tbuckley/cabot-search huggingface dataset:
EPID-25. DISTANCE TRAVELED FOR BRAIN TUMOR CARE IN PAKISTAN: AN LMIC PERSPECTIVE
Authors: Mohammad Hamza Bajwa, Mashal Shah, Erum Baig, Izza Tahir, Kinzah Ghazi, Rameen Bajwa, Altaf Ali Laghari, Saad Bin-Anis, Naveed Zaman Akhunzada, Jaleed Gilani, Noyan Jawed, Usman Khalid, Namra Qadeer, Areeb Lutfi, Huzaifa Rashid, Haleema Sadia, Mishal Gillani, Pakistan Brain Tumor Consortium, Sameen Siddiqi, Syed Ather Enam
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Global oncology development within LMICs (low- and middle-income countries) requires bridging gaps in healthcare systems. Brain tumor care in Pakistan is currently sparse and concentrated in urban centers. Distance traveled to a hospital dictates a patient’s access to care, neurosurgical access, and continuity of care through adjuvant chemoradiotherapy and primary care providers can be disrupted if patients cannot overcome the barriers due to extensive distances traveled. METHODS Data was collected as part of the Pakistan Brain Tumor Epidemiology Study (PBTES) regarding patients with brain tumors who underwent surgical procedures in 2019 at private and public major neurosurgical centers across Pakistan. Using patient addresses, we used a mapping software to calculate the distance traveled by each patient to the primary hospital. Analysis was done using appropriate statistical methods. RESULTS Out of 2403 patients, the mean distance traveled across the country was 240 km. The longest distance traveled within Pakistan was from Skardu to Karachi (2002 km) for resection of a pituitary adenoma (28 hours via car). Only 48% of patients were able to reach their primary hospital within 50 km. 52% of patients had to travel more than 50 km, and 18% had to travel upwards of 500 km to reach their primary hospital. Additionally, 101 patients traveled to Pakistan from other countries for brain tumor surgery (98 patients from Afghanistan [mean distance traveled: 723.6 km], 3 patients from Syria, Oman, and Sudan). CONCLUSION Prior studies have described a cut-off of 50 km as an acceptable limit for distance from the primary hospital in cancer patients for optimal follow-up and outcomes, which is achieved by only 48% of brain tumor patients in Pakistan. Most patients have poor access to surgical care for brain tumors, further compounded by repeat traveling for follow-ups and chemoradiotherapy.
Abstract 12819: Feasibility of Transradial Primary Percutaneous Coronary Intervention for STEMI Complicated by Cardiac Arrest
Authors: Nicholas Kassis, Anirudh Kumar, Leon Zhou, Chetan Huded, Grant W Reed, Amar Krishnaswamy, Joseph Martin, Rishi Puri, Khaled Ziada, Jaikirshan Khatri, A M Lincoff, Stephen G Ellis, Samir R Kapadia, Umesh N Khot
Journal: Circulation (2021)

Introduction: The American Heart Association recommends a “radial-first” strategy in patients with ST-elevation myocardial infarction (STEMI). It is uncertain whether the benefits of transradial (TR) access extends to high-risk patients who present with STEMI and cardiac arrest (CA). Methods: Consecutive patients with STEMI complicated by CA who underwent percutaneous coronary intervention (PCI) within 24 hours at the Cleveland Clinic between 2011-2018 were included. TR-PCI was implemented as the standard approach during the study period (2014). Temporal changes in the use and technical success rates of TR-PCI were assessed, and procedural outcomes were compared with those who underwent transfemoral (TF)-PCI as the initial attempted approach. To evaluate for predictors of major bleeding, variables were assessed in univariable logistic regression and those with p&lt;0.10 were included in multivariable analysis. Results: Among 216 patients, TR-PCI use increased from 2.9% in 2011 to 87.1% in 2018 (p&lt;0.001). TR-PCI was successful in 80/91 (87.9%) patients. Door-to-balloon-time (90 [68, 116] vs. 105 [76, 141] minutes, p=0.03) and contrast volume (150 vs. 153 mL, p=0.03) were significantly lower in TR-PCI relative to TF-PCI with no differences in fluoroscopy dose, mechanical circulatory support use (30.8% vs. 41.6%, p=0.14), or in-hospital mortality (13.2% vs. 19.2%, p=0.32). After adjusting for peripheral arterial disease, diabetes, fluoroscopy dose, mechanical circulatory support, and total femoral access, TR-PCI was an independent predictor for less major bleeding {OR=0.34 (95% CI [0.11-0.93], p=0.045)}. Conclusions: Among patients with STEMI and CA, TR-PCI is feasible and can be successfully adopted via implementation of a “radial-first” strategy. With a high technical success rate, no adverse effect on door-to-balloon-time, and reduced major bleeding, TR-PCI should be the initial access strategy in high-risk patients with STEMI and CA.
炎症性疾患における貧血に対するヘプシジンアンタゴニストの効果【JST・京大機械翻訳】
Authors: Sagar Poonam, Angmo Stanzin, Sandhir Rajat, Rishi Vikas, Yadav Hariom, Singhal Nitin Kumar
Journal: Pharmacology & Therapeutics (2021)
Abstract 13251: Left Bundle Branchpacing Post-Atrioventricular Junction Ablation for Atrial Fibrillation: A Propensity Score Matching Analysis
Authors: Weijian Huang, Mengxing Cai, Shengjie Wu, Lan Su, Songjie Wang, Rujie Zheng, Limeng Jiang, Yanlei He, Ling Zhu, Liyou Lian, Kenneth Ellenbogen
Journal: Circulation (2021)

Introduction: Although left bundle branch pacing (LBBP) has emerged as a novel pacing modality which can allow for safe atrioventricular junction (AVJ) ablation and lower pacing threshold compared to His bundle pacing (HBP), its long-term safety and efficacy in patients with atrial fibrillation (AF) is still unknown. Hypothesis: This study aimed to examine the long-term clinical feasibility, safety, and efficacy of LBBP in AF patients post-AVJ ablation and provide a balanced comparison of LBBP versus HBP. Methods: This study prospectively enrolled patients with AF and heart failure (HF) who underwent AVJ ablation and LBBP from July 2017 to December 2019. The control group patients were selected, by propensity score (PS) matching with a 1:1 ratio, among those HBP implantations performed in the years 2012-2019. Results: A total of 99 patients were enrolled in this study, with successful permanent LBBP post-AVJ ablation in 100% of patients (primary LBBP: 76; secondary LBBP: 23). Significantly improvements were observed in LVEF, tricuspid regurgitation, and mitral regurgitation at 1-year follow-up (p&lt;0.05). The proportion of patients whose acute threshold &lt;1 V@0.5ms was 97.9% and only one patient had an increase in threshold ≥1 V@0.5ms at 1-year follow-up. Further, patients with LBBP as an active-group was compared to patients with HBP (control-group) through PS matching with 170 successfully matched (PS-HBP, N=85; PS-LBBP, N=85). In the control-group, the success rate of permanent HBP was 81.9% (176/215), which was lower than that with LBBP (p&lt;0.001). No significant differences in clinical outcomes were observed between groups (p&gt;0.05), while lower thresholds, greater sensed R-wave amplitudes, and less complication were observed in PS-LBBP group (p&lt;0.05). Conclusions: LBBP is feasible, safe, and effective in AF and HF patients post-AVJ ablation, which has comparable clinical benefit, higher success rate, better pacing parameters, and less complication than HBP.
Abstract 12585: Human Heart Progenitors Regenerate Porcine Hearts via Migration and Fibroblast Repulsionhuman Heart Regeneration by Cardiac Pmigration and Fibroblast Repulsion
Authors: Christine M Poch
Journal: Circulation (2021)

Human heart regeneration is one of the most critical unmet clinical needs at a global level. Muscular regeneration is hampered both by the limited renewing capacity of adult cardiomyocytes and the onset of cardiac fibrosis, resulting in reduced compliance of the tissue. Pluripotent stem cell strategies have proven efficacious for heart regeneration in rodents, pigs and primates, but approaches to specifically drive cell migration to the site of injury and inhibit subsequent fibrosis have been elusive. By virtue of human cardiac progenitor lineage tracing and single-cell transcriptomics, we uncover coordinated muscular regeneration in injured non-human primate heart bio-mimics. Remuscularization occured via directed migration of human ventricular progenitors to site of injury, concomittant fibroblast repulsion targeting fibrosis, and ultimately functional replacement of damaged cardiac muscle by differentiation and electromechanical integration. Single-cell RNAseq captured distinct capabilities, such as migration towards a CXCL12 gradient and fibroblast repulsion regulated by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Injection of human cardiac progenitors into hypo-immunogenic CAG-LEA29Y transgenic porcine hearts following radiofrequency ablation injury proved their chemotactic response and ability to generate a remuscularized scar in vivo . Transplantation of ~500 million cryopreserved human embryonic stem cell-derived progenitors vs cadiomyocytes similarly enhance cardiac function in pigs with myocardial infarctions. However, the risk of graft-associated ventricular arrhythmias from ectopic pacemaker automaticity shown by electroanatomical mapping is significantly lower in progenitor- compared to cardiomyocyte-treated hearts. Moreover, progenitor grafts exhibit larger CD31 + blood vessel networks and lower CD68 + immune cell infiltration. Our study demonstrates that inherent developmental programs within cardiac progenitors are sequentially activated in the context of disease, allowing the cells to sense, counteract injury and integrate into the host environment. As such, they may represent an ideal bio-therapeutic for functional heart rejuvenation.
Lymphocyte Cytosolic Protein 1 I232F Mutation Impairs Granulocytic Proliferation with a G2/M Block in Severe Neutropenia
Authors: Upendra Mahat, Bhavuk Garg, Hrishikesh M Mehta, Heesun J. Rogers, Andrei Ivanov, Chao-Yie Yang, Aron Flagg, Seth J. Corey
Journal: Blood (2021)
Proceedings of the Philadelphia County Medical Society
Journal: JAMA (1896)

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Abstract 6980: Peroxynitrite-Mediated Mitochondrial Autophagy is Activated for the Development of Global Cerebral Ischemia Induced by Cardiac Arrest
Authors: Yi Li, Nan Chen, Cong Geng, Shiqi Lu, Jun Jin
Journal: Circulation (2021)

Introduction: Mitochondrial dysfunction is implicated in ischemic brain after cardiac arrest, and the timely removal of damaged mitochondria is critical for cellular homeostasis. Mitochondrial autophagy is a mitochondrial quality control mechanism via selective degradation of mitochondria but its role in the ischemic brain remains controversial. Peroxynitrite, as a representative of reactive nitrogen species, is an important neurologic damage factor in the brain injury but its role in cardiac arrest is unknown. Methods: Male Sprague-Dawley rats underwent 8-minute asphyxial cardiac arrest and cardiopulmonary resuscitation. Survival, neurological deficit and mitochondrial function were assessed for up to 72 hours following cardiac arrest. Western blotting, immunofluorescence and enzyme-linked immunosorbent assay were used to evaluate activated mitochondrial autophagy and peroxynitrite production. To further explore the underlying mechanism, FeTMPyP was used to act as a peroxynitrite decomposition catalyst. Results: After resuscitation from cardiac arrest, PINK1/Parkin-induced mitochondrial autophagy was activated and peroxynitrite was increased in the ischemic brain. Peroxynitrite scavenger with FeTMPyP treatment significantly prevented the generation of peroxynitrite, inhibited mitochondrial autophagy activation, reduced neurological damages and improved mitochondrial and neurological outcome after cardiac arrest. Moreover, peroxynitrite induced serine 616 phosphorylation of Drp1 and Drp1 translocation to the mitochondria, which was responsible for mitochondrial autophagy activation. Conclusions: Mitochondrial autophagy activation mediated by peroxynitrite could be a key event in the pathogenesis of brain injury induced by cardiac arrest and provides a promising therapeutic strategy.
Abstract 14488: Modifiable Risk Factor Burden Among Young Adults With Heart Failure
Authors: vardhmaan jain, Kartik Gupta, Muthiah Vaduganathan
Journal: Circulation (2021)

Background: Recent population data have suggested that HF may be presenting at younger ages. Little is known about the relative importance of traditional prognostic factors in this growing cohort. Methods: We analyzed data of 1,071 participants aged ≥ 18 years with self-reported HF enrolled in 6 cycles of NHANES from January 1, 1999 to December 31, 2010. We describe mortality trajectories through median follow-up of 6.7 ± 4.3 years by age group (young [n=154] 18-54y; middle [n= 190] 55-65y; and older [n=727] &gt;65y). Multivariable Cox proportional hazards models were constructed to determine if age, gender, hypertension, diabetes, obesity, smoking, and eGFR differentially associate with mortality across age groups using interaction testing. Results: Younger patients with HF were more often Black, had better kidney function, and had higher rates of diabetes, obesity, and smoking than middle-age and older adults. Age modified the association of obesity and diabetes on subsequent risk of mortality such that diabetes was associated with higher mortality risk in young (adj HR 2.11; 95% CI: 1.04 -4.31) and middle-aged adults (adj HR 2.18; 95% CI: 1.34- 3.57) as compared with older adults (adj HR 1.27; 95% CI: 1.04-1.55); P-interaction&lt;0.05. Similarly, obesity was associated with higher risk of mortality in younger (adj HR 2.07; 95% CI: 1.02-4.22) compared with middle-aged (adj HR 0.61; 95% CI: 0.37- 1.01) and older adults (adj HR 1.03; 95% CI: 0.85-1.26); P-interaction&lt;0.05. Predictive accuracy of multivariable models declined with increasing age, with a Harrel’s C- statistic of 0.71 in young, 0.67 in middle-aged, and 0.66 in older adults. Conclusion: Modifiable risk factors such as obesity and diabetes are more common in younger adults with HF and may have greater relative importance in forecasting subsequent mortality than in middle-aged and older adults. These data underscore the need for treatment approaches targeting these core risk factors earlier in life.
Abstract P336: Endogenous Alpha-1a Adrenergic Receptors Promote Cardiomyocyte Survival Through Suppression Of Rip Kinase-mediated Necroptosis
Authors: Jiandong Zhang, Peyton Sandroni, Wei Huang, Brian C Jensen
Journal: Circulation Research (2021)

Our previous work has demonstrated essential protective roles for the endogenous cardiomyocyte alpha-1A adrenergic receptor (α1A-AR) subtype in mouse models of heart failure. However, the underlying mechanism of this protective phenotype is unclear. To address this gap in knowledge, we bred a mouse line lacking α1A-ARs on cardiomyocytes by crossing αMHC-cre mice with floxed α1A mice (CMKO= cre+ fl/fl, CMWT= cre- fl/fl), and subjected males to permanent LAD ligation. CMKO mice had increased serum HMGB1 level, larger infarcts and higher mortality. We found that RIP1/3-mediated programmed necrosis (necroptosis), but not apoptosis was exaggerated in CMKO mice 3 days after ligation. We then tested whether RIP1 inhibition with Nec-1s could mitigate this injury. Mice were given Nec-1s (1.65 mg/kg) or vehicle 10 mins prior to LAD ligation, followed by daily IV injection. Nec-1s treatment diminished post-ligation RIP1 (0.62±0.02 vs. 0.78±0.23 A.U., p=NS) and RIP3 expression (0.33±0.1 vs. 0.26±0.10 A.U., p=NS) in CMWT and CMKO mice respectively. Serum level of HMGB1 on D3 was markedly reduced in both CMWT (45.1%) and CMKO (61.1 %) after Nec-1s treatment. There was no difference between Nec-1s treated CMWT and CMKO mice (147±53 vs. 174±37 pg/mL, p=NS), indicating that blocking the RIP kinase pathway abrogates the exaggerated cell death in CMKO mice after ligation. Likewise, Nec-1s-treated CMKO mice had similar infarct areas to CMWT controls (16.2±4.5 vs. 19.9±4.6%, p=NS), further confirming that targeting necroptosis abrogates pathological damage. Collectively these Nec-1s data suggest that RIP-mediated necroptosis may account for larger infarcts in CMKO mice. Interestingly, expression of the apoptosis markers c-caspase-3 and PARP was similar between CMWT and CMKO mice, suggesting that the α1A-AR specifically regulates necroptosis. In sum, our data demonstrate that RIP kinase-mediated necroptosis contributes to susceptibility to injury in mice lacking cardiomyocyte α1A-ARs.
Anticoagulation in Cancer Patients with Atrial Fibrillation and Grade 3-4 Thrombocytopenia
Authors: Genady Drozdinsky, Noam Arad, Galia Spectre, Nir Livneh, Itamar Poran, Pia Raanani, Anna Falanga, Hugo ten Cate, Anat Gafter-Gvili, Avi Leader
Journal: Blood (2021)
An Autosomal Dominant Form of Ras-Related C3 Botulinum Toxin Substrate 2 (RAC2) Is Associated with Haematopoiesis Failure
Authors: Chantal Lagresle-Peyrou, Aurélien Olichon, Hanem Sadek, Philippe Roche, Claudine Tardy, Natael Sorel, Boris Bessot, Cindy Da Silva, Alain Fischer, Despina Moshous, Yves Collette, Capucine Picard, Jean-Laurent Casanova, Isabelle André, Marina Cavazzana
Journal: Blood (2021)
NCOG-01. RADIATION THERAPY MANAGEMENT FOR METASTATIC DISEASE TO THE BRAIN IN NSCLC PATIENTS – SURVIVAL OUTCOMES OF THE BRITISH COLUMBIA POPULATION 1996-2016
Authors: Terry Stubbs, Kimberly DeVries, Ryan Proulx, Clement Ho, Arthur Cheung, Alan Nichol, Andra Krauze
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Radiation therapy (RT) for brain metastases in patients with non-small cell lung cancer (NSCLC) has undergone considerable evolution but remains controversial. METHODS Records for 2212 patients with NSCLC who received RT to the brain at one of six locations between 1996-2016 were retrospectively analyzed. Data were obtained from the institutional cancer registry following ethics approval. Overall survival (OS) was calculated from diagnosis of lung cancer to death, and Kaplan-Meier curves were compared by Log-rank and Cox regression. RESULTS Median OS was 11.8 months (95%CI 11-12.6 months). Median age was 65, and 1254 patients (57%) were female. ECOG performance status at diagnosis was 0 (12%), 1 (31%), 2 (17%), 3 (14%), 4 (2%), and unknown (24%). Younger age (HR=0.99, 95%CI 0.98-0.99), female sex (HR=0.80, 95%CI 0.74-0.88), and better ECOG performance status (p&amp;lt; 0.0001) were associated with superior OS. There was better OS in 932 patients (42%) that received chemotherapy (HR=0.63, 95%CI 0.58-0.69) and 603 (27%) that underwent surgery (HR=0.55, 95%CI 0.50-0.61). 2004 patients (91%) received 1 RT course, while 208 (9%) received multiple courses in various combinations of whole brain RT (WBRT) and stereotactic radiosurgery (SRS). SRS (HR=0.70, 95%CI 0.57-0.86) and multiple RT courses (HR=0.55, 95%CI 0.46-0.65) were associated with better OS. Median time from primary diagnosis to brain RT was 2.5 months, and from end of first brain RT to death was 3.5 months. A longer diagnosis to brain RT interval was associated with better OS (HR=0.95, 95%CI 0.95-96). CONCLUSIONS NSCLC patients with brain metastases continue to face poor prognosis, particularly when lung cancer diagnosis to first brain RT interval is short. Our analysis revealed younger age, female sex, and better ECOG performance status as predictors of superior survival. SRS and multiple RT courses also revealed superior survival, likely the result of patient selection and hence interpreted with caution.
BIOM-30. BLOOD COUNTS THROUGH TREATMENT COURSE IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIATION
Authors: Davy Deng, Lubna Hammoudeh, Daniel Cagney, J Ricardo McFaline-Figueroa, Ugonma Chukwueke, David Reardon, Eudocia Quant Lee, Lakshmi Nayak, Mary Jane Lim-Fat, Keith Ligon, Wenya Linda Bi, Omar Arnaout, Brian Alexander, Patrick Wen, Rifaquat Rahman
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Glioblastoma (GBM) patients are treated with radiation therapy (RT), temozolomide, and corticosteroids which can affect hematologic and immunologic parameters. We examined lymphocytes, neutrophil-to-lymphocyte ratio and platelet measurements and their association with progression-free survival (PFS) overall survival (OS). METHODS We identified 759 newly diagnosed adult GBM patients treated at our institution in the temozolomide (TMZ) era with blood counts that could be automatically extracted from the electronic medical record during chemoradiation (CRT, defined as within 42 days of RT) and at first recurrence. Linear regression and Cox modeling were used to evaluate outcomes. RESULTS Median age was 60.3 years; 87% had KPS ≥ 70, 37.5% had gross total resection, and 90% received TMZ. Prior to RT, 56.4% (375/665) patients had a lymphocyte measurement &amp;lt; 1.0 × 1000 cells [K]/μL. Within 42 days of CRT, 81.7% (536/656) had a lymphocyte measurement &amp;lt; 1.0 K/μL, 37.8% (248/656) &amp;lt; 0.5 K/μL. 10.7% (58/544) patients developed grade 2 or higher neutropenia, 9.1% (50/547) patients developed grade 2 or higher thrombocytopenia. On multivariable analysis (MVA), older age (AHR1.03, p&amp;lt; 0.001), unmethylated MGMT status (AHR2.56,p&amp;lt; 0.001), lower RT dose (&amp;lt;54Gy, AHR 3.45, p&amp;lt; 0.001), male sex (AHR1.45, p=0.02), non-gross total resection (AHR1.63, p&amp;lt; 0.001), lymphopenia during CRT (AHR0.63, p=0.008) and higher NLR during CRT (AHR1.02, p=0.001) were significantly associated with worse OS. Older age (AHR1.01, p=0.02), unmethylated MGMT status (AHR2.44, p&amp;lt; 0.001), lower RT dose (AHR1.82, p=0.02), higher NLR during CRT (AHR1.03, p &amp;lt; 0.001) were significantly associated with worse PFS on MVA. At first recurrence, median lymphocyte count was 0.7 K/μL with 74% (348/468) patients &amp;lt; 1.0 K/μL and 27% &amp;lt; 0.5 K/μL. CONCLUSION Lymphopenia and higher neutrophil-to-lymphocyte ratio are associated with inferior outcomes. Persistent lymphopenia at time of first recurrence may have implications for clinical trial eligibility and immunotherapy approaches in recurrent GBM.