tbuckley/cabot-search huggingface dataset:
QIM19-132: Trastuzumab Induced Cardiotoxicity: Are We Monitoring and Managing Appropriately?
Authors: Heather Katz, Hassaan Jafri, Emilia Cindy Leigh, Layana Biglow, Madhulika Urella, Maria Tria Tirona
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Per the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer (available at NCCN.org ), left ventricular ejection fraction (LVEF) should be evaluated prior to and during treatment with trastuzumab. Optimal frequency of assessment is unknown. The FDA label recommends monitoring prior to and every 3 months during therapy. Trastuzumab should be held for 4–8 weeks when LVEF decreases ≥16% from pretreatment values or LVEF is below normal limits and decreases ≥10% from pretreatment values. Trastuzumab should be permanently discontinued for persistent (&gt;8 weeks) LVEF decline or if trastuzumab is stopped &gt; 3 times for cardiomyopathy (trastuzumab package insert). Methods: A retrospective chart review was performed analyzing 98 charts of patients with stage I–III HER2-positive breast cancer who were seen at the Edwards Comprehensive Cancer Center (ECCC) in Huntington, WV from January 1, 2012–December 30, 2017. Patients who received trastuzumab at ECCC (59) were further reviewed to see if cardiac function was assessed prior to treatment, at 3 month intervals, and if trastuzumab was held or discontinued permanently if indicated. Results: Analysis of 98 patient charts with stage I–III HER2-positive breast cancer was performed. 59 patients (60.2%) received trastuzumab under supervision of medical oncology at ECCC and continued in the study. LVEF was evaluated in all patients (100%) prior to treatment. LVEF was evaluated every 3 months in 36 (61%) patients while 23 (38.9%) occurred at longer time intervals. Preserved EF was seen in 41 (69.4%) patients. 18 (30.5%) patients had a decrease in LVEF by the defined criteria. Trastuzumab was not held appropriately in 4 of those patients (22.2%). 10 of 18 patients that had a drop in LVEF had persistent LVEF decline or had stopped treatment &gt; 3 times for cardiomyopathy. Trastuzumab was permanently discontinued appropriately in 4 of the 10 patients (40%). Conclusions: Better compliance is needed to monitor LVEF at 3-month intervals while on trastuzumab. Improvement to recognize when to hold trastuzumab to prevent cardiotoxicity is needed. Better documentation, easier accessibility to previous EF results, and a multidisciplinary team (breast navigator, cardiologist, oncologist, and pharmacist) will likely improve adherence to current recommendations for cardiac assessment and to determine if Trastuzumab should be held or stopped.
HSR19-087: Intensity of Symptom Management After Palliative Care Referral Not Associated With Reduced Imaging Intensity for Cancer Patients During the End-of-Life Period
Authors: Benjamin L. Franc, Kesav Raghavan, Timothy P. Copeland, Maya Ladenheim, Angela Marks, Steven Z. Pantilat, David O’Riordan, David Seidenwurm, Michael Rabow
Journal: Journal of the National Comprehensive Cancer Network (2019)

Purpose: For patients with advanced cancer, palliative care (PC) referral itself results in improved quality of life and lower total health care costs. While our earlier research suggests that PC referral alone does not appear to affect imaging utilization, the effect of the intensity of services for PC symptom management on utilization of imaging services is unknown. We sought to evaluate whether an association exists between the intensity of PC symptom management services and utilization of high-cost imaging at the end-of-life. Methods/Materials: Adult cancer patients who died between January 1, 2012–May 31, 2015 were identified. A PC symptom management intensity score was determined for each patient during the last year of life based upon the number of inpatient and outpatient PC service visits and the number of problems addressed within the 8 defined domains for palliative care. Frequency of utilization of nonemergent oncologic imaging was determined for the last 3 months and the last month of life. Using chi-square and Wilcoxon-rank sum tests, effects of low (&lt;20 th percentile) and high (&gt;80 th percentile) PC symptom management intensity score on the proportion of patients imaged and mean number of studies per patient (mean imaging intensity [MII]) were compared for the last 3 months and last month of life. Results: 3,772 decedents were included, with 3,523 (93.4%) never referred to PC and 249 (6.6%) referred to PC, largely before the last month of life (70.3%). Within the last 3 months and last month of life, the proportion of patients imaged was significantly greater ( P &lt;.001) in patients with high PC symptom management intensity scores when compared to those with low PC symptom management intensity scores. There was no significant difference in the mean number of imaging studies received by either group in the last 1 month or 3 months of life. ( P &gt;.05). Conclusions: The intensity of PC symptom management in end-of-life oncologic care was not associated with decreased use of nonemergent, high-cost cancer imaging in our cohort. This may suggest an opportunity for reduced high-cost imaging through further clarification of the goals of care with both patients and oncologists, although the role of imaging in the setting of PC during the end-of-life period warrants further study as well.
Correction: Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma
Authors: Shamzah Araf, Jun Wang, Koorosh Korfi, Celine Pangault, Eleni Kotsiou, Ana Rio-Machin, Tahrima Rahim, James Heward, Andrew Clear, Sameena Iqbal, Jeff K. Davies, Peter Johnson, Maria Calaminici, Silvia Montoto, Rebecca Auer, Claude Chelala, John G. Gribben, Trevor A. Graham, Thierry Fest, Jude Fitzgibbon, Jessica Okosun
Journal: Leukemia (2019)
Safeguard function of PU.1 shapes the inflammatory epigenome of neutrophils
Authors: Josephine Fischer, Carolin Walter, Alexander Tönges, Hanna Aleth, Marta Joana Costa Jordão, Mathias Leddin, Verena Gröning, Tabea Erdmann, Georg Lenz, Johannes Roth, Thomas Vogl, Marco Prinz, Martin Dugas, Ilse D. Jacobsen, Frank Rosenbauer
Journal: Nature Immunology (2019)
Abstract 14618: Augmented Neutrophil Extracellular Traps Formation Promotes Atherosclerosis Development in Socially Defeated Apoe-/- Mice
Authors: Keita yamamoto, Hiroyuki Yamada, Kensuke Terada, Shinichiro Motoyama, Naotoshi Wada, Makoto Saburi, Takeshi Sugimoto, Masakazu Kikai, Noriyuki Wakana, Satoaki Matoba
Journal: Circulation (2017)

Objective: Depression is an independent risk factor of cardiovascular disease (CVD); however, the causal association remains undefined. We exposed mice to repeated social defeat (RSD) to precipitat...
Characterization and Therapeutic Application of Mesenchymal Stem Cells with Neuromesodermal Origin from Human Pluripotent Stem Cells
Authors: Huiyan Wang, Dairui Li, Zhichen Zhai, Xiaoran Zhang, Weijun Huang, Xiaoyong Chen, Lihua Huang, Huanyao Liu, Jiaqi Sun, Zhengwei Zou, Yubao Fan, Qiong Ke, Xingqiang Lai, Tao Wang, Xiaoping Li, Huiyong Shen, Andy Peng Xiang, Weiqiang Li
Journal: Theranostics (2019)

Rationale: Mesenchymal stem cells (MSC) hold great promise in the treatment of various diseases including autoimmune diseases, inflammatory diseases, etc., due to their pleiotropic properties. However, largely incongruent data were obtained from different MSC-based clinical trials, which may be partially due to functional heterogeneity among MSC. Here, we attempt to derive homogeneous mesenchymal stem cells with neuromesodermal origin from human pluripotent stem cells (hPSC) and evaluate their functional properties. Methods: Growth factors and/or small molecules were used for the differentiation of human pluripotent stem cells (hPSC) into neuromesodermal progenitors (NMP), which were then cultured in animal component-free and serum-free induction medium for the derivation and long-term expansion of MSC. The resulted NMP-MSC were detailed characterized by analyzing their surface marker expression, proliferation, migration, multipotency, immunomodulatory activity and global gene expression profile. Moreover, the in vivo therapeutic potential of NMP-MSC was detected in a mouse model of contact hypersensitivity (CHS). Results: We demonstrate that NMP-MSC express posterior HOX genes and exhibit characteristics similar to those of bone marrow MSC (BMSC), and NMP-MSC derived from different hPSC lines show high level of similarity in global gene expression profiles. More importantly, NMP-MSC display much stronger immunomodulatory activity than BMSC in vitro and in vivo, as revealed by decreased inflammatory cell infiltration and diminished production of pro-inflammatory cytokines in inflamed tissue of CHS models. Conclusion: Our results identify NMP as a new source of MSC and suggest that functional and homogeneous NMP-MSC could serve as a candidate for MSC-based therapies.
Outcomes and Clinical Features of Patients with 1q+ Multiple Myeloma Treated with Lenalidomide, Bortezomib, and Dexamethasone
Authors: Timothy M. Schmidt, Nisha Joseph, Levani Odikadze, Leonard Heffner, Craig C Hofmeister, Madhav V Dhodapkar, Vikas A. Gupta, Lawrence H. Boise, David L. Jaye, Sagar Lonial, Ajay K Nooka, Jonathan L Kaufman
Journal: Blood (2018)
EPR19-071: Risk of Hematologic Toxicities and Health-Related Quality of Life Events in Patients With Hematologic Malignancies Treated With Ibrutinib: A Combined Analysis of 6 Phase III Trials
Authors: Miguel Quirch, Sriman Swarup, Anita Sultan, Wai L. Thein, Zayar M. Oo, Nyein H. Yu, Myo H. Zaw, Donald P. Quick, Kyaw Z. Thein
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Bruton’s tyrosine kinase (BTK) is essential for signaling of B-cell and chemokine receptors. Ibrutinib targets BTK and has become frontier in many hematologic malignancies. We undertook systematic review and pooled analysis of randomized controlled trials (RCTs) to determine the risk of hematologic toxicities and health-related quality of life (HRQOL) events associated with ibrutinib. Methods: We performed a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through September 2018. Phase III RCTs that mention hematologic toxicities and HRQOL events as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% CI. Random effects model was applied. Results: 6 phase III RCTs with a total of 1,811 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle-cell lymphoma, and Waldenstrom’s macroglobulinemia were eligible. Studies compared Ibrutinib (I) vs ofatumumab, I vs chlorambucil, I+ bendamustine (B) + rituximab (R) vs placebo + B+ R, I vs temsirolimus and I vs R were included in the analysis. The relative risks (RR) of all-grade side effects were as follows: anemia, 0.812 (95% CI: 0.565–1.168; P =.261); neutropenia, 0.956 (95% CI: 0.720–1.268; P =.754); thrombocytopenia, 1.054 (95% CI: 0.450–2.470; P =.904); fatigue, 0.896 (95% CI: 0.761–1.056; P =.192); pyrexia, 1.123 (95% CI: 0.893–1.413; P =.322); and arthralgia, 1.863 (95% CI: 1.101–3.152; P =.020). The RR of high-grade adverse effects were as follows: anemia, 0.522 (95% CI: 0.371–0.733; P &lt;.0001); neutropenia, 0.969 (95% CI: 0.751–1.249; P =.807); thrombocytopenia, 0.608 (95% CI: 0.252–1.470; P =.270); fatigue, 0.618 (95% CI: 0.396–0.964; P =.034); pyrexia, 1.165 (95% CI: 0.534–2.542; P =.701); and arthralgia, 3.623 (95% CI: 0.743–17.663; P =.111). Conclusion: Ibrutinib increased the risk of all-grade arthralgia whereas the risks of high-grade anemia and fatigue were significantly lower in the study arm, favoring ibrutinib.
Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer
Authors: Loredana Puca, Katie Gavyert, Verena Sailer, Vincenza Conteduca, Etienne Dardenne, Michael Sigouros, Kumiko Isse, Megan Kearney, Aram Vosoughi, Luisa Fernandez, Heng Pan, Samaneh Motanagh, Judy Hess, Adam J. Donoghue, Andrea Sboner, Yuzhuo Wang, Ryan Dittamore, David Rickman, David M. Nanus, Scott T. Tagawa, Olivier Elemento, Juan Miguel Mosquera, Laura Saunders, Himisha Beltran
Journal: Science Translational Medicine (2019)

Histologic transformation to small cell neuroendocrine prostate cancer occurs in a subset of patients with advanced prostate cancer as a mechanism of treatment resistance. Rovalpituzumab tesirine (SC16LD6.5) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) and was initially developed for small cell lung cancer. We found that DLL3 is expressed in most of the castration-resistant neuroendocrine prostate cancer (CRPC-NE) (36 of 47, 76.6%) and in a subset of castration-resistant prostate adenocarcinomas (7 of 56, 12.5%). It shows minimal to no expression in localized prostate cancer (1 of 194) and benign prostate (0 of 103). DLL3 expression correlates with neuroendocrine marker expression, RB1 loss, and aggressive clinical features. DLL3 in circulating tumor cells was concordant with matched metastatic biopsy (87%). Treatment of DLL3-expressing prostate cancer xenografts with a single dose of SC16LD6.5 resulted in complete and durable responses, whereas DLL3-negative models were insensitive. We highlight a patient with neuroendocrine prostate cancer with a meaningful clinical and radiologic response to SC16LD6.5 when treated on a phase 1 trial. Overall, our findings indicate that DLL3 is preferentially expressed in CRPC-NE and provide rationale for targeting DLL3 in patients with DLL3-positive metastatic prostate cancer.
Is there a ‘recent occupational paradox’ where highly active physically active workers die early? Or are there failures in some study methods?
Authors: Roy J Shephard
Journal: British Journal of Sports Medicine (2019)

Occupational epidemiology studies in the 1980s and 1990s demonstrated a beneficial effect of physically active employment on risks of premature death,1 with HR of ~1.50 for sedentary employees (see the online supplement for a detailed discussion). However, that accepted wisdom was disputed in a recent meta-analysis which claimed that male employees faced ‘detrimental health consequences associated with high-level occupational activity, even after adjusting for relevant factors’.2 Such a view challenges existing physical activity guidelines and poses the intriguing problem why occupational activity might be bad for men but not women.

Here the author scrutinises the choice of articles for this meta-analysis, the characteristics of apparently hazardous activity and potential confounding by covariates, focusing on the male data. Possible reasons why women do not show an occupational paradox are discussed in the online supplemental material.

### Supplementary file

[bjsports-2018-100344supp001.docx] 

Articles for the meta-analysis were drawn from 13 countries, but 5 of 16 were written by the study authors, leading to some similarities in the determination of active individuals and choice of co-variates. Moreover, participants in 5 of 16 studies lived around Copenhagen, with a potential for subject overlap; the author does not believe that this was evaluated. Studies provided ~30 to 5668 male …
The Driving Force: Nuclear Mechanotransduction in Cellular Function, Fate, and Disease
Authors: Melanie Maurer, Jan Lammerding
Journal: Annual Review of Biomedical Engineering (2019)

Cellular behavior is continuously affected by microenvironmental forces through the process of mechanotransduction, in which mechanical stimuli are rapidly converted to biochemical responses. Mounting evidence suggests that the nucleus itself is a mechanoresponsive element, reacting to cytoskeletal forces and mediating downstream biochemical responses. The nucleus responds through a host of mechanisms, including partial unfolding, conformational changes, and phosphorylation of nuclear envelope proteins; modulation of nuclear import/export; and altered chromatin organization, resulting in transcriptional changes. It is unclear which of these events present direct mechanotransduction processes and which are downstream of other mechanotransduction pathways. We critically review and discuss the current evidence for nuclear mechanotransduction, particularly in the context of stem cell fate, a largely unexplored topic, and in disease, where an improved understanding of nuclear mechanotransduction is beginning to open new treatment avenues. Finally, we discuss innovative technological developments that will allow outstanding questions in the rapidly growing field of nuclear mechanotransduction to be answered.
BIO19-022: Reducing Patient Waiting Times for Treatment Decision Making, Helps in Improving the Treatment Planning Process
Authors: Naresh Ramarajan, Farzana Begum, Gitika Srivastava
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Availability of care is an important characteristic of effective primary healthcare systems. Imbalanced oncologist to patient ratios (∼1600: 1.8 M in India, ∼23,000: 15 M in USA), impedes access to expertise. On average it takes a week or more to get an online expert review from leading cancer hospitals in the United States and in India. Such delays have an important psychosocial impact on the patient and caregivers. Patients worldwide often race to start treatments at non-expert centers and may experience worse health outcomes from lack of expert tumor board review of their cases. This study aimed to examine the impact of Navya, a health services technology, on reducing the patient wait time in real-time treatment decision making. Methods: Navya generates personalized treatment plans that maps 98.8% within NCCN Resource Stratified Guidelines [SABCS 2017, NCCN 2018]. This is vetted on mobile by oncologists at tertiary centers like TMC NCG to provide expert opinion reports to patients. Since 2015, approximately 25,775 patients from 60 countries have reached out for an online opinion. On the ground, 78% of patients received evidence-based treatments recommended by Navya [ASCO 2017]. The Navya system releases preliminary system-generated opinions for patients whose treatment plans fit high confidence based on NCCN Guidelines and prior expert reviews. The mean reduction in time between a system-generated opinion and an expert-reviewed opinion was studied in a prospective cohort of patients between July 1, 2017, and August 30, 2018. Results: 313 patients received a system-generated treatment plan in the study period. Only approximately 10% of these plans were modified by experts to add additional treatment details since these were cases with high confidence in treatment decision-making. Navya delivered a preliminary treatment plan on an average of 86 hours (SD, 153 hours) prior to the expert response time. Of the 313 patients studied, 44% of patients would have waited an additional 3 days longer to receive an expert-reviewed recommendation. Conclusions: Navya’s NCCN and evidence-based treatment plans reduce the patient waiting times for an expert opinion average by 86 hours. This rapid confirmation of the right treatment plan at the time of patient need has potential to relieve patient anxieties at critical junctures in treatment decision-making and helps improve the treatment-planning process.
Abstract 19747: The Effect of Internal vs. External Shocks on Myocardial Injury in an Animal Model of Myocardial Infarction
Authors: Nicole R Bianco, Ramu Perumal, Steven J Szymkiewicz
Journal: Circulation (2015)

Introduction: ICD use early after myocardial infarction (MI) has not proven advantageous, possibly in part due to myocardial injury associated with intracardiac defibrillation shocks. Previous studies have reported myocardial injury with internal defibrillation, but external defibrillation from the wearable cardioverter defibrillator (WCD) has not been investigated. The goal of this study was to determine the acute damage to the heart caused by external defibrillation from the WCD as compared to an ICD in an animal model of myocardial infarction (MI) using typical energy levels and times to shock. Methods: Two weeks after MI creation, 20 pigs were anesthetized and induced into VF through direct current applied to the right ventricular endocardium via an implanted transvenous lead. Control animals received 20-J internal shocks from the dual-coil defibrillator lead after 30 seconds of VF, while experimental animals received 150-J external shocks from a WCD after 45 seconds of VF. Each animal received a total of five consecutive internal or external shocks. Blood samples were collected at baseline (prior to first shock), immediately after the last shock, and at 4- and 24-hours post-shocks to determine myocardial biomarkers. Animals that did not survive 24 hours, control animals that had to be rescue-defibrillated externally, or those requiring &gt;5 shocks were excluded from analysis (n=6, 3 per arm). Differences were determined using t-tests. Results: Troponin I (cTnI), a specific marker of myocardial damage, was elevated above baseline in both the ICD (n = 7) and WCD (n = 7) groups at the 4 hr and 24 hr post-shock time points (Figure). However, the cTnI at 4 hr and 24 hr was significantly higher in the ICD control group as compared to the WCD (p &lt; 0.05). Conclusions: In an animal model of myocardial injury, cardiac-specific cTnI increases are significantly greater following internal 20-J shocks than external 150-J shocks, indicating less myocardial damage with external shocks.
Exercise Delivers Brain Benefits
Authors: Anita Slomski
Journal: JAMA (2019)

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Abstract 16638: Predictive Validity of Common Cardiovascular Disease Risk Scores Overall and in Relation to Race and Gender
Authors: Johanna Wilson, Cecile A Lengacher, Ponrathi Athilingam, Yangxin Huang, David M Diamond, Steven E Reis, Kevin E Kip
Journal: Circulation (2016)

Background: Cardiovascular risk score algorithms are routinely used in clinical practice and research. Whereas multiple approaches exist, there is concern related to accuracy of the algorithms when...
Mediation of the Effect of Glycemia on the Risk of CVD Outcomes in Type 1 Diabetes: The DCCT/EDIC Study
Authors: Ionut Bebu, Barbara H. Braffett, Trevor J. Orchard, Gayle M. Lorenzi, John M. Lachin
Journal: Diabetes Care (2019)

The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has demonstrated the major role of hyperglycemia as a risk factor for clinical cardiovascular outcomes in type 1 diabetes (T1D). We assessed whether and to what extent the effect of glycemia is mediated by other established cardiovascular disease (CVD) risk factors.