells in the field of view was assessed by fluorescent microscopy with DAPI nuclear staining. For each condition, six fields of view were counted and the average percentage was calculated. Experiments were performed in three repetitions. Results: In the absence of MS5 stromal cells, docetaxel treatment of PC3-luc cells resulted in only 14.1 % survival. Co-culturing with stromal cells demonstrated a protective effect on chemotherapy induced cell death, with up to 61,8 % survival of PC3-luc cells after docetaxel treatment. AMD3100 eversed this protective effect completely, as combined treatment with AMD3100 and docetaxel in the co-culture setting resulted in a drop in the percentage of viable cells from 61.8 % to 19.9 % (P&amp;lt;0.0042). Conclusion: Murine stromal MS5 cells protect PC3-luc tumor cells against docetaxel – induced cell death in an in vitro co-culture system. Treatment with AMD3100 almost completely abolished the effect of the presence of stromal cells when the prostate cancer cells were treated with docetaxel. These data underscore the relevance to focus for further research on the role of CXCR4 inhibitors as a potentiating adjunct to conventional chemotherapy. 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 522. doi:10.1158/1538-7445.AM2011-522
Intermittent Etidronate Therapy to Prevent Corticosteroid-Induced Osteoporosis
Authors: Jonathan D. Adachi, William G. Bensen, Jacques Brown, David Hanley, Anthony Hodsman, Robert Josse, David L. Kendler, Brian Lentle, Wojciech Olszynski, Louis-George Ste.-Marie, Alan Tenenhouse, Arkadi A. Chines, Algis Jovaisas, William C. Sturtridge, Tassos P. Anastassiades, John G. Hanly, Janet E. Pope, Reginald Dias, Zebulun D. Horowitz, Simon Pack
Journal: New England Journal of Medicine (1997)

Osteoporosis is a recognized complication of corticosteroid therapy. Whether it can be prevented is not known. We conducted a 12-month, randomized, placebo-controlled study of intermittent etidronate (400 mg per day for 14 days) followed by calcium (500 mg per day for 76 days), given for four cycles, in 141 men and women (age, 19 to 87 years) who had recently begun high-dose corticosteroid therapy. The primary outcome measure was the difference in the change in the bone density of the lumbar spine between the groups from base line to week 52. Secondary measures included changes in the bone density of the femoral neck, trochanter, and radius and the rate of new vertebral fractures.
SAT0202 Identification of thiopurine methyltransferase (TPMT) activity can predict azathioprine-related hematotoxicity in the maintenance therapy of systemic lupus erythematosus patients
Authors: Z. Zhan, D. Chen, F. Lian, Q. Qiu, L. Liang, X. Yang
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> To investigate the azathioprine-related adverse drug reactions (ARDs) in the maintenance therapy of systemic lupus erythematosus (SLE) patients and the relationship between thiopurine methyltransferase (TPMT) activity and these ARDs. <h3>Methods</h3> TPMT activity of 250 patients with SLE and AZA maintain therapy was determined by high performance liquid chromatography (HPLC). The ARDs of AZA were followed up. <h3>Results</h3> The most common ARDs was hematotoxicity (8.4%), followed by gastrointestinal reactions (7.6%), hepatotoxicity (3.2%), alopecia (2%). 1 case suffered acute pancreatitis. Leukopenia (8.0%) and thrombocytopenia (3.6%) were the most frequent ARDs of hematotoxicity. The mean TPMT activity was 12.36±7.07U/mlRBC (range 1.72-30.03U/ml RBC). The activity of TPMT showed a normal skewness distribution.The mean TPMT activity of cases who experienced hematotoxicity and alopecia was much lower than the cases who never experienced these ARDs (P&lt;0.001). No significan difference between the mean TPMT value of cases with hepatotoxicity or gastrointestinal reactionsand the control mean (P&gt;0.05) was seen. The cases with low TPMT activity tend to suffer hematotoxicity at the low dose of AZA (50mg/d). <h3>Conclusions</h3> The most common AZA related -ARDs was hemototoxicity in the maintain therapy of SLE. This study demonstrates that AZA-induced hematotoxicity is related to the reduced TPMT activity. The cases with low TPMT activity tend to experience hematotoxicity at the low dose of AZA. Azathioprine dose selection based on TPMT activity testing may minimize the risk of hemototoxicity. <h3>Disclosure of Interest</h3> None Declared