tbuckley/cabot-search huggingface dataset:
Localization of the primary tumor (LPT) and maintenance strategies after first line oxaliplatin (Ox), fluoropyrimidine (FP), and bevacizumab (Bev) in metastatic colorectal cancer (mCRC): Results from the AIO 0207 trial.
Authors: Anke C. Reinacher-Schick, Stefanie Noepel-Duennebacke, Jan Hertel, Andrea Tannapfel, Dirk Arnold, Axel Hinke, Susanna Hegewisch-Becker
Journal: Journal of Clinical Oncology (2017)

3543 Background: Numerous trials have examined the prognostic and predictive value of the LPT in mCRC, but little is known about the predictive value of LPT on different maintenance strategies. We analyzed progression-free survival (PFS) and overall survival (OS) from start of maintenance according to LPT in patients (pts) from the AIO KRK 0207 trial. Methods: Following a 24-week standard induction 471 pts were randomized to FP/Bev, Bev mono or no treatment with 454 pts being evaluable for PFS. Right sided primary tumors were defined as located in the caecum, ascending colon, transverse colon up to the splenic flexure; left colon was defined as splenic flexure, descending and sigmoid colon and rectum. Results: Data on LPT was available in 414 pts. for PFS (91%). LPT was left sided (LPTl) in 291 (70%) and right-sided (LPTr) in 123 (30%) of pts, respectively (remaining pts: status was either unknown, n = 37 or LPT was located in both regions, n = 3). Median PFS1 was 3.9 months (mos.) for LPTr and 5.3 mos. for LPTl (p = 0.11; HR 1.19, 95%CI 0.96 - 1.48). Analyses on PFS did not demonstrate a major predictive impact of LPT on the efficacy of the three maintenance strategies. The pairwise comparison of treatment arms showed a better PFS for FP/Bev vs no treatment independent from LPT (left: p &lt; 0.0001; HR = 2.39, 95%CI 1.73-3.31; right: p = 0.011; HR 1.78, 95%CI 1.14-2.80). In addition, Bev mono vs no treatment was superior in LPTl (p = 0.0032; HR 1.54, 95%CI 1.15-2.06) with less difference in LPTr (p = 0.17; HR 1.36, 95%CI 0.87-2.14). Analysis for OS (429 evaluable pts) confirmed the strong prognostic impact of LPT (left vs right: 24.0 vs 16.7 months; p &lt; 0.0001; HR = 1.65, 95%CI 1.32 - 2.06), but without major interaction between LPT and maintenance arms. The impact related to RAS mutational status will be reported. Conclusions: The strong prognostic factor of the LPT is confirmed in pts with mCRC undergoing Ox/FP/Bev induction therapy while there seems to be no major predictive impact of LPT on different maintenance strategies. Clinical trial information: EudraCT-Nr: 2008-007974-39.
Effect of Early-Life Geohelminth Infections on the Development of Wheezing at 5 Years of Age
Authors: Philip J. Cooper, Martha E. Chico, Maritza G. Vaca, Carlos A. Sandoval, Sofia Loor, Leila D. Amorim, Laura C. Rodrigues, Mauricio L. Barreto, David P. Strachan
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Exposures to geohelminths during gestation or early childhood may reduce risk of wheezing illness/asthma and atopy during childhood in tropical regions.Objectives: To investigate the effect of maternal and early childhood geohelminths on development of wheeze/asthma and atopy during the first 5 years of life.Methods: A cohort of 2,404 neonates was followed to 5 years of age in a rural district in coastal Ecuador. Data on wheeze were collected by questionnaire and atopy was measured by allergen skin prick test reactivity to 10 allergens at 5 years. Stool samples from mothers and children were examined for geohelminths by microscopy.Measurements and Main Results: A total of 2,090 (86.9%) children were evaluated at 5 years. Geohelminths were observed in 45.5% of mothers and in 34.1% of children by 3 years. Wheeze and asthma were reported for 12.6% and 5.7% of children, respectively, whereas 14.0% had skin test reactivity at 5 years. Maternal geohelminths were associated with an increased risk of wheeze (adjusted odds ratio, 1.41; 95% confidence interval, 1.06–1.88), whereas childhood geohelminths over the first 3 years of life were associated with reduced risk of wheeze (adjusted odds ratio, 0.70; 95% confidence interval, 0.52–0.96) and asthma (adjusted odds ratio, 0.60; 95% confidence interval, 0.38–0.94) but not skin prick test reactivity. The effects on wheeze/asthma were greatest with later age of first infection, were observed only in skin test–negative children, but were not associated with parasite burden or specific geohelminths.Conclusions: Although maternal exposures to geohelminths may increase childhood wheeze, childhood geohelminths during the first 3 years may provide protection through a nonallergic mechanism.Registered as an observational study (ISRCTN41239086).
What is the agreement between pathological features of parotid gland and labial salivary gland biopsies?
Authors: Guillermo Carvajal Alegria, Sebastian Costa, Sandrine Jousse-Joulin, Pascale Marcorelles, Jacques-Olivier Pers, Alain Saraux, Valérie Devauchelle-Pensec, Divi Cornec
Journal: Annals of the Rheumatic Diseases (2017)

We read with a great interest the recent contribution by Mossel et al ,1 which brings new important data on the diagnostic value of major salivary ultrasonography (SGUS) for primary Sjogren’s syndrome (pSS), as reported in previous studies2–10 and stresses the need to evaluate the inclusion of SGUS into future classification criteria for the disease.

In their cohort of 103 consecutive patients clinically suspected for pSS, Mossel et al reported a good agreement between SGUS and labial and parotid salivary gland biopsy. Agreement was reported to be marginally higher for parotid gland biopsy (absolute agreement of 83%) than for minor labial salivary gland biopsy (absolute agreement 79%). However, the …
Breast cancer biomarker discordance between primary and sites of metastasis: A systematic review.
Authors: Isis Ching Yeung, Mark Clemons, Christina L. Addison, Brian Hutton, Xiaofu Zhu, Sasha Mazzerello, Angel Arnaout
Journal: Journal of Clinical Oncology (2013)

e11574 Background: Systemic treatment choices for breast cancer patients with recurrent disease are usually based on the ER/PR/Her2 biomarker status of the primary cancer. Biomarker discordance between the primary and metastatic sites is well recognised and could have important therapeutic implications. A systematic review was conducted to assess the extent of biomarker discordance between the primary cancer and metastasis, and whether is influenced by the site of metastasis. Methods: An electronic search of multiple literature databases implemented by an information scientist was conducted to identify studies reporting outcomes of ER/PR/Her2 receptor stability between primary site and recurrent disease. Seven reviewers independently screened the 5034 abstracts and full text articles, which were identified according to pre-defined selection criteria. The same reviewers performed data collection from all included studies. Studies that were identified reported on receptor conversion between primary sites of breast cancer and various sites of metastasis including lymph node, liver, brain, lung, skin, GI sites and bone marrow. Results: Preliminary results from 385 eligible studies consistently demonstrated discordance between the primary and metastatic sites. When discordance occurred, the general trend was for loss of hormone receptor. ER hormone status was more stable (discordance 10.2-32.5%) than PR (discordance 25.5-40.7%). HER2 was found to have lower rates of discordance (2.6-14.5%). In general, higher ER/PR discordance was found in bone (40-68%) and liver (0-54%) when compared to other sites brain (36%), lung (9-18%), skin (6-22%), GI (15-40%). In the prospective studies, biomarker discordance led to change in patient management in up to 20% of the patient population. Conclusions: Our results demonstrate that biomarker discordance between primary and distant metastases does occur in breast cancer, occurs more frequently with PR, and the extent of discordance is influenced by the site of metastasis. Further research is required to have a better explanation about the pathophysiology of the biomarker status change and its clinical implications.
Abstract 18909: Interaction Between a Novel Protein Glycan Derived Inflammation Biomarker (GlycA) and HDL Particle Subclasses on Mortality in a Cardiac Catheterization Cohort
Authors: Robert W McGarrah, Damian Craig, Carol Haynes, Z. Elaine Dowdy, Svati H Shah, William E Kraus
Journal: Circulation (2015)

Background: GlycA, a novel serum inflammatory biomarker composed of enzymatically glycosylated acute phase proteins, is associated with cardiovascular events in a primary prevention population. Emerging data suggest that inflammation may adversely impact HDL function. We sought to define the role of GlycA as a biomarker of adverse events in a secondary prevention population and to understand potential interactions between GlycA and HDL subclasses. Methods: GlycA and medium and small HDL particles (MS-HDL) were measured with NMR spectroscopy in 7,617 individuals in the CATHGEN biorepository. Cox proportional hazards modeling was used to test the relationship of GlycA, MS-HDL and the GlycA*MS-HDL interaction term with time-to-death in multivariable models adjusted for 11 CV risk factors and stratified by diabetes status. We then assessed the ability of GlycA, MS-HDL, and GlycA*MS-HDL to improve risk discrimination in clinical models. Results: Over a mean time-to-event of 2547 days, 2318 individuals died. Higher GlycA levels were associated with increased risk of death (HR 1.34 [1.29-1.39], p&lt;0.0001). In diabetes-stratified models, the greatest quartile of GlycA in patients without diabetes conferred greater risk of mortality than the lowest quartile of GlycA in patients with diabetes. In models containing MS-HDL (main effect HR 0.69 [0.66-0.72], p&lt;0.0001), addition of GlycA (HR 1.28 [1.24-1.32], p&lt;0.0001) and GlycA*MS-HDL (p&lt;0.0001) demonstrated independent associations of these variables with mortality. MS-HDL levels were associated with lower mortality risk at lower GlycA levels but with increased mortality risk at greater GlycA levels. There was an increasing improvement of model fit characteristics with incremental addition of GlycA, MS-HDL and GlycA*MS-HDL to robust clinical models. Conclusion: GlycA is associated with an increased risk of mortality in a secondary prevention population. The interaction of GlycA with MS-HDL suggests that greater systemic inflammation can modify the association of HDL subclasses with clinical outcomes and at the highest levels of GlycA, may reverse the protective effect of HDL. These findings have implications for the interpretation of diagnostic and therapeutic tools involving HDL measurements.
Impact of Preexisting Mental Illness on All-Cause and Breast Cancer–Specific Mortality in Elderly Patients With Breast Cancer
Authors: Kristy Iglay, Melissa L. Santorelli, Kim M. Hirshfield, Jill M. Williams, George G. Rhoads, Yong Lin, Kitaw Demissie
Journal: Journal of Clinical Oncology (2017)

Purpose Limited data are available on the survival of patients with breast cancer with preexisting mental illness, and elderly women are of special interest because they experience the highest incidence of breast cancer. Therefore, we compared all-cause and breast cancer-specific mortality for elderly patients with breast cancer with and without mental illness. Methods A retrospective cohort study was conducted by using SEER-Medicare data, including 19,028 women ≥ 68 years of age who were diagnosed with stage I to IIIa breast cancer in the United States from 2005 to 2007. Patients were classified as having severe mental illness if an International Classification of Diseases, Ninth Edition, Clinical Modification code for bipolar disorder, schizophrenia, or other psychotic disorder was recorded on at least one inpatient or two outpatient claims during the 3 years before breast cancer diagnosis. Patients were followed for up to 5 years after breast cancer diagnosis to assess survival outcomes, which were then compared with those of patients without mental illness. Results Nearly 3% of patients had preexisting severe mental illness. We observed a two-fold increase in the all-cause mortality hazard between patients with severe mental illness compared with those without mental illness after adjusting for age, income, race, ethnicity, geographic location, and marital status (adjusted hazard ratio, 2.19; 95% CI, 1.84 to 2.60). A 20% increase in breast cancer-specific mortality hazard was observed, but the association was not significant (adjusted hazard ratio, 1.20; 95% CI, 0.82 to 1.74). Patients with severe mental illness were more likely to be diagnosed with advanced breast cancer and aggressive tumor characteristics. They also had increased tobacco use and more comorbidities. Conclusion Patients with severe mental illness may need assistance with coordinating medical services.
Positive CD63 basophil activation test is common in patients with chronic spontaneous urticaria and concomitant autoimmune thyroiditis and therefore may represent a good marker for immunoreactivity
Authors: G. Balakirski, H. F. Merk, Hossein Zadeh Mandana Attar, S. Röseler, J. M. Baron, G. Wurpts, J. Plange
Journal: Allergy (2017)
AWARE: Randomized study of an EMR-based intervention targeting hereditary cancer (CA) risk awareness in peri-op CA patients (pts).
Authors: Michael J. Hall, Elizabeth Handorf, Yana Chertock, Cindy A Keleher, Mark Siemon, Stephen C. Rubin, Elin R. Sigurdson, Robert Uzzo, Michelle Savage, Mary Beryl Daly
Journal: Journal of Clinical Oncology (2017)

e13119 Background: Pts having CA surgery have high information needs related to diagnosis, stage, and what caused their CA. Direct EMR access via web portals has grown, and offers a novel means to integrate supplemental health information into the e-chart, such as relevant genetic risk of CA. The AWARE trial (Advancing Web-based Medical Record Access and Risk Evaluation for Cancer Patients) studied the impact of providing personalized pathology (pPATH) and pers/fam history (PFHx) summaries enhanced with information about genetic CA risk and risk assessment. Methods: Peri-op CA pts completed baseline and 3-mo follow-up surveys. Pts randomized to enhanced (E) arm received pPATH &amp; PFHx summaries with embedded tailored info about genetic CA risk and relevant high-risk features. Unenhanced (U) arm got pPATH &amp; PFHx only. Use of summaries and 2 “Genetic risk: Learn more” links was tracked. Outcomes-Primary: awareness, knowledge (of genetic CA risk); Secondary: perceived risk, use of “Learn more” links, intentions/actions toward risk assessment--were stratified by genetic risk factors reported at baseline (0-1, 2+) &amp; use of “Learn more” links. Results: 171 pts consented; men (p = 0.003) &amp; non-White (p = 0.02) were more likely to decline the study. Overall 149 (87%) were randomized &amp; eligible to use AWARE: 109 (73%) logged in, 120 (81%) completed follow-up. Predictors of AWARE use: White race (p &lt; 0.05), sib w/CA (p &lt; 0.05), and use intention (p = 0.005). Reporting 2+ genetic risk factors at baseline predicted use of pPATH, PFHx, and “Learn more” (all p &lt; 0.001). Awareness increased overall (p &lt; 0.002), but between arm changes in primary outcomes were not significant. E arm (vs U) was borderline more likely to seek risk assessment (32% v 18%, p = 0.09), with impact stronger in pts reporting baseline 0-1 (p = 0.035) vs 2+ risk factors (p = 0.7). Among E arm pts who used “Learn more” links, intentions (p = 0.054) &amp; behaviors (p = 0.035) to seek risk assessment increased. Conclusions: AWARE increased genetic risk awareness overall, but primary outcomes were not met. Usage data and secondary outcomes highlight potential for EMR-based interventions to positively impact preventive behaviors toward genetic risk assessment.
Abstract 439: Modeling Diabetic Cardiomyopathy Model Using Human Induced Pluripotent Stem Cell-derived Cardiomyocytes
Authors: Yuichi Horikoshi, Anna Williams, Xiaowen Bai, Yasheng Yan, Wai-Meng Kwok, Zeliko Bosnjak
Journal: Circulation Research (2016)

Background: Diabetic cardiomyopathy (DCM) is one of the major cardiac complications in diabetic patients. However, the underlying mechanisms and pathogenesis of diabetic cardiomyopathy are only partially understood and the specific therapeutic target remains unknown. Here, we developed an in vitro diabetic cardiomyopathy model through simple metabolic manipulation using human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs). Methods: After 30 days from initial differentiation, iPSC-CMs were cultured with maturation medium (containing fatty acid but no glucose) for 3 days to obtain matured cardiomyocyte properties. Maturation extent of iPSC-CMs was analyzed using patch-clamp to analyze electrophysiological properties and RT-PCR to analyze cardiomyocyte-specific structure proteins and ion channel expression. Matured iPSC-CMs were then treated with 11 mM glucose for 2 days. 11 mM glucose represents mild glucose conditions in diabetic patients. Cardiomyopathy phenotype of iPSC-CMs was evaluated by analyzing brain natriuretic peptide (BNP) secretion from iPSC-CMs using ELISA. Result: Differentiated iPSCs-CMs were immature. Following 3 day culture in maturation medium, iPSC-CMs exhibited the cardiomyocyte maturation characteristics: 1) an increase of contractility with diminished automaticity, suggesting progressive maturation toward adult cardiomyocytes, 2) the lower maximal diastolic potential and increased amplitude, indicating functional maturation, and 3) an upregulation of the following gene expression: sarcomeric proteins (e.g., TNNI3, MYL2 and MYL3) and potassium channel α-subunit genes (KCNJ12 and KCNJ4). Matured iPSC-CMs treated with 11 mM glucose showed increase in cell size and BNP secretion (17-fold increase vs. control cells without glucose, p&lt;0.01). These results suggested that cardiomyocytes exposure to the maturation medium followed by diabetic milieu of glucose recapitulate DCM in vitro . Conclusion: We conclude that the phenotype of DCM can be modeled using cultured iPSC-derived cardiomyocytes through diabetic extracellular milieu. This clinically relevant stem cell model would be a powerful platform to study novel mechanisms of DCM and the specific therapeutic targets.
Long-Term Use of Long-Acting Insulin Analogs and Breast Cancer Incidence in Women With Type 2 Diabetes
Authors: Jennifer W. Wu, Laurent Azoulay, Agnieszka Majdan, Jean-François Boivin, Michael Pollak, Samy Suissa
Journal: Journal of Clinical Oncology (2017)

Purpose The association between long-acting insulin analogs and increased breast cancer risk is uncertain, particularly with the short follow-up in previous studies. We assessed this risk long term in women with type 2 diabetes. Methods A population-based cohort of women 40 years or older, all of whom were treated with long-acting (glargine, detemir) or neutral protamine Hagedorn (NPH) insulin between 2002 and 2012, was formed using the United Kingdom's Clinical Practice Research Datalink. Women were followed until February 2015 or breast cancer diagnosis. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% CIs of incident breast cancer, comparing long-acting insulin analogs with NPH overall, as well as by duration and cumulative dose. Results The cohort included 22,395 women who received insulin treatment, with 321 incident breast cancer events occurring during up to 12 years of follow-up (incidence rate 3.3 per 1,000 person-years). Compared with NPH insulin, insulin glargine was associated with an increased risk of breast cancer (HR, 1.44; 95% CI, 1.11 to 1.85), mainly increasing 5 years after glargine initiation (HR, 2.23; 95% CI, 1.32 to 3.77) and after > 30 prescriptions (HR, 2.29; 95% CI, 1.26 to 4.16). The risk was particularly elevated among prior insulin users (HR, 1.53; 95% CI, 1.10 to 2.12) but not for new users, which included fewer patients and for which one cannot rule out an HR of 1.81. The risk associated with insulin detemir was not significantly elevated (HR, 1.17; 95% CI, 0.77 to 1.77). Conclusion Long-term use of insulin glargine is associated with an increased risk of breast cancer in women with type 2 diabetes. The risk associated with insulin detemir remains uncertain because there are fewer users of this insulin.
Analysis of circulating tumor DNA in localized lung cancer for detection of molecular residual disease and personalization of adjuvant strategies.
Authors: Aadel Chaudhuri, Jacob J. Chabon, Alexander F. Lovejoy, Aaron M. Newman, Henning Stehr, Tej D. Azad, Justin N. Carter, David J. Merriott, Chih Long Liu, David Matthew Kurtz, Jonathan C. Dudley, Sukhmani Kaur Padda, Joseph B Shrager, Joel W. Neal, Heather A. Wakelee, Billy W. Loo, Ash A. Alizadeh, Maximilian Diehn
Journal: Journal of Clinical Oncology (2017)

8519 Background: Identifying localized non-small cell lung cancer (NSCLC) patients with residual disease following curative intent therapy is difficult due to normal tissue changes caused by surgery or radiation and an inability to detect microscopic disease. Analysis of circulating tumor DNA (ctDNA) might enable identification of molecular residual disease (MRD) and personalization of adjuvant treatment approaches but has not been explored in lung cancer. Methods: We applied CAPP-Seq, an ultra-sensitive next-generation sequencing based ctDNA quantitation method, to pre- and post-treatment blood samples from a cohort of 41 patients treated with chemoradiation, radiotherapy or surgery for stage I-III primary lung cancer. Detection of ctDNA at a single MRD time-point within 4 months of treatment completion was compared with surveillance by cross-sectional imaging. Furthermore, we developed an approach for identification of tumor mutation burden based on mutations detected in plasma, leveraging whole exome sequencing data from 1,177 NSCLCs sequenced by TCGA. Results: Median follow-up time was 35 months. Pre-treatment ctDNA was detected in 38 (93%) patients and 19 (46%) had detectable post-treatment ctDNA MRD. MRD+ patients displayed significantly inferior 3-year freedom from progression (0% vs. 92%; HR 38; P &lt; 0.0001) and 3-year overall survival (8% vs. 75%; HR 12; P &lt; 0.0001) than MRD- patients. Detection of ctDNA MRD had positive and negative predictive values for disease progression of 100% and 93%, respectively. Furthermore, we non-invasively identified activating EGFR mutations or high mutational burden (≥5 CAPP-Seq non-synonymous mutations, corresponding to &gt; 200 non-synonymous mutations per exome or &gt; 4 single nucleotide variants per megabase of exome) in 47% of patients with detectable ctDNA MRD, suggesting potentially favorable responses to TKIs and immune checkpoint inhibitors, respectively. Conclusions: Our results indicate that ctDNA analysis accurately detects MRD in localized lung cancer patients and could facilitate personalized adjuvant treatment at early time-points when disease burden is minimal.
Hepatic stellate cell-targeted imatinib nanomedicine versus conventional imatinib: A novel strategy with potent efficacy in experimental liver fibrosis
Authors: Nesrine S. El-Mezayen, Wessam F. El-Hadidy, Wessam M. El-Refaie, Th.I. Shalaby, Mahmoud M. Khattab, Aiman S. El-Khatib
Journal: Journal of Controlled Release (2017)