tbuckley/cabot-search huggingface dataset:
Abstract 11030: Impact of the New Heart Allocation Policy on Access to Heart Transplantation
Authors: Jessica R Golbus, Weijing Tang, Jinming Li, Kashvi Gupta, Mary N Walsh, Ji Zhu, Monica M Colvin, Brahmajee K Nallamothu
Journal: Circulation (2021)

Introduction: In 2018, a new heart allocation policy was implemented to promote uniform access to transplantation by mandating sharing of donor hearts over larger geographic areas rather than by location within a given Donation Service Area (DSA). The long-term impact of this policy on sharing across DSAs is unknown. Methods: Using data from the Scientific Registry of Transplant Recipients, we assessed the association between the new policy and organ sharing at the level of each DSA. We included adult, single-organ heart transplants performed in the mainland US between Oct 1, 2015 and Dec 31, 2020. For each DSA, we evaluated the proportion of donor hearts imported from another DSA, the proportion exported, and their log-transformed ratio (sharing ratio). We performed multivariable regression with heteroscedasticity to evaluate the association between policy period and sharing ratio, adjusting for deaths per DSA population, household income and urbanicity. Results: The new policy was associated with increased importation and exportation of donor hearts across DSAs (Figure). The mean import proportion increased from 0.31 (95% CI: 0.27 to 0.36) to 0.74 (95% CI: 0.71 to 0.78) and the mean export proportion from 0.36 (95% CI: 0.31 to 0.40) to 0.75 (95% CI: 0.71 to 0.79) after the policy change. In addition, the mean sharing ratio of import:export shifted from 1.22 (95% CI: 0.91 to 1.53) to 1.01 (95% CI: 0.96 to 1.07) suggesting more balance across DSAs. The variance of the log-transformed sharing ratio was negatively associated with the new policy (β = -1.55; 95% CI, -1.82 to -1.27; P &lt; .001), indicating a 79% drop in the variation of the sharing ratio and more uniform access. Deaths per DSA population was associated with the log-transformed sharing ratio while household income and urbanicity were not. Conclusion: The new policy is associated with more balanced sharing of hearts. The broader impact on waitlist survival and post-transplant outcomes remains unknown.
Interobserver Agreement Rates on Fibroblast Activation Protein Inhibitor–Directed Molecular Imaging and Therapy
Authors: Sebastian E. Serfling, Philipp E. Hartrampf, Yingjun Zhi, Takahiro Higuchi, Steven P. Rowe, Lena Bundschuh, Markus Essler, Andreas K. Buck, Ralph Alexander Bundschuh, Rudolf A. Werner
Journal: Clinical Nuclear Medicine (2022)

Fibroblast activation protein (FAP) has emerged as a novel target for FAP inhibitor (FAPI)-directed molecular imaging and endoradiotherapy (ERT). We aimed to assess the interobserver agreement rates for interpretation of 68Ga-FAPI-4 PET/CT and decision for ERT.A random order of 68Ga-FAPI-4 PET/CTs from 49 oncology patients were independently interpreted by 4 blinded readers. Per scan, visual assessment was performed, including overall scan impression, number of organ/lymph node (LN) metastases, and number of affected organs/LN regions. Moreover, a maximum of 3 target lesions, defined as largest in size and/or most intense, per organ compartment were identified, which allowed for an additional quantitative interobserver assessment of LN and organ lesions. To investigate potential reference tissues, quantification also included unaffected liver parenchyma and blood pool. Readers also had to indicate whether FAPI-directed ERT should be considered (based on intensity of uptake and widespread disease). Interobserver agreement rates were evaluated using intraclass correlation coefficients (ICCs) and interpreted according to Cicchetti (with 0.4-0.59 indicating fair, and 0.6-0.74 good, agreement).On a visual basis, the agreement rate for an overall scan impression was fair (ICC, 0.42; 95% confidence interval [CI], 0.27-0.57). The concordance rate for number of affected LN areas was also fair (ICC, 0.59; 95% CI, 0.45-0.72), whereas the number of LN metastases, number of affected organs, and number of organ metastases achieved good agreement rates (ICC, ≥0.63). In a quantitative analysis, concordance rates for LN were good (ICC, 0.70; 0.48-0.88), but only fair for organ lesions (ICC, 0.43; 0.26-0.60). In regards to background tissues, ICCs were good for unaffected liver parenchyma (0.68; 0.54-0.79) and fair for blood pool (0.43; 0.29-0.58). When readers should decide on ERT, concordance rates were also fair (ICC, 0.59; 95% CI, 0.46-0.73).For FAPI-directed molecular imaging and therapy, a fair to good interobserver agreement rate was achieved, supporting the adoption of this radiotracer for clinical routine and multicenter trials.
Modulation of the Human Pancreatic Ductal Adenocarcinoma Immune Microenvironment by Stereotactic Body Radiotherapy
Authors: Bradley N. Mills, Haoming Qiu, Michael G. Drage, Chunmo Chen, Jocelyn S. Mathew, Jesse Garrett-Larsen, Jian Ye, Taylor P. Uccello, Joseph D. Murphy, Brian A. Belt, Edith M. Lord, Alan W. Katz, David C. Linehan, Scott A. Gerber
Journal: Clinical Cancer Research (2021)

Stereotactic body radiotherapy (SBRT) is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC), which can effectively prime cytotoxic T cells by inducing immunogenic tumor cell death in preclinical models. SBRT effects on human PDAC have yet to be thoroughly investigated; therefore, this study aimed to characterize immunomodulation in the human PDAC tumor microenvironment following therapy.Tumor samples were obtained from patients with resectable PDAC. Radiotherapy was delivered a median of 7 days prior to surgical resection, and sections were analyzed by multiplex IHC (mIHC), RNA sequencing, and T-cell receptor sequencing (TCR-seq).Analysis of SBRT-treated tumor tissue indicated reduced tumor cell density and increased immunogenic cell death relative to untreated controls. Radiotherapy promoted collagen deposition; however, vasculature was unaffected and spatial analyses lacked evidence of T-cell sequestration. Conversely, SBRT resulted in fewer tertiary lymphoid structures and failed to lessen or reprogram abundant immune suppressor populations. Higher percentages of PD-1+ T cells were observed following SBRT, and a subset of tumors displayed more clonal T-cell repertoires.These findings suggest that SBRT augmentation of antitumor immunogenicity may be dampened by an overabundance of refractory immunosuppressive populations, and support the continued development of SBRT/immunotherapy combination for human PDAC.
IL-9/STAT3/fatty acid oxidation–mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity
Authors: Liuling Xiao, Xingzhe Ma, Lingqun Ye, Pan Su, Wei Xiong, Enguang Bi, Qiang Wang, Miao Xian, Maojie Yang, Jianfei Qian, Qing Yi
Journal: Journal of Clinical Investigation (2022)

CD8+ T cell longevity regulated by metabolic activity plays important roles in cancer immunotherapy. Although in vitro–polarized, transferred IL-9–secreting CD8+ Tc9 (cytotoxic T lymphocyte subset 9) cells exert greater persistence and antitumor efficacy than Tc1 cells, the underlying mechanism remains unclear. Here, we show that tumor-infiltrating Tc9 cells display significantly lower lipid peroxidation than Tc1 cells in several mouse models, which is strongly correlated with their persistence. Using RNA-sequence and functional validation, we found that Tc9 cells exhibited unique lipid metabolic programs. Tc9 cell–derived IL-9 activated STAT3, upregulated fatty acid oxidation and mitochondrial activity, and rendered Tc9 cells with reduced lipid peroxidation and resistance to tumor- or ROS-induced ferroptosis in the tumor microenvironment. IL-9 signaling deficiency, inhibiting STAT3, or fatty acid oxidation increased lipid peroxidation and ferroptosis of Tc9 cells, resulting in impaired longevity and antitumor ability. Similarly, human Tc9 cells also exhibited lower lipid peroxidation than Tc1 cells and tumor-infiltrating CD8+ T cells expressed lower IL9 and higher lipid peroxidation– and ferroptosis-related genes than circulating CD8+ T cells in patients with melanoma. This study indicates that lipid peroxidation regulates Tc9 cell longevity and antitumor effects via the IL-9/STAT3/fatty acid oxidation pathway and regulating T cell lipid peroxidation can be used to enhance T cell–based immunotherapy in human cancer.
Global, regional, and national trends in opioid analgesic consumption from 2015 to 2019: a longitudinal study
Authors: Chengsheng Ju, Li Wei, Kenneth K C Man, Zixuan Wang, Tian-Tian Ma, Adrienne Y L Chan, Ruth Brauer, Celine S L Chui, Esther W Chan, Yogini H Jani, Yingfen Hsia, Ian C K Wong, Wallis C Y Lau
Journal: The Lancet Public Health (2022)

Previous studies have reported an extremely unbalanced global access to opioid analgesics. We aimed to determine contemporary trends and patterns of opioid analgesic consumption at the global, regional, and national levels.We analysed the global pharmaceutical sales data of 66 countries or regions from the IQVIA-Multinational Integrated Data Analysis System database on opioid analgesics between 2015 and 2019. Opioid analgesic consumption was measured in milligram morphine equivalent per 1000 inhabitants per day (MME per 1000/day). The global, regional, and national trend changes were estimated using linear regressions. Factors associated with consumption patterns and trend changes were explored in multivariable linear regression analyses.Overall opioid analgesic sales in the 66 countries or regions increased from 27·52 MME per 1000/day (16·63-45·54) in 2015 to 29·51 MME per 1000/day (17·85-48·79) in 2019 (difference per year 3·96%, 95% CI 0·26 to 7·80). Sales reduced yearly in North America (-12·84%; 95% CI -15·34 to -10·27) and Oceania (-2·96%; -4·20 to -1·70); increased in South America (28·69%; 7·18 to 54·53), eastern Europe (7·68%; 3·99 to 11·49), Asia (5·74%; 0·61 to 11·14), and western and central Europe (1·64%; 0·52 to 2·78); and did not differ in Africa or central America and the Caribbean. The global opioid consumption patterns were associated with country-level Human Development Index (p=0·040), cancer death rate excluding leukaemia (p=0·0072), and geographical location (p<0·0001). In 2019, opioid analgesic consumption ranged from 0·01 MME per 1000/day to 5·40 MME per 1000/day in the 17 countries and regions in the lowest consumption quartile, despite high income levels and cancer death rates in some of them.Global opioid analgesic consumption increased from 2015 to 2019. The trend changes were distinctive across regions, which could reflect the different actions in response to known issues of opioid use and misuse. Disparities in opioid analgesic consumption remained, indicating potential inadequate access to essential pain relief in countries with low consumption.None.
Quality and Safety in Healthcare, Part XCIV
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2022)

For existing goods or services, Six Sigma uses the steps of DMAIC and the statistical analysis of data to decrease variation and errors, improve the value of an organization's outputs to the customers, and increase the profitability of the organization. In health care, in view of the training required and other issues, Six Sigma is best used for large complex problems, although it has also been applied successfully to smaller issues. Many examples of the use of Six Sigma and Lean Six Sigma in health care are reviewed.
A Randomized Phase II Study of Anti-CSF1 Monoclonal Antibody Lacnotuzumab (MCS110) Combined with Gemcitabine and Carboplatin in Advanced Triple-Negative Breast Cancer
Authors: Sherko Kuemmel, Mario Campone, Delphine Loirat, Rafael Lopez Lopez, J. Thaddeus Beck, Michelino De Laurentiis, Seock-Ah Im, Sung-Bae Kim, Ava Kwong, Guenther G. Steger, Esther Zamora Adelantado, Francois P. Duhoux, Richard Greil, Irene Kuter, Yen-Shen Lu, Ariadna Tibau, Mustafa Özgüroğlu, Christian W. Scholz, Christian F. Singer, Estela Vega, Pauline Wimberger, Claudio Zamagni, Xuan-Mai Couillebault, Liqiong Fan, Nelson Guerreiro, Jennifer Mataraza, Janna Sand-Dejmek, Arlene Chan
Journal: Clinical Cancer Research (2021)

This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC).Female patients with advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m2) and carboplatin (dose in mg calculated by area under the curve [mg/mL/min] × (glomerular filtration rate [mL/min] + 25 [mL/min]) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient.Patients received lacnotuzumab + gem-carbo (n = 34) or gem-carbo (n = 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months [90% confidence interval (CI), 4.47-8.64] in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45-7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand.Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1-CSF1 receptor pathway in TNBC.
Clinical relevance of adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma who underwent surgery following neoadjuvant modified FOLFIRINOX
Authors: So Heun Lee, Changhoon Yoo, Sora Kang, Heung-Moon Chang, Jae Ho Jeong, Kyu-pyo Kim, Baek-Yeol Ryoo
Journal: International Journal of Surgery (2022)
Abstract EP51: Trends, Predictors And Outcomes Of Cardiovascular Complications Associated With Polycystic Ovary Syndrome During Delivery Hospitalizations-A United States National Database Analysis (2002-2019)
Authors: Salman Zahid, Muhammad Z Khan, Smitha Narayana Gowda, Nadeen N. Faza, Michael Honigberg, Arthur J Vaught, Carolyn Guan, Anum A Minhas, Erin Michos
Journal: Circulation (2022)

Background: Women with polycystic ovary syndrome (PCOS) have increased risk of pregnancy-associated complications. However, there is scarcity of data on the trends, outcomes, and predictors of cardiovascular (CV) complications associated with PCOS diagnosis during delivery hospitalizations in the United States. Methods and Results: We used data from the National Inpatient Sample. ICD-9 or ICD-10 codes were used to identify delivery hospitalizations and PCOS diagnosis. A total of 71,436,308 weighted US hospitalizations for deliveries were identified from 2002 to 2019. Of the included hospitalizations, 0.3% were among women with PCOS (n=195,675). PCOS women were older (mean 30 vs 28 years, p&lt;0.01) and had higher prevalence of diabetes, obesity, and dyslipidemia. After adjustment for age, race/ethnicity, comorbidities, insurance status and median household income, PCOS remained an independent predictor of CV complications at delivery including preeclampsia (aOR 1.56, 95% CI 1.54-1.59, p&lt;0.01), eclampsia (aOR 1.58, 95% CI 1.54-1.59, p&lt;0.01), peripartum cardiomyopathy (aOR 1.79, 95% CI 1.49-2.13, p&lt;0.01), and heart failure (aOR 1.76, 95% CI 1.27-2.45, p&lt;0.01) (Figure, Panel A), compared to no PCOS. An increase in overall prevalence of PCOS, and of obesity among those with PCOS, was also observed during the study period (Figure, Panel B). Moreover, delivery hospitalizations with PCOS diagnosis were associated with increased length (3 vs 2 days, p&lt;0.01) and cost of hospitalization ($6,310 vs $4,468, p&lt;0.01). Conclusions: Over a 17-year period, prevalence of PCOS and obesity increased among childbearing U.S. women. Women with PCOS had higher risks of preeclampsia/eclampsia, peripartum cardiomyopathy, heart failure, pulmonary edema, and venous thromboembolism. Moreover, delivery hospitalizations with PCOS diagnosis were associated with increased length and cost of hospitalization. Strategies to optimize pre-pregnancy cardiometabolic health may be particularly important to improve maternal CV outcomes.
THE EFFECT OF POPULATION SCREENING FOR ATRIAL FIBRILLATION ON CLINICAL OUTCOMES: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
Authors: Satyam Krishan, Muhammad Faraz Anwaar, Khawaja Hassan Akhtar, Siddharth Agarwal, Shari Clifton, Jessica Reese, Abhishek Deshmukh, Zain Ul Abideen Asad
Journal: Journal of the American College of Cardiology (2022)
Novel CaMKII-δ Inhibitor Hesperadin Exerts Dual Functions to Ameliorate Cardiac Ischemia/Reperfusion Injury and Inhibit Tumor Growth
Authors: Junxia Zhang, Ruqi Liang, Kai Wang, Wenjia Zhang, Mao Zhang, Li Jin, Peng Xie, Wen Zheng, Haibao Shang, Qingmei Hu, Jiayi Li, Gengjia Chen, Fujian Wu, Feng Lan, Lipeng Wang, Shi-Qiang Wang, Yongfeng Li, Yong Zhang, Jinghao Liu, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao, Xiaoguang Lei, Yan Zhang
Journal: Circulation (2022)

Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease, the leading cause of morbidity and mortality worldwide. At present, there is no effective therapy for reducing cardiac I/R injury. CaMKII (Ca2+/calmodulin-dependent kinase II) plays a pivotal role in the pathogenesis of severe heart conditions, including I/R injury. Pharmacological inhibition of CaMKII is an important strategy in the protection against myocardial damage and cardiac diseases. To date, there is no drug targeting CaMKII for the clinical therapy of heart disease. Furthermore, at present, there is no selective inhibitor of CaMKII-δ, the major CaMKII isoform in the heart.A small-molecule kinase inhibitor library and a high-throughput screening system for the kinase activity assay of CaMKII-δ9 (the most abundant CaMKII-δ splice variant in human heart) were used to screen for CaMKII-δ inhibitors. Using cultured neonatal rat ventricular myocytes, human embryonic stem cell-derived cardiomyocytes, and in vivo mouse models, in conjunction with myocardial injury induced by I/R (or hypoxia/reoxygenation) and CaMKII-δ9 overexpression, we sought to investigate the protection of hesperadin against cardiomyocyte death and cardiac diseases. BALB/c nude mice with xenografted tumors of human cancer cells were used to evaluate the in vivo antitumor effect of hesperadin.Based on the small-molecule kinase inhibitor library and screening system, we found that hesperadin, an Aurora B kinase inhibitor with antitumor activity in vitro, directly bound to CaMKII-δ and specifically blocked its activation in an ATP-competitive manner. Hesperadin functionally ameliorated both I/R- and overexpressed CaMKII-δ9-induced cardiomyocyte death, myocardial damage, and heart failure in both rodents and human embryonic stem cell-derived cardiomyocytes. In addition, in an in vivo BALB/c nude mouse model with xenografted tumors of human cancer cells, hesperadin delayed tumor growth without inducing cardiomyocyte death or cardiac injury.Here, we identified hesperadin as a specific small-molecule inhibitor of CaMKII-δ with dual functions of cardioprotective and antitumor effects. These findings not only suggest that hesperadin is a promising leading compound for clinical therapy of cardiac I/R injury and heart failure, but also provide a strategy for the joint therapy of cancer and cardiovascular disease caused by anticancer treatment.
Attribution of Cancer Origins to Endogenous, Exogenous, and Preventable Mutational Processes
Authors: Vincent L. Cannataro, Jeffrey D. Mandell, Jeffrey P. Townsend
Journal: Molecular Biology and Evolution (2022)

Mutational processes in tumors create distinctive patterns of mutations, composed of neutral "passenger" mutations and oncogenic drivers that have quantifiable effects on the proliferation and survival of cancer cell lineages. Increases in proliferation and survival are mediated by natural selection, which can be quantified by comparing the frequency at which we detect substitutions to the frequency at which we expect to detect substitutions assuming neutrality. Most of the variants detectable with whole-exome sequencing in tumors are neutral or nearly neutral in effect, and thus the processes generating the majority of mutations may not be the primary sources of the tumorigenic mutations. Across 24 cancer types, we identify the contributions of mutational processes to each oncogenic variant and quantify the degree to which each process contributes to tumorigenesis. We demonstrate that the origination of variants driving melanomas and lung cancers is predominantly attributable to the preventable, exogenous mutational processes associated with ultraviolet light and tobacco exposure, respectively, whereas the origination of selected variants in gliomas and prostate adenocarcinomas is largely attributable to endogenous processes associated with aging. Preventable mutations associated with pathogen exposure and apolipoprotein B mRNA-editing enzyme activity account for a large proportion of the cancer effect within head-and-neck, bladder, cervical, and breast cancers. These attributions complement epidemiological approaches-revealing the burden of cancer driven by single-nucleotide variants caused by either endogenous or exogenous, nonpreventable, or preventable processes, and crucially inform public health strategies.