tbuckley/cabot-search huggingface dataset:
Abstract P231: The Impact Of Intelligence In Youth On Cardiovascular Diseases Among 54-61 Years Old Americans
Authors: Joana Tome, Logan Cowan
Journal: Circulation (2022)

Introduction: The association between intelligence measured in youth and all cause-mortality has been previously established, where people with lower intelligence had a higher mortality risk. Few studies have looked at the relationship between intelligence and CVD morbidity. Hypothesis: We assessed the hypothesis that higher intelligence in youth is associated with lower odds of CVD adjusting for the social determinants of health. Methods: Our sample population consisted of 9,964 men and women who participated in the National Longitudinal Survey of Youth 1979 and responded to the 2018 survey (round 28). The intelligence was measured when participants were around 15 to 23 years of age using the Armed Forces Qualification Test and was scored as a percentile and z-scored. CVDs were measured as self-reports of a doctor ever diagnosing hypertension, myocardial infarction, angina, congestive heart failure, ischemic stroke, or general heart problems in 54-61 years old Americans. Crude and adjusted for age, sex, ethnicity, highest grade of education completed, and total net family income logistic regression models were used to test the association between intelligence and CVD. Results: Conclusions: In conclusion, the current findings suggest that higher intelligence may be a protective factor against CVD. Previous associations in populations younger than ours were attenuated, suggesting that the relationship may no longer exist when including older Americans. However, identifying the most vulnerable groups as priority areas for reducing CVD morbidities is key to reducing impact and promoting health equity. The data from this study can inform health and social policies, which can help reduce the burden of CVD. Public health efforts that account for variation and contribution of intelligence, as well as social determinants of health, are needed to reduce CVD and its risk factors.
Abstract MP75: Cardiac Biomarkers And Frailty In The Atherosclerosis Risk In Communities (ARIC) Study
Authors: Pablo Martinez-Amezcua, Stephen P Juraschek, Christie M Ballantyne, Daniel E Forman, Kelley P Gabriel, Michael Griswold, Ron C Hoogeveen, Anna Kucharska-newton, Pamela L Lutsey, Kuni Matsushita, Diego Ramonfaur, Elizabeth Selvin, Amil M Shah, B Gwen Windham, Priya Palta
Journal: Circulation (2022)

Introduction: Frailty, an increased vulnerability to stressors, is associated with adverse health outcomes. Cardiovascular disease (CVD) is associated with frailty, but whether circulating cardiac biomarkers of subclinical myocardial injury and strain (e.g., high-sensitivity cardiac troponin T [hs-cTnT] and natriuretic peptide [NT-proBNP]) are associated with frailty is unknown. Methods: We conducted a cross-sectional analysis of levels of hs-cTnT and NT-proBNP assessed among participants of the ARIC study at visit 5 (2011-2013, mean age: 75.5 years, 42% male, 21% Black). We used the Fried frailty phenotype that counts the presence of each component (weight loss, low physical activity, slow gait, exhaustion, and low grip strength) to classify participants as frail (≥3), pre-frail (1-2), or robust (0 components). Participants without prevalent CVD (stroke, myocardial infarction, or heart failure) were classified into hs-cTnT and NT-proBNP quartiles; those with prevalent CVD were considered in a separate group. Using adjusted multinomial logistic regression models, we tested the hypothesis that hs-cTnT and NT-proBNP are positively associated with odds of being pre-frail and frail, vs. robust. Results: Among 5,162 participants, 1,039 had prevalent CVD (20%), 2,447 (48%) were pre-frail, and 358 (7%) frail. Biomarker concentrations had graded associations with frailty and pre-frailty, vs. robust. Estimates comparing the 4 th vs. 1 st quartile, (e.g., hs-cTnT frail vs. robust OR=4.37 [95% CI: 2.69-7.09]) were similar to those observed for prevalent CVD vs. 1 st quartile (e.g., hs-cTnT frail vs. robust OR=5.11 [3.19-8.17]). All frailty components were positively associated with cardiac biomarker concentrations and CVD (Table), except exhaustion with NT-proBNP. Conclusions: Cardiac biomarker concentrations, even in the absence of CVD, may help identify people at greater risk for frailty. Future research should examine the role of changes in biomarkers from mid-life on the risk of frailty
The Role of the TP53 Pathway in Predicting Response to Neoadjuvant Therapy in Esophageal Adenocarcinoma
Authors: Smita Sihag, Samuel C. Nussenzweig, Henry S. Walch, Meier Hsu, Kay See Tan, Sergio De La Torre, Yelena Y. Janjigian, Steven B. Maron, Geoffrey Y. Ku, Laura H. Tang, Pari M. Shah, Abraham Wu, David R. Jones, David B. Solit, Nikolaus Schultz, Karuna Ganesh, Michael F. Berger, Daniela Molena
Journal: Clinical Cancer Research (2022)

In patients with locally advanced esophageal adenocarcinoma, response to neoadjuvant therapy strongly predicts survival, but robust molecular predictors of response have been lacking. We therefore sought to discover meaningful predictors of response in these patients.We retrospectively identified all patients with adenocarcinoma of the lower esophagus or gastroesophageal junction who (i) were treated with multimodality therapy with curative intent at our institution from 2014 through 2020 and (ii) underwent prospective sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. Clinicopathologic and genomic data were analyzed to identify potential genomic features, somatic alterations, and oncogenic pathways associated with treatment response.In total, 237 patients were included. MDM2 amplification was independently associated with poor response to neoadjuvant therapy [OR, 0.10 (95% confidence interval, 0.01-0.55); P = 0.032], when accounting for significant clinicopathologic variables, including clinical stage, tumor grade, and chemotherapy regimen. Moreover, TP53 pathway alterations, grouped according to inferred severity of TP53 dysfunction, were significantly associated with response to neoadjuvant therapy (P = 0.004, q = 0.07). Patients with MDM2 amplifications or truncating biallelic TP53 mutations had similar outcomes in terms of poor responses to neoadjuvant therapy and, consequently, shorter progression-free survival, compared with patients with TP53 pathway wild-type tumors. Thus, worsening TP53 dysfunction was directly correlated with worse outcomes.MDM2 amplification and TP53 status are associated with response to therapy in patients with esophageal adenocarcinoma. Given the dearth of actionable targets in esophageal adenocarcinoma, MDM2 inhibition, in combination with cytotoxic chemotherapy, may represent an important therapeutic strategy to overcome treatment resistance and improve outcomes in these patients.
Four Patterns of Abnormal Ring-Like Uptakes on Dedicated Breast PET
Authors: Shinsuke Sasada, Azusa Kai, Yuri Kimura, Norio Masumoto, Takayuki Kadoya
Journal: Clinical Nuclear Medicine (2021)

Abstract The high resolution of dedicated breast PET (dbPET) enables the visualization of small breast cancers and a heterogeneity of breast tumors. Some tumors present with a ring-like appearance, the central uptake defect possibly reflecting intratumoral fibrosis and necrosis, associated with high-grade malignancy, and a triple-negative subtype. However, a ring-like finding is not only found in high-grade breast cancers. We describe 4 representative patterns of ring-like uptakes on dbPET: high-grade invasive cancer, intracystic tumor, extended noninvasive carcinoma, and change after vacuum-assisted breast biopsy. Ring-like uptakes on dbPET should be evaluated in association with clinical information.
First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl
Authors: Jae H Park, Eric S. Winer, Scott F. Huntington, Gottfried von Keudell, Shreya Vemuri, Madhulika Shukla, Julie C Kinoshita, Victoria Falco, Steven D. Gore, Richard M. Stone, Omar Abdel-Wahab, Martin S. Tallman
Journal: Blood (2021)
Abstract MP26: Replacing Sedentary Behavior Time With Various Daily-life Physical Activities And Structured Exercises, Recommended Physical Activity, And Incident Coronary Heart Disease
Authors: Xiang Li, Hao Ma, Tao Zhou, Lu Qi
Journal: Circulation (2022)

Introduction: While excessive sedentary behavior time has been associated with cardiovascular diseases, it is largely unknown to what extend substituting sedentary behaviors with various physical activities may offset the risk of coronary heart disease (CHD). Hypothesis: We hypothesize that reallocating time from sedentary behavior to various daily-life physical activities and structured exercises might be associated with lower risk of CHD. We particularly examined such reallocations according to whether or not the participants meet the recommended physical activity level. Method: A total of 468,960 UK Biobank participants free of CHD were included. Sedentary behavior time was quantified by summing up the time spent on television watching, computer use (not at work), and driving. Physical activities were categorized as daily-life activities (walking for pleasure, light DIY, and heavy DIY) and structured exercise (strenuous sports and other exercises). We used iso-temporal substitution model to estimate the effect of replacing sedentary behavior with each type of physical activity for the same amount of time. Results: During a median follow-up of 11 years, 7,982 incident CHD cases were documented. Sedentary behavior time was significantly associated with a higher risk of CHD, independent of physical activity. In comparison of the extreme categories (≥6 vs. &lt;2 h/d), the HR for CHD was 1.31 (95% CI: 1.18-1.46). Replacing 30 minutes of sedentary behavior per day with an equal time of various physical activities was significantly associated with a 3%-12% risk reduction of CHD. Replacing 1 hour of sedentary behaviors with different types of physical activities was associated with a 6%-23% risk reduction of CHD. Sedentary behavior-to-strenuous sports reallocations showed the largest reduction in CHD risk when replacing sedentary behavior. Moreover, reallocations of sedentary behavior to various physical activities showed particularly greater benefits among those who did not meet the physical activity recommendations. Conclusion: Our study indicates that replacing sedentary behavior time with various daily-life activities or structured exercise was associated with significant reductions in CHD risk.
<i>Smarca4</i> Inactivation Promotes Lineage-Specific Transformation and Early Metastatic Features in the Lung
Authors: Carla P. Concepcion, Sai Ma, Lindsay M. LaFave, Arjun Bhutkar, Manyuan Liu, Lydia P. DeAngelo, Jonathan Y. Kim, Isabella Del Priore, Adam J. Schoenfeld, Manon Miller, Vinay K. Kartha, Peter M.K. Westcott, Francisco J. Sánchez-Rivera, Kevin Meli, Manav Gupta, Roderick T. Bronson, Gregory J. Riely, Natasha Rekhtman, Charles M. Rudin, Carla F. Kim, Aviv Regev, Jason D. Buenrostro, Tyler Jacks
Journal: Cancer Discovery (2021)

Abstract SMARCA4/BRG1 encodes for one of two mutually exclusive ATPases present in mammalian SWI/SNF chromatin remodeling complexes and is frequently mutated in human lung adenocarcinoma. However, the functional consequences of SMARCA4 mutation on tumor initiation, progression, and chromatin regulation in lung cancer remain poorly understood. Here, we demonstrate that loss of Smarca4 sensitizes club cell secretory protein–positive cells within the lung in a cell type–dependent fashion to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient primary tumors lack lung lineage transcription factor activities and resemble a metastatic cell state. Mechanistically, we show that Smarca4 loss impairs the function of all three classes of SWI/SNF complexes, resulting in decreased chromatin accessibility at lung lineage motifs and ultimately accelerating tumor progression. Thus, we propose that the SWI/SNF complex via Smarca4 acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution. Significance: We demonstrate cell-type specificity in the tumor-suppressive functions of SMARCA4 in the lung, pointing toward a critical role of the cell-of-origin in driving SWI/SNF-mutant lung adenocarcinoma. We further show the direct effects of SMARCA4 loss on SWI/SNF function and chromatin regulation that cause aggressive malignancy during lung cancer evolution. This article is highlighted in the In This Issue feature, p. 275
Colon Transit Scintigraphy in Schaaf-Yang Syndrome
Authors: Jose R. Infante, Alvaro Baena, Andres Martinez, Juan I. Rayo, Justo Serrano
Journal: Clinical Nuclear Medicine (2021)

Abstract Schaaf-Yang syndrome is a genetic disorder characterized by delayed psychomotor development, hypotonia, intellectual disability, feeding difficulties, and variable dysmorphic facial features. It is an extremely rare disorder with over 250 cases reported in the medical literature. This condition has been determined to be inherited by an autosomal dominant pattern. We present colon transit scintigraphy of a 6-year-old boy with history of chronic constipation with poor response to medical treatment, clinical characteristics, and gene mutations consistent with this syndrome. After oral administration of 111 In-DTPA, planar and SPECT/CT images showed rapid proximal colonic transit and anorectal retention.
A contemporary simple risk score for prediction of contrast-associated acute kidney injury after percutaneous coronary intervention: derivation and validation from an observational registry
Authors: Roxana Mehran, Ruth Owen, Mauro Chiarito, Usman Baber, Samantha Sartori, Davide Cao, Johny Nicolas, Carlo Andrea Pivato, Matteo Nardin, Prakash Krishnan, Annapoorna Kini, Samin Sharma, Stuart Pocock, George Dangas
Journal: The Lancet (2021)
NCD Countdown 2030: efficient pathways and strategic investments to accelerate progress towards the Sustainable Development Goal target 3.4 in low-income and middle-income countries
Authors: David A Watkins, William T Msemburi, Sarah J Pickersgill, Yoshito Kawakatsu, Adrian Gheorghe, Katie Dain, Kjell Arne Johansson, Sanaa Said, Nina Renshaw, Mieraf T Tolla, Pakwanja D Twea, Cherian Varghese, Kalipso Chalkidou, Majid Ezzati, Ole Frithjof Norheim
Journal: The Lancet (2022)
Combination of Trastuzumab, Pertuzumab, and Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer Harboring <i>HER2</i> Mutations: Results From the IFCT-1703 R2D2 Trial
Authors: Julien Mazieres, Claire Lafitte, Charles Ricordel, Laurent Greillier, Elodie Negre, Gérard Zalcman, Charlotte Domblides, Jeannick Madelaine, Jaafar Bennouna, Céline Mascaux, Denis Moro-Sibilot, François Pinquie, Alexis B. Cortot, Josiane Otto, Jacques Cadranel, Alexandra Langlais, Franck Morin, Virginie Westeel, Benjamin Besse
Journal: Journal of Clinical Oncology (2022)

HER2 exon 20 insertions and point mutations are oncogenic drivers found in 1%-2% of patients with non-small-cell lung cancer (NSCLC). No targeted therapy is approved for this subset of patients. We prospectively evaluated the effectiveness of the combination of two antibodies against human epidermal growth factor 2 (HER2 [HER2] trastuzumab and pertuzumab with docetaxel; trastuzumab and pertuzumab) and docetaxel.The IFCT 1703-R2D2 trial is a multicenter, nonrandomized phase II study. Patients with HER2-mutated, advanced NSCLC who progressed after ≥ 1 platinum-based treatment were enrolled. Patients received pertuzumab at a loading dose of 840 mg and 420 mg thereafter; trastuzumab at an 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at a dose of 75 mg/m2 every 3 weeks. The primary outcome was the objective response rate (ORR). Other end points included the duration of response, progression-free survival, and safety (NCT03845270).Forty-five patients were enrolled and treated. The median age was 64.5 years (range, 31-84 years), 35% were smokers, 72% were females, 15% had an Eastern Cooperative Oncology Group performance status of 2, and 30% had brain metastases. The objective response rate was 29% (n = 13), and 58% had stable disease (n = 26). The median progression-free survival was 6.8 months (95% CI, 4.0 to 8.5). The median duration of response in patients with a confirmed response (n = 13) was 11 months (95% CI, 2.9 to 14.9). Grade 3/4 treatment-related adverse events were observed in 64% of the patients. No patient discontinued treatment because of toxicity. The most frequent grade ≥ 3 treatment-related adverse events were neutropenia (33%), diarrhea (13%), and anemia (9%).Triple therapy with trastuzumab, pertuzumab, and docetaxel is feasible and effective for HER2-mutated pretreated advanced NSCLC. These results highlight the effectiveness of the HER2 antibody-based strategy, which should be considered for these patients.
Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14)
Authors: Nizar J. Bahlis, Rachid Baz, Simon J. Harrison, Hang Quach, Shir-Jing Ho, Annette Juul Vangsted, Torben Plesner, Philippe Moreau, Simon D. Gibbs, Sheryl Coppola, Xiaoqing Yang, Abdullah Al Masud, Jeremy A. Ross, Orlando Bueno, Jonathan L. Kaufman
Journal: Journal of Clinical Oncology (2021)

PURPOSE Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab. METHODS This phase I study ( NCT03314181 ) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity. RESULTS Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd. CONCLUSION VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).
Adjuvant Osimertinib in EGFR-Mutant Early-Stage NSCLC: Does HRQoL Influence Decisions?
Authors: Tejas Patil, Paul A. Bunn
Journal: Clinical Cancer Research (2022)

Summary The ADAURA adjuvant randomized trial demonstrated that osimertinib prolonged DFS. It has now been reported that health-related quality of life (HRQoL) was not adversely affected by adjuvant osimertinib. Does this mean that adjuvant osimertinib should now be standard as we await survival results? See related article by Majem et al., p. 2286
The Impact of Alcohol and Other Substance Use Disorders on Mortality in Patients With Eating Disorders: A Nationwide Register-Based Retrospective Cohort Study
Authors: Angelina Isabella Mellentin, Anna Mejldal, Maria Mercedes Guala, René Klinkby Støving, Lene Stryhn Eriksen, Elsebeth Stenager, Lotte Skøt
Journal: American Journal of Psychiatry (2022)

Objective: Research is lacking on the contribution of different types of substance use disorders (SUDs) to excess mortality across the full spectrum of eating disorders. The authors assessed the association of alcohol use disorders and other SUDs with mortality in anorexia nervosa, bulimia nervosa, and unspecified eating disorder compared with matched control subjects. Methods: A retrospective cohort study was conducted using Danish nationwide registers. The study included 20,759 patients with eating disorders and 83,036 matched control subjects. Hazard ratios were calculated to compare all-cause mortality risk between eating disorder patients and control subjects both with and without a lifetime SUD diagnosis (abuse or dependence of alcohol, cannabis, or hard drugs). Results: For patients with each type of eating disorder, a higher risk of all-cause mortality was observed relative to control subjects without SUDs among those who abused alcohol and/or cannabis (adjusted hazard ratios for the anorexia nervosa, bulimia nervosa, and unspecified eating disorder patients, respectively, were 11.28 [95% CI=7.01, 18.16], 5.86 [95% CI=3.37, 10.1], and 10.86 [95% CI=6.74, 17.50]), or hard drugs alone or in combination with alcohol and/or cannabis (adjusted hazard ratios, respectively, were 22.34 [95% CI=15.13, 33.00], 11.43 [95% CI=7.14, 18.28], and 15.53 [95% CI=10.15, 23.78]), than in those without SUDs (adjusted hazard ratios, respectively, were 3.21 [95% CI=2.43, 4.23], 1.24 [95% CI=0.88, 1.77], and 4.75 [95% CI=3.57, 6.31]). Control subjects with SUDs also exhibited an elevated risk of all-cause mortality relative to control subjects without SUDs, although to a much lesser extent than eating disorder patients with SUDs. Conclusions: SUDs have an additive effect on excess mortality in patients with eating disorders. The prevention and treatment of SUDs in this patient group is thus imperative to reduce mortality.