tbuckley/cabot-search huggingface dataset:
Health Literacy and Cardiovascular Disease: Fundamental Relevance to Primary and Secondary Prevention: A Scientific Statement From the American Heart Association
Authors: Jared W. Magnani, Mahasin S. Mujahid, Herbert D. Aronow, Crystal W. Cené, Victoria Vaughan Dickson, Edward Havranek, Lewis B. Morgenstern, Michael K. Paasche-Orlow, Amy Pollak, Joshua Z. Willey
Journal: Circulation (2018)

Health literacy is the degree to which individuals are able to access and process basic health information and services and thereby participate in health-related decisions. Limited health literacy is highly prevalent in the United States and is strongly associated with patient morbidity, mortality, healthcare use, and costs. The objectives of this American Heart Association scientific statement are (1) to summarize the relevance of health literacy to cardiovascular health; (2) to present the adverse associations of health literacy with cardiovascular risk factors, conditions, and treatments; (3) to suggest strategies that address barriers imposed by limited health literacy on the management and prevention of cardiovascular disease; (4) to demonstrate the contributions of health literacy to health disparities, given its association with social determinants of health; and (5) to propose future directions for how health literacy can be integrated into the American Heart Association’s mandate to advance cardiovascular treatment and research, thereby improving patient care and public health. Inadequate health literacy is a barrier to the American Heart Association meeting its 2020 Impact Goals, and this statement articulates the rationale to anticipate and address the adverse cardiovascular effects associated with health literacy.
Racial disparity in breast cancer immune microenvironment.
Authors: Ahmed Elkhanany, Eriko Katsuta, Kazuaki Takabe
Journal: Journal of Clinical Oncology (2018)

1081 Background: Racial disparity in breast cancer (BC) goes beyond access to care. Biology of HER2- and Triple Negative (TNBC) tumors has been shown to differ between African Americans (AF) and Caucasians (CF), contributing to survival difference. Additionally, tumor infiltrating lymphocytes (TILs) incurred favorable response to neoadjuvant therapy in ER- and TNBC. We hypothesized that TIL composition of immune microenvironment (IME) differs between AF and CF, potentially explaining such biologic disparity. Methods: Using The Cancer Genome Atlas (TCGA), we applied recently described gene expression deconvolutional algorithm CIBERSORT, estimating 22 IME cell proportions. Clinical and PAM50 data were accessed from XENA. Cytolytic activity appended from Rooney et al. Results: 183 AF Pts had worse disease-free survival (5-year DFS 21% vs. 26%, HR 1.67[1.02-2.73]) and cumulative incidence of disease (sHR 1.75[1.09-2.81]) compared with 752 CF Pts, adjusted for age and stage. DFS gap was most prominent in Basal subtype (HR 3[1.03-9.1]). Certain TILs impacted DFS and OS. Higher CD8 T cell fractions improved DFS and OS (HR 0.75[0.59-0.9] and 0.8[0.65-0.95]). Higher activated NK and γδT cell fractions predicted better DFS (HR 0.64 and 0.06). M2 macrophages incurred poor DFS (HR 11.6[1.07-126]). On adjusting for race, activated NK, γδT and M2 macrophage retained respective outcome, but not CD8 T cells. Regulatory T cells (Tregs) did not impact DFS or OS. Comparing AF to CF IME, CD8 T cells were higher in ER+ Pts only. Tregs were higher in whole cohort, Basal and TNBC subtypes. T follicular helper cells were higher in TNBC/Basal, and activated dendritic cells were higher in ER+/Luminal subtypes. Higher memory B, Plasma cells and Macrophages were seen in all subtypes except Basal (p < 0.01). Cytolytic activity was similar between AF and CF. It correlated with γδT cells (r2 0.41, 0.49 in AF) and memory CD4 cells (r2 0.4, 0.3 in AF), but not DFS or OS. Conclusions: IME in BC significantly differs by race, with AF having more Tregs in Basal/TNBC, and more CD8 T cells only in Luminal subtypes. This IME in Basal subtype (and TNBC phenotype) can explain independent worse outcome for this cohort. Incomplete deconvolution of heterogenous Tregs might explain lack of outcome correlation.
Association of Clinical and Economic Outcomes With Permanent Pacemaker Implantation After Transcatheter Aortic Valve Replacement
Authors: Talal Aljabbary, Feng Qiu, Shannon Masih, Jiming Fang, Gabby Elbaz-Greener, Peter C. Austin, Josep Rodés-Cabau, Dennis T. Ko, Sheldon Singh, Harindra C. Wijeysundera
Journal: JAMA Network Open (2018)

<h3>Importance</h3> The literature is inconsistent regarding the impact of permanent pacemaker implantation after transcatheter aortic valve replacement. <h3>Objective</h3> To evaluate clinical and economic outcomes in patients who required permanent pacemaker implantation during the index hospitalization after transcatheter aortic valve replacement. <h3>Design, Setting, and Participants</h3> This retrospective, population-based cohort study using data from a multicenter registry included patients who underwent a transcatheter aortic valve replacement procedure from April 1, 2010, to March 31, 2015, in Ontario, Canada, with follow-up to March 31, 2017. Patients who had a previously implanted permanent pacemaker or who died during the index hospitalization were excluded. Inverse probability of treatment weighting using the propensity score was used to adjust for baseline differences between the pacemaker and nonpacemaker groups. <h3>Exposures</h3> Patients received a permanent pacemaker during the index hospitalization after transcatheter aortic valve replacement. <h3>Main Outcomes and Measures</h3> All-cause mortality, readmission, readmission for heart failure, emergency department visits, and cumulative 1-year health care costs. <h3>Results</h3> The study cohort consisted of 1263 patients (mean [SD] age, 82.3 [7.2] years; 595 [47.1%] female; 137 [10.8%] rural), of whom 186 (14.7%) required permanent pacemaker insertion during the index hospitalization after transcatheter aortic valve replacement. Mean follow-up was 990 days. After propensity score weighting, over the entire follow-up period, pacemaker implantation was associated with significantly higher all-cause mortality (43.9% vs 31.7%; hazard ratio [HR], 1.40; 95% CI, 1.01-1.94;<i>P</i> = .04), all-cause readmission (80.9% vs 70.6%; HR, 1.28; 95% CI, 1.15-1.43;<i>P</i> &lt; .001), and emergency department visits (95.5% vs 87.3%; HR, 1.28; 95% CI, 1.08-1.52;<i>P</i> = .004). Pacemaker implantation was also associated with significantly greater readmission for heart failure (33.9% vs 19.1%; HR, 1.90; 95% CI, 1.53-2.36;<i>P</i> &lt; .001). There were no statistically significant differences between groups in adjusted cumulative health care costs 1 year after discharge. <h3>Conclusions and Relevance</h3> New permanent pacemaker implantation after transcatheter aortic valve replacement was associated with significantly greater morbidity and mortality at long-term follow-up. However, this did not translate to a difference in cumulative health care costs after hospital discharge.
Adjuvant denosumab in early breast cancer: Disease-free survival analysis of 3,425 postmenopausal patients in the ABCSG-18 trial.
Authors: Michael Gnant, Georg Pfeiler, Guenther G. Steger, Daniel Egle, Richard Greil, Florian Fitzal, Viktor Wette, Marija Balic, Ferdinand Haslbauer, Elisabeth Melbinger-Zeinitzer, Vesna Bjelic-Radisic, Jonas C. S. Bergh, Raimund Jakesz, Christian Marth, Paul Sevelda, Brigitte Mlineritsch, Ruth Exner, Christian Fesl, Sophie Frantal, Christian F. Singer
Journal: Journal of Clinical Oncology (2018)

500 Background: Adjuvant aromatase inhibitors (AI) are standard of care for postmenopausal women with hormone receptor positive (HR+) early stage breast cancer but cause osteoporosis and fractures. ABCSG-18 showed previously that adjuvant denosumab significantly reduces clinical fractures (primary endpoint, HR = 0.5, p < 0.0001, Lancet 2015). Here, we present the impact of adjuvant denosumab on disease-free survival. Patients and Methods: 3,425 postmenopausal patients with early HR+ BC receiving adjuvant AI were recruited in 58 trial centers into this prospective, double-blind, placebo-controlled, phase-III trial. Patients were randomized 1:1 to receive either denosumab 60mg s.c. (N = 1712) or placebo (N = 1713) q6 months during AI therapy. We here present results of ABCSG-18's secondary endpoint disease-free survival (DFS), including relevant subgroup and sensitivity analyses (accounting for cross-over either by censoring or by using a rank preserving structural failure time model). Results: After a median follow-up (FU) of 72 months, 287 events occurred in the placebo group, and 240 in the denosumab group. DFS was significantly improved in the denosumab arm (HR = 0.823, 95% CI 0.69-0.98, Cox p = 0.026*). In the denosumab group, DFS was 89.2% (95% CI 87.6-90.7) at 5 years and 80.6% (78.1-83.1) at 8 years of FU, compared to 87.3%, (85.7-89.0) at 5 years and 77.5% (74.8-80.2) at 8 years for patients who received placebo. Similar results were obtained from sensitivity analyses. No case of osteonecrosis of the jaw (ONJ) was recorded so far, despite proactive adjudication of potential cases by an independent expert panel. One potential atypical femur fracture was seen in the denosumab arm. Conclusion: Adjuvant denosumab improves disease-free survival of HR+ postmenopausal breast cancer patients receiving AI. Based on these results and the previously reported dramatic reduction of fractures, adjuvant denosumab 60mg s.c. q6 months should be offered to postmenopausal HR+ breast cancer patients receiving AI. * descriptive, without controlling for multiplicity. Clinical trial information: EudraCT #: 2005-005275-15.
Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies
Authors: Azad Saei, Marta Palafox, Touati Benoukraf, Nishi Kumari, Patrick William Jaynes, Prasanna Vasudevan Iyengar, Eva Muñoz-Couselo, Paolo Nuciforo, Javier Cortés, Christopher Nötzel, Nesaretnam Barr Kumarakulasinghe, John Lalith Charles Richard, Zul Fazreen Bin Adam Isa, Brendan Pang, Marta Guzman, Zhou Siqin, Henry Yang, Wai Leong Tam, Violeta Serra, Pieter Johan Adam Eichhorn
Journal: The Journal of Experimental Medicine (2018)

RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses being short-lived. This is partially mediated through the loss of negative feedback loops after MAPK inhibition and reactivation of upstream signaling. Here, we demonstrate that the deubiquitinating enzyme USP28 functions through a feedback loop to destabilize RAF family members. Loss of USP28 stabilizes BRAF enhancing downstream MAPK activation and promotes resistance to RAF inhibitor therapy in culture and in vivo models. Importantly, we demonstrate that USP28 is deleted in a proportion of melanoma patients and may act as a biomarker for response to BRAF inhibitor therapy in patients. Furthermore, we identify Rigosertib as a possible therapeutic strategy for USP28-depleted tumors. Our results show that loss of USP28 enhances MAPK activity through the stabilization of RAF family members and is a key factor in BRAF inhibitor resistance.
Validation of U.S. mortality prediction models for hospitalized heart failure in the United Kingdom and Japan
Authors: Toshiyuki Nagai, Varun Sundaram, Ahmad Shoaib, Yasuyuki Shiraishi, Shun Kohsaka, Kieran J. Rothnie, Susan Piper, Theresa A. McDonagh, Suzanna M.C. Hardman, Ayumi Goda, Atsushi Mizuno, Mitsuaki Sawano, Alan S. Rigby, Jennifer K. Quint, Tsutomu Yoshikawa, Andrew L. Clark, Toshihisa Anzai, John G.F. Cleland
Journal: European Journal of Heart Failure (2018)
Association of high microsatellite instability (MSI-H) with a high immunoscore (IS) compared to PD-L1 expression and increased survival in patients (pts) with metastatic colorectal cancer (mCRC) treated with oxaliplatin (Ox) and fluoropyrimidine (FP): A pooled analysis of the AIO KRK 0207 and RO91 trials.
Authors: Stefanie Noepel-Duennebacke, Hendrik Juette, Karsten Schulmann, Ullrich Graeven, Rainer Porschen, Jan Stoehlmacher, Susanna Hegewisch-Becker, Axel Mosig, Dirk Arnold, Anke C. Reinacher-Schick, Andrea Tannapfel
Journal: Journal of Clinical Oncology (2017)

3595 Background: MSI-H is an established prognostic marker in early colon cancer. Moreover, MSI-H, tumor immune cell infiltration and PD-L1 expression are also discussed as potential predictive biomarkers for immunotherapy. However, little is known about the prognostic value of these biomarkers and their association among each other in mCRC. Methods: We analyzed samples from pts. with mCRC uniformly treated with a FP and Ox within two randomized AIO trials (KRK 0207 and RO91). MS status was assessed by immunohistochemistry (IHC) of mismatch repair proteins and subsequent fragment length analysis in case of protein loss or incoherent results. PD-L1 expression was determined by IHC (1% expression threshold). Tumor lymphocytic infiltration (CD8 and CD45RO) was scored according to the immunoscore (IS) concept by Galon et al (J Transl Med 2016). Results: 41/550 cases (7.5%) displayed MSI-H. The mean IS of the total population was 0.57 (SD 0.97), the IS of MSI-H pts. was significantly higher (mean of 2.4; SD 1.4; p≤0.0001). 17 cases were PD-L1 positive (pos.) (3 %), only four of these were MSI-H. MSI-H status was significantly correlated with a higher IS, but not with PD-L1 expression (table 1). There was no difference in median overall survival (mOS) between MSI-H and MS stable (MSS) pts. (mOS MSI-H/MSS: 17.6/22.5 months (mos.), log rank: p=0.85), PD-L1 negative (neg.) and pos. pts. (mOS PD-L1 neg./pos.: 22.1/28.9 mos., log rank: p=0.49) and IS high or low pts. (mOS IS high/low: 21.1/22.1mo., log rank: p=0.25). Conclusions: In contrast to early stage colon cancer, none of these parameters was prognostic in mCRC patients. Panel-sequencing with a total of 35 genes including RAS, BRAF and POL-E on cases with PD-L1 expression, high IS or MSI-H status to further characterize these cases will be reported. Clinical trial information: AIO-R091, AIO-KRK-0207: EudraCT-Nr: 2008-007974-39. [Table: see text]
Prospective phase II multicenter trial of ablation after breast lumpectomy added to treat (ABLATE) breast cancer without radiation.
Authors: V. Suzanne Klimberg, Kristalyn Gallagher, Sheldon M. Feldman, Jeanette Y. Lee, Daniela A Ochoa, Joshua Matthew Varghise Mammen, Ronda S. Henry-Tillman, Tom Frazier, Marilee McGinness, Julie Barone, Robert M. Barone, Soheila Korourian
Journal: Journal of Clinical Oncology (2018)

562 Background: Background:A plethora of studies have failed to define a group of patients that can forgo radiation to complete BCS without a significant increase in recurrence rate. This has resulted in overtreatment with radiation of an estimated 85% of patients with favorable breast cancers. RFA added to standard BCS (eRFA) may not only reduce the need for re-excision for close or focally positive margins but may obviate the need for whole breast irradiation in favorable breast cancer patients. Methods: In an IRB-approved risk-adjusted protocol, 267 T0-2, No breast cancer patients from 7 different sites were screened for a Phase II multicenter protocol of BCS followed by cavitary RFA (eRFA) without adjuvant radiation and followed for margins, recurrence, breast pain, cosmesis and QOL. Results: 242 patients were accrued to the study with a median follow-up of 36 months. Re-excision for positive margins was < 5%. The in breast recurrence rate was 2.5%. In this risk adjusted model XRT was added when SLNB was positive. 20% of cohort received XRT. Breast pain @ 6 months was 19% with RFA+XRT Versus 1.7% with RFA alone(p < 0.05). Cosmesis was good or excellent in > 90% of patients. QOL did not change after eRFA. Conclusions: eRFA may be a new paradigm for treating favorable patients that desire lumpectomy who either cannot or do not want radiation. A majority of the patients avoided re-excision, WBI and/or mastectomy. Treatment in lieu of XRT is safe and effective and may increase definitive treatment compliance for patients as it is complete at the time of surgery. Clinical trial information: 01153035.
Influence of CYP2D6 polymorphism in the outcome of breast cancer patients undergoing tamoxifen adjuvant treatment.
Authors: Isabel Blancas, Carols Jose Rodriguez Gonzalez, Antonio Jesús Muñoz-Serrano, María Teresa Delgado, Marta Legerén, Beatriz Gonzalez Astorga, Jose Miguel Jurado, Marisol Yélamos, Silvia Sequero, Fernando Rodríguez-Serrano
Journal: Journal of Clinical Oncology (2018)

e12521 Background: CYP2D6 is the enzyme responsible for the conversion of Tamoxifen (T) to its active metabolites. Genetic polymorphisms of the CYP2D6 gene have been reported as the main cause of variation in the metabolism of T, in fact CYP2D6 gene has more than 100 different allele forms that cover a wide range of activity from ultrarapid to poor metabolizer. Methods: CYP2D6 polymorphism were tested in 87 breast cancer patients undergoing T therapy in the adjuvant setting. We used the activity score system (AS) to translate CYP2D6 genotype into a quantitative measure of phenotype. For each patient, AS value was established as the sum of the value assigned to each allele, 0 (*4, *5), 0.5 (*9, *10, *17, *41), 1 (*1, *2, *35) or 2 (*1xN, *2xN). According to AS value we divided the patients in two groups: Slow Metabolizers (SM) (AS < 1.5) (40.2% of the patients) and Rapid Metabolizer (RM) (AS≥1.5) (59.8% of the patients). We evaluated disease free survival (DFS) and Overall Survival (OS) in both groups. Results: Most frequent genotypes were extensive metabolizers (79.3%) followed by intermediate (12.6%), poor (5.7%) and ultra-rapid metabolizers (2.3%), and more that 70% allele frequency corresponded to *1 (32.8%), *2 (21.3%) and *4 (20.1%) polymorphisms. With a median follow up of 74.9 months (m) (range 8.0-80.0m) the DFS was 75.5m [95% Confidence Interval (CI) 72.6; 78.5] and the OS was 78.4m (95% CI 76.5; 80.3). The DFS of SM was 71.3m (95% CI 64.8; 77.9) vs of RM that was 78.3m (95% CI 76.3-80.4) (p = 0.037). OS of SM was 76.7m (95% CI 72.3; 81.1) vs of RM that was 79.5m (95% CI 78.5; 80.5) (p = ns). Conclusions: Patients classified as SM according to CYP2D6 polymorphism presented a significant lower DFS during T treatment with respect to RM patients. There were found no differences in OS. These results support the hypothesis that SM patients may do not get the same benefit of T treatment as RM patients. Probably, difference in OS was not observed because after disease relapse, T treatment was interrupted in most cases, and replaced by other treatments.
Clinical trial design and dissemination: comprehensive analysis of clinicaltrials.gov and PubMed data since 2005
Authors: Magdalena Zwierzyna, Mark Davies, Aroon D Hingorani, Jackie Hunter
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To investigate the distribution, design characteristics, and dissemination of clinical trials by funding organisation and medical specialty. <h3>Design</h3> Cross sectional descriptive analysis. <h3>Data sources</h3> Trial protocol information from clinicaltrials.gov, metadata of journal articles in which trial results were published (PubMed), and quality metrics of associated journals from SCImago Journal and Country Rank database. <h3>Selection criteria</h3> All 45 620 clinical trials evaluating small molecule therapeutics, biological drugs, adjuvants, and vaccines, completed after January 2006 and before July 2015, including randomised controlled trials and non-randomised studies across all clinical phases. <h3>Results</h3> Industry was more likely than non-profit funders to fund large international randomised controlled trials, although methodological differences have been decreasing with time. Among 27 835 completed efficacy trials (phase II-IV), 15 084 (54.2%) had disclosed their findings publicly. Industry was more likely than non-profit trial funders to disseminate trial results (59.3% (10 444/17 627) <i>v</i> 45.3% (4555/10 066)), and large drug companies had higher disclosure rates than small ones (66.7% (7681/11 508) <i>v</i> 45.2% (2763/6119)). Trials funded by the National Institutes of Health (NIH) were disseminated more often than those of other non-profit institutions (60.0% (1451/2417) <i>v</i> 40.6% (3104/7649)). Results of studies funded by large drug companies and NIH were more likely to appear on clinicaltrials.gov than were those from non-profit funders, which were published mainly as journal articles. Trials reporting the use of randomisation were more likely than non-randomised studies to be published in a journal article (6895/19 711 (34.9%) <i>v</i> 1408/7748 (18.2%)), and journal publication rates varied across disease areas, ranging from 42% for autoimmune diseases to 20% for oncology. <h3>Conclusions</h3> Trial design and dissemination of results vary substantially depending on the type and size of funding institution as well as the disease area under study.
Primary spinal cord glioblastoma: A systematic review.
Authors: Ashmeet Bhatia, Qijing Zhang, Edwin Lok, Eric T. Wong
Journal: Journal of Clinical Oncology (2014)

e13035 Background: Primary spinal cord glioblastoma (PSCG) is rare, accounting for only 1.5% of all spinal cord tumors. However, it appears to have an aggressive course and poor prognosis.The objective of this study was to gain a more in depth understanding of the clinical presentation of PSCG and factors that may affect patient survival. Methods: A systematic literature search was conducted within PubMed, covering the years from 1936 to 2013. Search was conducted for case descriptions of PSCG. Inclusion criteria included primary tumor originating in the spinal cord, with specified location and patient demographics. Results: A total of 222 citations were found, out of which 49 met the inclusion criteria and most were in the form of case reports or case series. In the selected citations, there were 64 women and 55 men (n=119). Their median age was 20 (range 0.7 to 88) years. The median overall survival (OS) was 10.0 (95%CI 0.6 to 72.0) months for those with age ≤59 years compared to 1.9 (95%CI 1.0 to 20.0) months for those with age >59 years (P=0.0176). The most commonly affected region was the thoracic spinal cord (n=54) compared to cervical (n=47) and lumbar (n=33) with some having multiple sections involved. Patients who received radiotherapy lived longer than those without, with median survival of 12.0 (95%CI 1.0-72.0) months versus 5.0 (95%CI 0.6 to 16.6) months, respectively (P<0.0001). Patients with PSCG located in the cervical spinal cord had significantly shorter median overall survival than those with PSCG at other sections of the spinal cord, 8.0 (range 1.0 to 34.0) months versus 11.5 (range 0.6 to 72.0) months, respectively (P=0.0383). Out of 63 patients whose data was available, 50 were reported to have metastasis, either in the brain, spine, or outside the central nervous system like the liver or spleen. Conclusions: Older age and involvement of the cervical spinal cord are unfavorable prognostic factors in PSCG. Treatment with radiation therapy is associated with prolonged patient survival. AB and QZ contributed equally.
A Rare Case of Retroperitoneal Follicular Dendritic Cell Sarcoma Identified by 99mTc-HYNIC-TOC SPECT/CT
Authors: Yi Li, Xiaoping Xu, Junyan Xu, Dan Huang
Journal: Clinical Nuclear Medicine (2018)

Abstract Follicular dendritic cell sarcoma is a very rare neoplasm, which is not lymphoma, but originates from a type of immune cells called follicular dendritic cells. We presented a 37-year-old woman who has suffered from obstructive jaundice, weight loss and right upper abdominal pain for 2 months. The contrast CT revealed masses located in the region of pancreatic head and lots of enlarged retroperitoneal lymph nodes, both of which were enhanced on the artery phase of CT images. Meanwhile, 99m Tc-HYNIC-TOC SPECT/CT revealed high activity in the corresponding lesions. After biopsy, the masses were pathologically confirmed as retroperitoneal follicular dendritic cell sarcoma.