tbuckley/cabot-search huggingface dataset:
Prognostic significance of <i>KRAS</i> mutation rate in metastatic colorectal cancer (mCRC) patients (pts).
Authors: Bruno Vincenzi, Fotios Loupakis, Andrea Sartore Bianchi, Antonio Russo, Francesco Mannavola, Giuseppe Perrone, Chiara Cremolini, Daniele Rossini, Elena Ongaro, Erica Bonazzina, Emanuela Dell'Aquila, Marco Imperatori, Giovanna De Maglio, Alfredo Falcone, Daniele Santini, Andrea Onetti-Muda, Salvatore Siena, Giuseppe Aprile, Giuseppe Tonini
Journal: Journal of Clinical Oncology (2015)

e22075 Background: Activating mutations of KRAS genes have a well-established role as predictors of resistance to anti-EGFR monoclonal antibodies in mCRC pts. Their prognostic value is controversial, and no data regarding the prognostic value of mutation rate, defined as the % of mutated alleles/tumor sample are available We aimed to evaluate the prognostic value of KRASmutation rate in a homogenous cohort of mCRC patients receiving first-line doublet plus bevacizumab. Methods: This multicentric retrospective study enrolled 397 KRAS mutant mCRC patients from 6 Italian centers, and 305 patients were fully evaluable for our analysis. Mutational status and KRAS mutation rate have been obtained through pyrosequencing analysis. We excluded patients with less than 60% of cancer cells in tumor tissue. No patients received anti-EGFR containing anticancer therapy, at any time. Median mutation rate was 40% and was adopted as cut off value. The primary endpoint was PFS, OS was a secondary endpoint. Results: At univariate analysis, a KRAS mutational rate higher than 40% was significantly associated with lower PFS (7.3 ms ws vs 9.1 ms; P < 0.0001) and OS (21 ms vs 31 ms; P = 0.004). A multivariate model adjusted for age at diagnosis, site of origin of tumor tissue (primary cancer vs metastases) referral center, number of metastatic sites, and first-line chemotherapy backbone demonstrated that KRAS mutation rate remained a significant predictor of PFS and OS in the whole population. Conclusions: Our data demonstrated an association between KRAS mutation rate and prognosis in patients treated with bevacizumab-containing first-line therapy for mCRC. These data deserve to be verified in an independent validation set. PFS OS HR (95% C.I.) HR (95% C.I.) Survival Analysis (unadjusted) KRAS mutation rate > 40% 1 1 KRAS mutation rate < 40% 0.63 (0.458 -0.794) 0.661 (0.442-0.844) P < 0.001 P = 0.004 Survival Analysis (adjusted) KRAS mutation rate > 40% 1 1 KRAS mutation rate < 40% 0.67 (0.532-0.821) 0.710 (0.521-0.853) P = 0.003 P = 0.012
Abstract 14442: The Risk vs. Benefit Calculus of Anticoagulation in Patients With Ibrutinib-Related Atrial Fibrillation
Authors: Ruchi N Patel, Arushi Singh, Nausheen Akhter
Journal: Circulation (2021)

Introduction: Ibrutinib increases risk of atrial fibrillation (AF) as well as bleeding from platelet dysfunction. Among patients with ibrutinib-related atrial fibrillation (IRAF), there is no data on embolic or hemorrhagic stroke risk with anticoagulation use, and no specific guidelines regarding anticoagulation given the concern for bleeding risk. We sought to describe rates of stroke, bleeding and anticoagulation use among IRAF patients. Methods: We performed a single-center retrospective review of 169 patients who were treated with ibrutinib. Patients were followed from 2013 to 2021 using manual chart review. Results: Of 169 patients, 43 developed IRAF (25.4%), 4 developed other SVTs (2.4%), 50 were female (30.0%), 31 had or developed CHF (18.3%), and 112 had or developed HTN (66.3%). Mean age at ibrutinib initiation was 66.0 years. Over a mean follow-up of 4.5 years, 2 IRAF patients developed ischemic or embolic strokes (4.7%), one of whom was on anticoagulation (CHA2DS2-VASc of 7) and 2 developed hemorrhagic stroke (4.7%), one of whom was on anticoagulation (CHA2DS2-VASc of 7). Two IRAF patients developed gastrointestinal bleeding requiring transfusions (4.7%), one of whom was on anticoagulation (CHA2DS2-VASc of 4). Of the 43 IRAF patients, 20 were on anticoagulation (CHA2DS2-VASc range: 1-7), and 7 patients were on antiplatelet therapy, 4 of which were on both anticoagulation and antiplatelet therapies. Table 1 describes CHA2DS2-VASc and HASBLED scores and anticoagulation use across our population. Conclusions: In this single-center experience of IRAF, after a 4.5-year follow-up, anticoagulation practices varied among patients across a range of CHA2DS2-VASc and HASBLED scores but there were only 2 embolic or ischemic strokes (4.7%). However, the incidence of major bleeding including hemorrhagic stroke and gastrointestinal bleeding was 9.3% (4/43). The necessity of anticoagulation in the IRAF population needs further study.
Analysis of BNT162b2‐ and CVnCoV‐elicited sera and of convalescent sera toward SARS‐CoV‐2 viruses
Authors: Sascha Hein, Marie‐Luise Herrlein, Ines Mhedhbi, Daniela Bender, Vanessa Haberger, Nuka Benz, Jonathan Eisert, Julia Stingl, Michael Dreher, Doris Oberle, Jessica Schulze, Christin Mache, Matthias Budt, Christoph Hildt, Thorsten Wolff, Eberhard Hildt
Journal: Allergy (2021)

Summary Background The mRNA vaccine BNT162b2 (Comirnaty, BioNTech/Pfizer) and the vaccine candidate CVnCoV (Curevac) each encode a stabilized spike protein of SARS‐CoV2 as antigen but differ with respect to the nature of the mRNA (modified versus unmodified nucleotides) and the mRNA amount (30 μg versus 12 μg RNA). This study characterizes antisera elicited by these two vaccines in comparison to convalescent sera. Methods Sera from BNT162b2 vaccinated healthcare workers, and sera from participants of a phase I trial vaccinated with 2, 4, 6, 8, or 12 μg CVnCoV and convalescent sera from hospitalized patients were analyzed by ELISA, neutralization tests, surface plasmon resonance (SPR), and peptide arrays. Results BNT162b2‐elicited sera and convalescent sera have a higher titer of spike‐RBD‐specific antibodies and neutralizing antibodies as compared to the CVnCoV‐elicited sera. For all analyzed sera a reduction in binding and neutralizing antibodies was found for the lineage B.1.351 variant of concern. SPR analyses revealed that the CVnCoV‐elicited sera have a lower fraction of slow‐dissociating antibodies. Accordingly, the CVnCoV sera almost fail to compete with the spike‐ACE2 interaction. The significance of common VOC mutations K417N, E484K, or N501Y focused on linear epitopes was analyzed using a peptide array approach. The peptide arrays showed a strong difference between convalescent sera and vaccine‐elicited sera. Specifically, the linear epitope at position N501 was affected by the mutation and elucidates the escape of viral variants to antibodies against this linear epitope. Conclusion These data reveal differences in titer, neutralizing capacity, and affinity of the antibodies between BNT162b2‐ and CVnCoV‐elicited sera, which could contribute to the apparent differences in vaccine efficacy.
Abstract 12595: Fragmented QRS With Benign Early Repolarization Pattern is a Strong Predictor of Adverse Events in Patients With Suspected Acute Coronary Syndrome
Authors: Abdullah Ahmad, Ziad Faramand, Ahmad Mahmoud, Richard Gregg, Salah S Al-Zaiti
Journal: Circulation (2021)

Introduction: Early repolarization pattern (ERP) and fragmented QRS (fQRS) are well studied ECG markers of risk in various clinical populations. Emerging evidence suggests that coexistence of these patterns constitutes a synergistic substrate for arrhythmogenic events. Examining the prognostic value of these patterns would have immediate clinical applications for the triage of high-risk patients, including those with suspected acute coronary syndrome (ACS). Methods: This was a prospective study that enrolled chest pain patients transported via ambulance to UPMC hospitals. ERP was manually over-read by a blinded physician according to published guidelines. fQRS was automatically calculated as QRS loop notching on 3-D vectorcardiogram using manufacturer software. Patients were classified to four groups: 1) no ERP or fQRS; 2) ERP only; 3) fQRS only; and 4) both fQRS/ERP. Study outcome was major adverse cardiac events (MACE) within 30 days of admission, defined as: ACS, death, coronary revascularization, cardiac arrest, ventricular dysrhythmia, cardiogenic shock, and acute heart failure. Two independent reviewers adjudicated outcomes from the charts. Results: After excluding those with wide QRS (&gt;110ms), this analysis included 1392 out of 1650 patients on whom ECG interpretation was available (Age 57 ± 16; 48% females, 41% Black, 20% with adjudicated 30-day MACE). The prevalence of patients with no ERP/fQRS, ERP-only, fQRS-only, and both fQRS/ERP were 13%, 22%, 24%, and 41% respectively. In univariate analysis, those with fQRS-only (OR: 1.74; [95% CI, 1.03-2.94], p=0.038), and fQRS/ERP (OR: 2.14; [95% CI, 1.32-3.48], p=0.002) were associated with MACE compared to no ERP or fQRS as reference group. In final multivariate model, controlling for demographic and clinical data, fQRS/ERP remained a strong predictor of MACE (OR: 2.27; [95% CI, 1.34-3.87], p=0.002). Conclusions: Coexistence of fQRS/ERP on presenting ECG provides a strong predictor for 30-day MACE in suspected ACS, independent of patient characteristics These qualitative patterns can be easily visualized by clinicians during ECG interpretation, enhancing their potential application. The incremental role of these patterns in established tools (e.g., TIMI) is yet to be determined.
Abstract 11730: Data Quality and Monitoring Completion Rates Are Similar Between Clinic-Applied and Self-Applied Continuous ECG Monitoring Patches Prior to and During COVID-19
Authors: Jack A Goergen, Mike Hsu, Alan Wilk, Lori Crosson, Judith C Lenane, Bradley P Knight, Rod S Passman
Journal: Circulation (2021)

Introduction: Prior to COVID-19, ECG patches (ECGp) were applied almost exclusively in-clinic (CA) by technicians which required an office visit and fee. Since the pandemic, direct-to-patient, self-applied patch use (SA) has substantially increased, though the metrics surrounding SA are unknown. This study compares monitoring completion rates and data quality between CA and SA ECGp prior to and during COVID-19. Hypothesis: CA and SA ECGp have similar data quality and monitoring completion metrics. Methods: We performed a retrospective cohort analysis of patients prescribed an iRhythm Zio XT patch at Northwestern Memorial Hospital during the “pre-COVID” (3/1/2019-3/1/2020) and “COVID” (4/1/2020-4/1/2021) timeframes. Differences in ECGp with data available, actual vs prescribed wear time, and analyzable data between groups were assessed. ECGp without data was defined as devices which were not returned or not activated. Results: The cohort included 29,118 ECGp prescriptions; 13,180 pre-COVID (45%). The cohort was 56% female with mean age of 59.3 + 17.7 years. Palpitations (29%) and atrial fibrillation (19%) were the most common indications. In the pre-COVID cohort, there were no (0%) SA ECGp and data were available for 12,932 CA patches. In the COVID cohort, 34% of ECGp were SA; data were available for 10,231 CA ECGp and 4,902 SA ECGp. Average delay between prescription and SA ECGp activation was 8.1 ± 12.2 days. Comparisons between percent analyzable data, wear times, and ECGp with data available are shown in figure 1. Conclusions: COVID-19 resulted in a rapid adoption of SA ECGp use. Compared to CA, SA was associated with an inherent delay in ECGp application and a higher proportion of ECGp without data. However, there was no difference in actual vs prescribed wear time and a small but statistically significant decrease in percent analyzable data. These differences must be balanced with the additional cost and need for in-person visit for CA vs SA.
NIMG-30. PATHOLOGICAL VALIDATION OF CONTRAST ENHANCEMENT AT AUTOPSY BETWEEN PATIENTS TREATED AND UNTREATED WITH CHEMOTHERAPY AND RADIATION
Authors: Allison Lowman, Samuel Bobholz, Michael Brehler, Savannah Duenweg, John Sherman, Fitzgerald Kyereme, Jennifer Connelly, Elizabeth Cochran, Wade Mueller, Anjishnu Banerjee, Peter LaViolette
Journal: Neuro-Oncology (2021)

Abstract Tumor heterogeneity in glioblastoma complicates delineation of active tumor using standard MR imaging. Pseudo-progression following treatment with chemotherapy and radiation (chemoRT) further complicates how tumors appear. T1-weighted subtraction maps (T1S) have been used to better identify subtly enhancing regions containing infiltrative tumor. This study examines the differences in tumor appearance between patients treated with chemoRT compared to a cohort opting out at autopsy, to understand how chemoRT changes contrast enhancement on MRI. Ten patients diagnosed with glioblastoma were recruited for whole brain donation for this study. Three patients received no treatment (chemoRT-), and seven received a combination of chemoRT and additional treatments (chemoRT+), including but not limited to bevacizumab (Bev) and tumor treating fields (TTF). Large tissue samples were taken at autopsy from whole brain samples sliced axially to align with the last clinical MRI using patient-specific 3D-printed slicing jigs. All tissue samples were hematoxylin and eosin (HE) stained and digitized at 40X resolution (27 total samples). The whole slide images (WSI) were annotated to outline regions containing necrosis without pseudopalisading cells, tumor with pseudopalisading necrosis, and infiltrative tumor. T1S were created for each patient by subtracting intensity normalized T1-weighted images from T1 post-contrast images (T1C). The annotated WSIs were aligned and resampled into MRI space using a custom software. A mixed effect model was used to compare the T1S intensity between chemoRT +/- cohorts within each pathological annotation, incorporating a random effect for subject. Mean T1S intensity was greater in untreated subjects when compared to chemoRT-subjects within each pathological annotation, including necrosis without pseudopalisading cells, tumor with pseudopalisading necrosis, and infiltrative tumor (p&amp;lt; 0.001). We show that chemoRT reduces the contrast enhancement in all aspects of pathologically validated tumor compartments, including infiltrative tumor. Future research is needed to examine if other patterns are evident in additional MR sequences.
Abstract 9936: Impact of Lipids on Cardiovascular Disease in Healthy Individuals Without Dyslipidemia and with a Low Burden of Risk Factors: MESA (Multi-Ethnic Study of Atherosclerosis)
Authors: Zhen Zhou, Kwok Leung Ong, Seamus P Whelton, Matthew A Allison, Andrea J Curtis, Michael J Blaha, Monique Breslin, Andrew Tonkin, Costan Magnussen, Matthew Budoff, Mark R Nelson
Journal: Circulation (2021)

Introduction: The association between lipids and CVD among healthy persons without dyslipidemia is incompletely defined. Objectives: To determine the cross-sectional associations of lipids with subclinical atherosclerosis and 10-year incident CVD events among healthy participants with a low burden of cardiovascular risk factors. Methods: The analysis included 1,204 participants from the Multi-Ethnic Study of Atherosclerosis, who had no prior CVD events and were without current smoking, hypertension (BP ≥130/80 mmHg or antihypertensive use), diabetes (fasting glucose ≥126 mg/dl or glucose-lowering drug use), and dyslipidemia (LDL-C ≥160 mg/dl, HDL-C &lt;40 mg/dl, TC ≥240 mg/dl, TG ≥150 mg/dl, or lipid-lowering drug use) at baseline. Multivariable relative risk regression and Cox proportional-hazard regression were used in the analyses for subclinical atherosclerosis (presence of carotid plaque and/or coronary artery calcium) and CVD, respectively. Results: At baseline, participants’ median (IQR) age was 54 (49-62) years, mean LDL-C, TC, and HDL-C values were 112.1, 188.0, and 57.9 mg/dl, and median TG was 83.0 mg/dl. Subclinical atherosclerosis was presented in 43% of (n=522) participants. A 1-SD higher LDL-C, TC, non-HDL-C, TC/HDL-C, LDL-C/HDL-C, and TG/HDL-C was associated with a 6-9% higher prevalence of subclinical atherosclerosis (all p&lt;0.05). Over 10 years, 42 CVD events were recorded. For every 1-SD higher LDL-C (23.4 mg/dl), HDL-C (13.5 mg/dl), and non-HDL-C (25.3 mg/dl), HRs (95%CIs) for 10-year incident CVD events were 1.40 (1.01-1.96), 0.63 (0.41-0.96), and 1.44 (1.02-2.02). Similar associations with CVD were also observed for TC/HDL-C, LDL-C/HDL-C, and TG/HDL-C. TG was not associated with any outcome. ( Table 1 ) Conclusions: Except for TG, all lipids were associated with atherosclerosis and/or incident CVD, demonstrating a continuum of risk for lipids with subclinical atherosclerosis and CVD among healthy persons without dyslipidemia.
Abstract P482: Elucidating And Characterizing The Molecular Mechanistic Role Of Phospholamban L39 Stop In The Pathophysiology Of Cardiomyopathy Using Patient-derived Human Induced Pluripotent Stem Cells And Humanized Knock-in Mouse Model Systems
Authors: Anichavezhi Devendran, Rasheed Bailey, Sumanta Kar, Francesca Stillitano, Irene Turnbull, Kenneth Fish, Nicole Dubois, Nadeera Wickramasinghe, Roger Hajjar, Kevin Costa, Evangelia Kranias, Maria Trivieri
Journal: Circulation Research (2021)

Background: Heart failure (HF) is a complex clinical condition associated with substantial morbidity and mortality worldwide. The contractile dysfunction and arrhythmogenesis related to HF has been linked to the remodelling of calcium (Ca ++ ) handling. Phospholamban (PLN) has emerged as a key regulator of intracellular Ca ++ concentration. Of the PLN mutations, L39X is intriguing as it has not been fully characterized. This mutation is believed to be functionally equivalent to PLN null (KO) but contrary to PLN KO mice, L39X carriers develop a lethal cardiomyopathy (CMP). Our study aims at using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from homozygous L39X carriers to elucidate the role of L39X in human pathophysiology. Our plan also involves the characterization of humanized L39X knock-in mice (KM), which we hypothesize will develop a CMP from mis-localization of PLN and disruption of Ca ++ signalling. Methodology and Results: Mononuclear cells from Hom L39X carriers were obtained to generate 11 integration-free patient-specific iPSC clones. The iPSC-CMs were derived using established protocols. Compared to the WT iPSC-CMs, the Hom L39X derived-CMs PLN had an abnormal cytoplasmic distribution and formed intracellular aggregates, with the loss of perinuclear localization. There was also a 70% and 50% reduction of mRNA and protein expression of PLN respectively in L39X compared to WT iPSC-CMs. These findings indicated that L39X PLN is both under-expressed and mis-localized within the cell. To validate this observation in-vivo, we genetically modified FVB mice to harbour the human L39X. Following electroporation, positively transfected mouse embryonic stem cells were injected into host blastocysts to make humanized KM that were subsequently used to generate either a protamine-Cre (endogenous PLN driven expression) or a cardiac TNT mouse (i.e., CMP specific). Conclusion: Our data confirm an abnormal intracellular distribution of PLN, with the loss of perinuclear accumulation and mis-localization, suggestive of ineffective targeting to or retention of L39X. The mouse model will be critically important to validate the in-vitro observations and provides an ideal platform for future studies centred on the development of novel therapeutic strategies including virally delivered CRISPR/Cas9 for in-vivo gene editing and testing of biochemical signalling pathways.
Survival and complications in patients with haemoglobin E thalassaemia in Sri Lanka: a prospective, longitudinal cohort study
Authors: Anuja P Premawardhena, Dileepa Senajith Ediriweera, Amir Sabouhanian, Angela Allen, David Rees, Shanthimala de Silva, Windsor Perera, Nimal Katugaha, Mahinda Arambepola, Robert C Yamashita, Sachith Mettananda, Nilam Jiffry, Vikita Mehta, Refai Cader, Dayananda Bandara, Timothy St Pierre, Giulia Muraca, Christopher Fisher, Abirami Kirubarajan, Shawn Khan, Stephen Allen, Sanath P Lamabadusuriya, David J Weatherall, Nancy F Olivieri
Journal: The Lancet Global Health (2021)
INNV-09. SURGICAL STRATEGIES FOR OLDER PATIENTS WITH GLIOBLASTOMA
Authors: Tanyeri Barak, Lee Hwang, Justin Chen, Lan Jin, Danielle Miyagishima, Kanat Yalcin, Shahiba Ogilvie, Joseph Antonios, Brianna Theriault, Anita Huttner, Declan McGuone, Nathan Lifton, Nicholas Blondin, Zachary Corbin, Yawei Zhang, Murat Gunel, Zeynep Erson-Omay, Robert Fulbright, Tanyeri Tabar, Jennifer Moliterno-Gunel
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE Though image-guided surgery with intraoperative magnetic resonance imaging (IoMRI) is associated with higher extent of resection, we aimed to determine the clinical outcome of its use, compared to other less time-consuming intraoperative ultrasound (IoUS), in this patient population. METHODS Clinical data of 221 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination of IoMRI + IoUS at Yale New Haven Hospital and Memorial Sloan Kettering Cancer Center were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed, including predictors of overall survival. RESULTS The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (HR=0.85, 95% CI 0.49-1.47; P= 0.56) or Karnofsky Performance Score (KPS) at 6 weeks postoperatively (OR=0.51, 95% CI 0.22-1.15; P= 0.102). On the contrary, the length of surgery (LOSx) was significantly longer (P&amp;lt; 0.0001) in the IoMRI group. Postoperative complications were significantly less in the IoUS-only group (OR=0.17, 95% CI 0.3-0.46; P=0.002) and in patients who had a preoperative KPS score of 70 or higher (OR=0.092, 95% CI 0.018-0.47; P=0.004). Patients with relatively lower preoperative KPS scores (&amp;lt; 70) showed significant clinical improvement at 6 weeks postoperatively (P=0.0002). Patients with postoperative complications were more likely to have lower KPS scores at 6 weeks postoperatively (OR=0.30, 95% CI 0.10-0.89; P= 0.031), while increased extent of resection was associated with improved KPS scores at 6 weeks postoperatively (OR=2.171, 95% CI 1.22-3.87; P= 0.009). CONCLUSION Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS scores. The use of IoMRI in this patient population does not appear to yield any survival benefit over IoUS but instead significantly prolongs the length of surgery, increasing the risk for potential postoperative complications.