tbuckley/cabot-search huggingface dataset:
Familial Risk in Patients With Carcinoma of Unknown Primary
Authors: N. Jewel Samadder, Ken Robert Smith, Heidi Hanson, Richard Pimentel, Jathine Wong, Kenneth Boucher, Wallace Akerley, Glynn Gilcrease, Cornelia M. Ulrich, Randall W. Burt, Karen Curtin
Journal: JAMA Oncology (2015)

<h3>Importance</h3> Carcinoma of unknown primary (CUP) accounts for 3% to 5% of all cancers and is associated with poor prognosis. Familial clustering of different cancer sites with CUP is unknown and may provide information regarding etiology, as well as elevated cancer risks in relatives. <h3>Objective</h3> To quantify the risk of cancer by site in first- and second-degree relatives and first cousins of individuals with CUP. <h3>Design, Setting, and Participants</h3> Nested case-control study of patients who received a diagnosis of CUP between 1980 and 2010 identified from the Utah Cancer Registry. Population controls with no CUP diagnosis were sex and age matched 10:1 to patients with CUP. Data about relatives were drawn from the Utah Population Database. <h3>Main Outcomes and Measures</h3> Familial aggregation of cancer risk in relatives of cases compared with controls using Cox regression analysis. <h3>Results</h3> For the 4160 index patients (median [interquartile range] age, 72 [62-81] years; 47.6% male) who had received a diagnosis of CUP, first-degree relatives were at an elevated risk of CUP themselves (hazard ratio [HR], 1.35 [95% CI, 1.07-1.70]), as well as lung (HR, 1.37 [95% CI, 1.22-1.54]), pancreatic (HR, 1.28 [95% CI, 1.06-1.54]), myeloma (HR, 1.28 [95% CI, 1.01-1.62]), and non-Hodgkin lymphoma (HR, 1.16 [95% CI, &gt;1.00-1.35]) cancers compared with controls without CUP. When the analysis was restricted to relatives of cancer-free controls, additional increased risks for colon (HR, 1.19 [95% CI, 1.06-1.33]) and bladder (HR, 1.18 [95% CI, &gt;1.00-1.38]) cancers were observed. Second-degree relatives of patients with CUP were at a slight increased risk of lung (HR, 1.14 [95% CI, 1.03-1.26]), pancreatic (HR, 1.17 [95% CI, 1.01-1.37]), breast (HR, 1.09 [95% CI, 1.02-1.16]), melanoma (HR, 1.09 [95% CI, &gt;1.00-1.19]), and ovarian (HR, 1.19 [95% CI, 1.02-1.39]) cancers. <h3>Conclusions and Relevance</h3> Relatives of patients with CUP are at increased risk of CUP and several other malignant neoplasms, including lung, pancreatic, and colon cancer. The present data may suggest sites of origin for CUP and provide cancer risk information for relatives of patients with CUP that can lead to effective intervention. Relatives of patients with CUP should be aware of the elevated risks for lung, pancreatic, and colon cancer and encouraged to modify risk factors and adhere to site-specific population cancer screening.
Abstract P010: Cardiac Risk Factors and 6-Year Change in high-sensitivity Cardiac Troponin-T.
Authors: Bill McEvoy, Mariana Lazo-Elizondo, Lu Shen, Vijay Nambi, Ron Hoogeveen, Christie Ballantyne, Roger Blumenthal, Josef Coresh, Elizabeth Selvin
Journal: Circulation (2014)

Introduction: Troponin measured with a highly sensitive assay (hs-cTNT) can detect subclinical myocardial injury and may be useful for risk stratification. However, little is known about temporal changes in hs-cTNT in the general population. Hypothesis: Traditional cardiac risk factors will predict change in hs cTNT. Methods: We analyzed data from 8698 ARIC Study participants, free of cardiovascular disease, who had hs-cTNT measured at visit 2 (1990-1992) and visit 4 (1996-1998). Hs-cTNT was categorized as: undetectable (&lt;5 ng/L), detectable (5-14 ng/L), and elevated (≥14 ng/L). We examined the association of baseline Framingham Risk Score (FRS) groups (low &lt;10%, intermediate 10-20%, high &gt;20%) and individual cardiac risk factors with change across hs-cTNT categories using Poisson regression and with absolute 6-year change using robust linear regression. Results: Over 6 years, 2124 study participants went from undetectable to detectable or elevated hs-cTNT and 353 went from detectable to elevated hs-cTNT. The mean crude 6-year hs-cTNT change (SD) within FRS groups were; low (+1.3 (6.0) ng/L), intermediate (+2.3 (9.3) ng/L), and high (+3.7 (8.3) ng/L). Higher baseline FRS was associated with an increase in hs-cTNT over 6 years ( Table ). This association was stronger for incident detectable hs-cTNT than for progression from detectable to elevated. Major predictors of change were baseline age, male gender, diabetes and hypertension. Black race/ethnicity and obesity were also associated with categorical hs-cTNT change. In addition to HDL-c, baseline hypercholesterolemia and smoking may be associated with downwards hs-cTNT change. Conclusions: Framingham Risk Score was positively associated with 6-year hs-cTNT change in middle-age adults. The modifiable risk factors primarily driving this association were diabetes, hypertension, and obesity. Additional studies are needed to evaluate if modifying these risk factors can prevent progression of subclinical myocardial damage.
Total Lesion Glycolysis in Positron Emission Tomography Can Predict Gefitinib Outcomes in Non–Small-Cell Lung Cancer with Activating EGFR Mutation
Authors: Bhumsuk Keam, Soo Jin Lee, Tae Min Kim, Jin Chul Paeng, Se-Hoon Lee, Dong-Wan Kim, Yoon Kyung Jeon, Doo Hyun Chung, Keon Wook Kang, June-Key Chung, Dae Seog Heo
Journal: Journal of Thoracic Oncology (2015)
Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease
Authors: José R. Naranjo, Hongyu Zhang, Diego Villar, Paz González, Xose M. Dopazo, Javier Morón-Oset, Elena Higueras, Juan C. Oliveros, María D. Arrabal, Angela Prieto, Pilar Cercós, Teresa González, Alicia De la Cruz, Juan Casado-Vela, Alberto Rábano, Carmen Valenzuela, Marta Gutierrez-Rodriguez, Jia-Yi Li, Britt Mellström
Journal: Journal of Clinical Investigation (2016)

Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD.
Reply to G.B. Holt
Authors: Alexi A. Wright, Angel Cronin, David M. O’Malley
Journal: Journal of Clinical Oncology (2016)

In his letter, Holt expressed concern that the survival difference we observed in our study between intraperitoneal (IP)/intravenous (IV) chemotherapy and IV chemotherapy may be a result of residual confounding between the two groups (eg, differences between institutional practices) rather than because of the treatment itself. The main finding of our study was that IP/IV chemotherapy was associated with a significantly improved survival compared with IV chemotherapy, with a hazard ratio (HR) of 0.68 obtained from a univariable Cox proportional hazards regression model within the propensity score–matched sample. We acknowledge that the standardized differences between groups after propensity score matching exceeded the standard threshold of 10% for some covariates (ie, age, Charlson score, primary tumor site, and histology); however, examination of the raw frequencies of these variables within the propensity score–matched sample demonstrates that they are reasonably well balanced between groups. In addition, when we conducted a multivariable Cox proportional hazards regression model that included these variables within the propensity score–matched sample—a doubly robust analysis—we obtained a similar HR of 0.71. We were concerned that our results might be a result of differences between institutions, rather than treatment, and performed a sensitivity analysis to examine this. Specifically, we excluded each institution, one by one, to ensure that the survival benefit observed was not driven by outcomes at a single institution. As reported in our article, the adjusted HRs ranged from 0.61 to 0.76 upon excluding each institution one by one, indicating that the survival benefit observed was not driven by outcomes at a single institution. We were further reassured that this was unlikely because institution was not significantly associated with overall survival in the full cohort (P5 .16) or within treatment subgroups within the propensity score–matched sample (P5 .77 for IP/IV and P 5 .11 for IV). Nevertheless, we performed additional analyses to address the potential for Simpson’s paradox. In brief, Simpson’s paradox occurs when an association does not appear within subgroups but does appear when data are combined, or vice versa. In the context of our study, Simpson’s paradox with the lurking variable of institution would be problematic if a survival benefit for IP/IV chemotherapy was not observed within institutions. As shown in Table 1, the overall survival was similar between institutions, and the central estimates were in favor of IP/IV for each institution, which is consistent with the aggregate results. In addition, we have included in Table 2 the raw percentages by institution that were omitted from Appendix Table A1 in our original article. Together, these results suggest that the survival benefit we observed was unlikely to be driven by differences in practices at any individual institution, particularly because the HR that we observed was similar to results from several prior randomized controlled trials.
Abstract 14029: New Findings in Women and Men Regarding Symptoms and Delay Times in Stemi
Authors: Eva Swahn
Journal: Circulation (2014)

Introduction: Myocardial infarction patients report higher prevalence of atypical symptoms in women, contributing to a less probability of a correct diagnosis. Studies exploring only the STEMI group where a prompt diagnosis is mandatory is lacking. We hypothesised that chest pain is equally common in women and men in a STEMI population. We further hypothesised that women have more associated symptoms than men in a STEMI population and thus a longer delay time. Methods: SymTime is a multicentre observational study where patients with a diagnosis of STEMI, admitted to CCUs where included. Within 24 h from admission they filled in a validated Swedish questionnaire, developed to measure how patients with MI describe their symptoms and actions in the pre-hospital phase. Results: 126 women and 406 men were included, mean age 70 and 64 (SD11) years respectively. After age adjustment, men had 5 times higher odds of having chest pain. Women had more symptoms in other typical locations. (Table) Only general feelings of illness (25 vs 13%, p = .001), fearfulness (31 vs 17 %, p.= 001) and nausea (49 vs 29 %, p &lt; .001) were more common in women. Women had longer delay times from symptom onset to first medical contact, median time 1:30 hours: minutes vs 1:05 in men (p = 0.03). Conclusion: Women had significantly less chest pain, one reason for longer delay times in women. The prevalence of other typical MI symptoms such as pain in the chin/teeth, throat, shoulders, arms or back was higher in women. These findings should be communicated to the health care system as well as the community in order to get a prompt and correct diagnosis of STEMI in both genders. Table. Main symptom(s) in women and men with STEMI
Six-minute walk test desaturation and echocardiographic findings in IPF: Correlational observations made in the European IPF registry (eurIPFreg)
Authors: Andreas Guenther, Fotios Drakopanagiotakis, Carlo Vancheri, Philippe Bonniaud, Athol Wells, Bruno Crestani
Journal: European Respiratory Journal (2014)

Background  Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder of unknown origin, which ultimately leads to death. Echocardiography is a simple, although often inaccurate, screening method for the presence of PH. We examined the correlation between echocardiographic and functional parameters in patients with IPF.  Methods  Data from the eurIPFreg, a European Registry for IPF and other IIPs, were used. Echocardiographic data as reported in the physician´s questionnaire were collected and correlated with functional parameters.  Results  Data from 243 patients with IPF with a mean age of 65,53± 13,82 years were analysed. The mean % predicted of FVC was 65,30 ± 23,39 and of DLCO 39,50 ±17,47. Right ventricle enlargement was reported in 23,5% and left ventricle enlargement in 11,1% of the patients, respectively. The median systolic pulmonary artery pressure (sPAP) was 36 mm Hg. The median left ventricle ejection fraction (LVEF) was 63,50 %. sPAP negatively correlated with the FVC ( % pred);p=0,026), the DLCO (% pred;p l 0,001), the 6 minute walking test distance (p=0,010) and the difference in oxygen saturation(DSpO2; end versus beginning of 6MWT; p l 0,001). When patients with left ventricle enlargement and LVEFl 40% were excluded, sPAP correlated only with DLCO (p=0,002) and the DSpO2 (p=0,002). In a linear regression analysis model including age, gender, FVC, DLCO, DSpO2 and 6MWD, sPAP correlated only with DSpO2 (pl 0,001, R 2 = 0,235).  Implications  The degree of oxygen desaturation during the six minute walk test may be indicative of elevated sPAP in IPF patients.
Abstract 13915: Risk Factors and Outcomes of Necrotizing Enterocolitis (NEC) in Congenital Heart Disease Patients Post-intervention
Authors: Nitesh Singhal, Cedric Manlhiot, Brian McCrindle, Glen V Arsdell, Venkatesan B Sivarajan
Journal: Circulation (2013)

INTRODUCTION: Necrotizing Enterocolitis (NEC) is a recognized complication in neonates with Congenital Heart Disease (CHD). To determine risk factors for NEC in CHD patients post-intervention (Surg...
Abstract 2342: ICD Therapy in Noncompaction Cardiomyopathy: Data From the German Left Ventricular Noncompaction Registry (ALKK)
Authors: Birgit Gerecke, Claudia Stollberger, Frank Gradaus, Horst Andresen, Rolf Engberding
Journal: Circulation (2009)

Noncompaction cardiomyopathy (NCCM) is considered to be a primary genetic cardiomyopathy with a high prevalence of heart failure, thromboembolic events, and arrhythmias. AHA/ACC/HRS guidelines 2008...
Significance of KIT exon 17 mutation depends on mutant level rather than positivity in core-binding factor acute myeloid leukemia
Authors: W Jang, J-H Yoon, J Park, G D Lee, J Kim, A Kwon, H Choi, K Han, C H Nahm, H-J Kim, W-S Min, M Kim, Y Kim
Journal: Blood Cancer Journal (2016)

KIT exon 17 mutation is a poor prognostic factor in core-binding factor acute myeloid leukemia. However, the mutation detection method used for risk assessment is not assigned. It is necessary to verify the analytical and clinical performance before applying new methods. Herein, we firstly applied a highly sensitive allele-specific, real-time quantitative PCR (AS-qPCR) assay to analyze KIT mutations, which demonstrated excellent sensitivity and specificity. Much higher incidence of KIT mutations (62.2%, 69/111) and prevalence of multiple mutations (43.5%, 30/69) were observed using AS-qPCR, which meant the existence of multiple KIT mutant subclones. The relative KIT mutant level was variable (median, 0.3 per control allele 100 copies, 0.002–532.7) and was divided into two groups: high (⩾10, n=26) and low (<10) mutant level. Interestingly, rather than mutation positivity, mutant level was found to be associated with clinical outcome. High mutant level showed significantly inferior overall survival (P=0.005) and event-free survival (P=0.03), whereas low level did not influence the prognosis. The follow-up data showed that the mutant level were along with fusion transcripts in the majority (n=29), but moved separately in some cases, including the loss of mutations (n=5) and selective proliferation of minor clones (n=2) at relapse. This study highlighted that the KIT mutation should be analyzed using sensitive and quantitative techniques and set a cutoff level for identifying the risk group.
Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer
Authors: E. A. Perez, E. H. Romond, V. J. Suman, J. Jeong, N. E. Davidson, C. E. Geyer, S. Martino, E. P. Mamounas, P. A. Kauffman, N. Wolmark
Journal: Journal of Clinical Oncology (2007)

512 Background: The joint efficacy analysis of NCCTG N9831 and NSABP B-31 demonstrated improved outcomes with the addition of trastuzumab (H) to doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) in women with surgically removed HER2- positive breast cancer (NEJM 2005). Following this report, patients randomized to AC→T and less than 6 months from completion of chemotherapy were eligible to receive H. We have updated the initial combined results of these two trials. Methods: Primary and secondary efficacy endpoint were disease free survival (DFS) and overall survival (OS). Cox modeling was performed. Hazard ratios are adjusted for nodal status, tumor size, T schedule, hormone receptor status, and trial (also age for OS). Results: Among the 3,969 women enrolled (ages: 22 to 80yrs), there have been 619 events (H group: 222, non-H: 397). First events were: recurrence (511), contralateral breast disease (18), other second primary cancers (48), and death without recurrence or second primary cancers (42). The median follow-up among the 3,711 women still alive is 2.9 years (range up to 6,4 years). The 4 yr DFS rate and 4 yr OS rate respectively were: 85.9% (95%CI: 84.0–87.8%) and 92.6% (95%CI: 91.2–94.2%) in H group and 73.1% (95%CI: 70.6–75.8%) and 89.4% (95%CI: 87.6–91.2%) in non- H group. Hazard ratio for adjuvant (H/non-H) was 0.49 (P&lt;0.0001; 95%CI: 0.41–0.58) for DFS and 0.63 (P=0.0004; 95%CI: 0.49–0.81) for OS.The rates of a first event per 1,000 women/year during yrs 1–4 were: 26.7, 52.9, 49.6 and 23.2 for H and 42.3, 102.3, 107.6 and 61.5 for non-H. The impact of crossover on clinical outcome will be explored. Conclusions: With an increase in the median follow-up of 11 months and with 225 additional events, the demonstration of substantial improvement in outcomes with the addition of trastuzumab to chemotherapy persist. This improvement continues in spite of some degree of cross-over occurring after the initial results were reported.Updated data regarding crossover outcomes and H duration (as they relate to disease free survival) will be presented. [Table: see text]
IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation
Authors: Roser Vento-Tormo, Carlos Company, Javier Rodríguez-Ubreva, Lorenzo de la Rica, José M. Urquiza, Biola M. Javierre, Radhakrishnan Sabarinathan, Ana Luque, Manel Esteller, Josep M. Aran, Damiana Álvarez-Errico, Esteban Ballestar
Journal: Genome biology (2016)

The role of cytokines in establishing specific transcriptional programmes in innate immune cells has long been recognized. However, little is known about how these extracellular factors instruct innate immune cell epigenomes to engage specific differentiation states. Human monocytes differentiate under inflammatory conditions into effector cells with non-redundant functions, such as dendritic cells and macrophages. In this context, interleukin 4 (IL-4) and granulocyte macrophage colony-stimulating factor (GM-CSF) drive dendritic cell differentiation, whereas GM-CSF alone leads to macrophage differentiation. Here, we investigate the role of IL-4 in directing functionally relevant dendritic-cell-specific DNA methylation changes. A comparison of DNA methylome dynamics during differentiation from human monocytes to dendritic cells and macrophages identified gene sets undergoing dendritic-cell-specific or macrophage-specific demethylation. Demethylation is TET2-dependent and is essential for acquiring proper dendritic cell and macrophage identity. Most importantly, activation of the JAK3-STAT6 pathway, downstream of IL-4, is required for the acquisition of the dendritic-cell-specific demethylation and expression signature, following STAT6 binding. A constitutively activated form of STAT6 is able to bypass IL-4 upstream signalling and instruct dendritic-cell-specific functional DNA methylation changes. Our study is the first description of a cytokine-mediated sequence of events leading to direct gene-specific demethylation in innate immune cell differentiation.
Atezolizumab, an Anti–Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study
Authors: David F. McDermott, Jeffrey A. Sosman, Mario Sznol, Christophe Massard, Michael S. Gordon, Omid Hamid, John D. Powderly, Jeffrey R. Infante, Marcella Fassò, Yan V. Wang, Wei Zou, Priti S. Hegde, Gregg D. Fine, Thomas Powles
Journal: Journal of Clinical Oncology (2016)

The objective was to determine the safety and clinical activity of atezolizumab (MPDL3280A), a humanized programmed death-ligand 1 (PD-L1) antibody, in renal cell carcinoma (RCC). Exploratory biomarkers were analyzed and associated with outcomes.Seventy patients with metastatic RCC, including clear cell (ccRCC; n = 63) and non-clear cell (ncc; n = 7) histologies, received atezolizumab intravenously every 3 weeks. PD-L1 expression was scored at four diagnostic levels (0/1/2/3) that were based on PD-L1 staining on tumor cells and tumor-infiltrating immune cells (IC) with the SP142 assay. Primary end points were safety and toxicity; secondary end points assessed clinical activity per Response Evaluation Criteria in Solid Tumors version 1.1 and immune-related response criteria. Plasma and tissue were analyzed for potential biomarkers of atezolizumab response.Grade 3 treatment-related and immune-mediated adverse events occurred in 17% and 4% of patients, respectively, and there were no grade 4 or 5 events. Sixty-three patients with ccRCC were evaluable for overall survival (median, 28.9 months; 95% CI, 20.0 months to not reached) and progression-free survival (median, 5.6 months; 95% CI, 3.9 to 8.2 months), and 62 patients were evaluable for objective response rate (ORR; 15%; 95% CI, 7% to 26%). ORR was evaluated on the basis of PD-L1 IC expression (IC1/2/3: n = 33; 18%; 95% CI, 7% to 35%; and IC0: n = 22; 9%; 95% CI, 1% to 29%). The ORR for patients with Fuhrman grade 4 and/or sarcomatoid histology was 22% (n = 18; 95% CI, 6% to 48%). Decreases in circulating plasma markers and acute-phase proteins and an increased baseline effector T-cell-to-regulatory T-cell gene expression ratio correlated with response to atezolizumab.Atezolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with metastatic RCC. Correlative studies identified potential predictive and pharmacodynamic biomarkers. These results have guided ongoing studies and combinations with atezolizumab in RCC.