tbuckley/cabot-search huggingface dataset:
COAST: An Open-Label, Phase II, Multidrug Platform Study of Durvalumab Alone or in Combination With Oleclumab or Monalizumab in Patients With Unresectable, Stage III Non–Small-Cell Lung Cancer
Authors: Roy S. Herbst, Margarita Majem, Fabrice Barlesi, Enric Carcereny, Quincy Chu, Isabelle Monnet, Alfredo Sanchez-Hernandez, Shaker Dakhil, D. Ross Camidge, Leanne Winzer, Yee Soo-Hoo, Zachary A. Cooper, Rakesh Kumar, John Bothos, Charu Aggarwal, Alex Martinez-Marti
Journal: Journal of Clinical Oncology (2022)

Durvalumab significantly improves overall survival for patients with unresectable stage III non-small-cell lung cancer and no progression after concurrent chemoradiotherapy (cCRT). Building upon that standard of care, COAST is a phase II study of durvalumab alone or combined with the anti-CD73 monoclonal antibody oleclumab or anti-NKG2A monoclonal antibody monalizumab as consolidation therapy in this setting.Patients with unresectable stage III non-small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0/1, and no progression after cCRT were randomly assigned 1:1:1, ≤ 42 days post-cCRT, to durvalumab alone or combined with oleclumab or monalizumab for up to 12 months, stratified by histology. The primary end point was investigator-assessed confirmed objective response rate (ORR; RECIST v1.1).Between January 2019 and July 2020, 189 patients were randomly assigned. At this interim analysis (data cutoff, May 17, 2021), median follow-up was 11.5 months (range, 0.4-23.4 months; all patients). Confirmed ORR was numerically higher with durvalumab plus oleclumab (30.0%; 95% CI, 18.8 to 43.2) and durvalumab plus monalizumab (35.5%; 95% CI, 23.7 to 48.7) versus durvalumab (17.9%; 95% CI, 9.6 to 29.2). Progression-free survival (PFS) was prolonged with both combinations versus durvalumab (plus oleclumab: hazard ratio, 0.44; 95% CI, 0.26 to 0.75; and plus monalizumab: hazard ratio, 0.42; 95% CI, 0.24 to 0.72), with higher 12-month PFS rates (plus oleclumab: 62.6% [95% CI, 48.1 to 74.2] and plus monalizumab: 72.7% [95% CI, 58.8 to 82.6] v durvalumab alone: 33.9% [95% CI, 21.2 to 47.1]). All-cause grade ≥ 3 treatment-emergent adverse events occurred in 40.7%, 27.9%, and 39.4% with durvalumab plus oleclumab, durvalumab plus monalizumab, and durvalumab, respectively.Both combinations increased ORR and prolonged PFS versus durvalumab alone. Safety was similar across arms with no new or significant safety signals identified with either combination. These data support their further evaluation in a phase III trial.
Inhibition of XPO1 Sensitizes Small Cell Lung Cancer to First- and Second-Line Chemotherapy
Authors: Alvaro Quintanal-Villalonga, Hirokazu Taniguchi, Yuan Hao, Andrew Chow, Yingqian A. Zhan, Shweta S. Chavan, Fathema Uddin, Viola Allaj, Parvathy Manoj, Nisargbhai S. Shah, Joseph M. Chan, Michael Offin, Metamia Ciampricotti, Jordana Ray-Kirton, Jacklynn Egger, Umesh Bhanot, Irina Linkov, Marina Asher, Michael H. Roehrl, Juan Qiu, Elisa de Stanchina, Travis J. Hollmann, Richard P. Koche, Triparna Sen, John T. Poirier, Charles M. Rudin
Journal: Cancer Research (2021)

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis and extreme lethality. The backbone of SCLC treatment over the past several decades has been platinum-based doublet chemotherapy, with the recent addition of immunotherapy providing modest benefits in a subset of patients. However, nearly all patients treated with systemic therapy quickly develop resistant disease, and there is an absence of effective therapies for recurrent and progressive disease. Here we conducted CRISPR-Cas9 screens using a druggable genome library in multiple SCLC cell lines representing distinct molecular subtypes. This screen nominated exportin-1, encoded by XPO1, as a therapeutic target. XPO1 was highly and ubiquitously expressed in SCLC relative to other lung cancer histologies and other tumor types. XPO1 knockout enhanced chemosensitivity, and exportin-1 inhibition demonstrated synergy with both first- and second-line chemotherapy. The small molecule exportin-1 inhibitor selinexor in combination with cisplatin or irinotecan dramatically inhibited tumor growth in chemonaïve and chemorelapsed SCLC patient-derived xenografts, respectively. Together these data identify exportin-1 as a promising therapeutic target in SCLC, with the potential to markedly augment the efficacy of cytotoxic agents commonly used in treating this disease. SIGNIFICANCE: CRISPR-Cas9 screening nominates exportin-1 as a therapeutic target in SCLC, and exportin-1 inhibition enhances chemotherapy efficacy in patient-derived xenografts, providing a novel therapeutic opportunity in this disease.
Cigarette Smoke Exposure and Acute Respiratory Distress Syndrome in Sepsis: Epidemiology, Clinical Features, and Biologic Markers
Authors: Farzad Moazed, Carolyn Hendrickson, Alejandra Jauregui, Jeffrey Gotts, Amanda Conroy, Kevin Delucchi, Hanjing Zhuo, Mikhaela Arambulo, Kathryn Vessel, Serena Ke, Thomas Deiss, Amy Ni, Aleksandra Leligdowicz, Jason Abbott, Mitchell J. Cohen, Pratik Sinha, Antonio Gomez, Kirsten Kangelaris, Lucy Kornblith, Michael Matthay, Neal Benowitz, Kathleen Liu, Carolyn S. Calfee
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Cigarette smoke exposure is associated with an increased risk of developing acute respiratory distress syndrome (ARDS) in trauma, transfusion, and nonpulmonary sepsis. It is unknown whether this relationship exists in the general sepsis population. Furthermore, it is unknown if patients with ARDS have differences in underlying biology based on smoking status. Objectives: To assess the relationship between cigarette smoke exposure and ARDS in sepsis and identify tobacco-related biomarkers of lung injury. Methods: We studied a prospective cohort of 592 patients with sepsis from 2009 to 2017. Plasma cotinine and urine NNAL [urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol] were measured to categorize smoking status. Plasma biomarkers of inflammation and lung injury were measured, including in a smaller cohort of trauma patients with ARDS to increase generalizability. Measurements and Main Results: Passive and active smoking were associated with increased odds of developing ARDS in patients with sepsis. Among patients with sepsis and ARDS, active cigarette smokers were younger and had lower severity of illness than nonsmokers. Patients with ARDS with cigarette smoke exposure had lower plasma levels of IL-8 (P = 0.01) and sTNFR-1 (soluble tumor necrosis factor 1; P = 0.01) compared with those without exposure. Similar biomarker patterns were observed in blunt trauma patients with ARDS. Conclusions: Passive and active smoking are associated with an increased risk of developing ARDS in patients with pulmonary and nonpulmonary sepsis. Among patients with ARDS, those with cigarette smoke exposure have less systemic inflammation, while active smokers also have lower severity of illness compared with nonsmokers, suggesting that smoking contributes to biological heterogeneity in ARDS.
Covid-19: Symptomatic infection with omicron variant is milder and shorter than with delta, study reports
Authors: Jacqui Wise
Journal: BMJ (2022)

Covid-19: Symptomatic infection with omicron variant is milder and shorter than with delta, study reports Jacqui WiseVaccinated people infected with the omicron variant of SARS-CoV-2 had symptoms for 6.87 days on average, compared with 8.89 days with the delta variant, data from the ZOE app have shown. 1Among those who had received two vaccine doses plus a booster the duration of symptoms was shorter still, at 4.4 days with omicron and 7.7 days with delta.The shorter presentations of symptoms suggest a shorter period of infectiousness with omicron, which could affect workplace health policies and public health guidance, said the study authors from King's College, London.However, this will need to be confirmed by viral load studies.2
Abstract EP03: 30-day Readmission Rates After Targeted Temperature Management For Cardiac Arrest
Authors: Justin Mark, Joshua Dodge, Miguel Belaunzaran, Waseem Wahood, Patrick Hardigan, Abdelrhman abumoawad
Journal: Circulation (2022)

Background: In its 2015 guidelines, the American Heart Association instituted a Class 1 recommendation for use of Targeted Temperature Management (TTM) in patients with cardiac arrest (CA) . Prior observational studies have suggested benefits using TTM in these patients, while many randomized control trials have failed to replicate these results. Regardless, there have been studies with contradictory conclusions addressing readmission rates in patients receiving TTM. Thus, we sought to ascertain this relationship further by identifying 30-day readmission rates in Out-of-Hospital Cardiac Arrest (OHCA) patients receiving TTM. Methods: We utilized the Healthcare Cost and Utilization Project (HCUP) National Readmission Database (NRD) for data collection and International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes to identify 353,380 cardiac arrest cases and clinical variables. The primary outcome includes all-cause readmission rates within 30 days from cardiac arrest index admission discharge. We then conducted a logistic regression analysis after accounting for variables to assess odds of 30-day readmission in these patients. Results: TTM following CA was associated with a decreased likelihood of readmission at 30 days(OR: 0.822, p = 0.006, 95% CI [0.716-0.945]). Comorbidities associated with an increased risk of readmission after controlling for the other variables include congestive heart failure(OR: 1.259, p = 0.027, 95% CI [1.207-1.313]) and renal failure (OR: 1.363, p = 0.031, 95% CI [1.304- 1.425]). Of these patients receiving TTM compared to those who did not receive TTM, there was a greater proportion of cardiogenic shock (23.7% vs. 12.3%, p &lt; 0.001), acute heart failure (20.1% vs. 17.3%, p &lt; 0.001), coronary artery disease (53.0% vs. 46.2%, p &lt; 0.001), ischemic cardiomyopathy (61.7% vs. 53.1%, p &lt; 0.001), ventricular tachycardia (9.6% vs. 8.6%, p = 0.045), and ventricular fibrillation (56.6% vs. 24.1%, p&lt;0.001). Conclusion: TTM following CA is associated with decreased odds of readmission at 30 days. Prior long-term comorbidities represented most of the covariates for readmissions in this patient population.
Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline
Authors: Bianca D. Santomasso, Loretta J. Nastoupil, Sherry Adkins, Christina Lacchetti, Bryan J. Schneider, Milan Anadkat, Michael B. Atkins, Kelly J. Brassil, Jeffrey M. Caterino, Ian Chau, Marianne J. Davies, Marc S. Ernstoff, Leslie Fecher, Pauline Funchain, Ishmael Jaiyesimi, Jennifer S. Mammen, Jarushka Naidoo, Aung Naing, Tanyanika Phillips, Laura D. Porter, Cristina A. Reichner, Carole Seigel, Jung-Min Song, Alexander Spira, Maria Suarez-Almazor, Umang Swami, John A. Thompson, Praveen Vikas, Yinghong Wang, Jeffrey S. Weber, Kathryn Bollin, Monalisa Ghosh
Journal: Journal of Clinical Oncology (2021)

PURPOSE To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell therapy. METHODS A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021. RESULTS The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell–related toxicities, including cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell–associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell–associated neurotoxicity syndrome should be managed with corticosteroids and supportive care. Additional information is available at www.asco.org/supportive-care-guidelines.
Prognostic Significance of DNA Methylation Profiles at MRI Enhancing Tumor Recurrence: a Report from the EORTC 26091 TAVAREC Trial
Authors: Kaspar Draaisma, C. Mircea S. Tesileanu, Iris de Heer, Martin Klein, Marion Smits, Jaap C. Reijneveld, Paul M. Clement, Filip Y.F. de Vos, Antje Wick, Paul J. Mulholland, Martin J.B. Taphoorn, Michael Weller, Olivier L. Chinot, Johan M. Kros, Tina Verschuere, Corneel Coens, Vassilis Golfinopoulos, Thierry Gorlia, Ahmed Idbaih, Pierre A. Robe, Martin J. van den Bent, Pim J. French
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Despite recent advances in the molecular characterization of gliomas, it remains unclear which patients benefit most from which second-line treatments. The TAVAREC trial was a randomized, open-label phase II trial assessing the benefit of the addition of the angiogenesis inhibitor bevacizumab to treatment with temozolomide in patients with a first enhancing recurrence of World Health Organization grade 2 or 3 glioma without 1p/19q codeletion. We evaluated the prognostic significance of genome-wide DNA methylation profiles and copy-number variations on the TAVAREC trial samples. Experimental Design: Isocitrate dehydrogenase (IDH) mutation status was determined via Sanger sequencing and IHC. DNA methylation analysis was performed using the MethylationEPIC BeadChip (Illumina) from which 1p/19q codeletion, MGMT promoter methylation (MGMT-STP27), and homozygous deletion of CDKN2A/B were determined. DNA methylation classes were determined according to classifiers developed in Heidelberg and The Cancer Genome Atlas (TCGA; “Heidelberg” and “TCGA” classifier respectively). Results: DNA methylation profiles of 122 samples were successfully determined. As expected, most samples were IDH-mutant (89/122) and MGMT promotor methylated (89/122). Methylation classes were prognostic for time to progression. However, Heidelberg methylation classes determined at time of diagnosis were no longer prognostic following enhancing recurrence of the tumor. In contrast, TCGA methylation classes of primary samples remained prognostic also following enhancing recurrence. Homozygous deletions in CDKN2A/B were found in 10 of 87 IDH-mutated samples and were prognostically unfavorable at recurrence. Conclusions: DNA methylome Heidelberg classification at time of diagnosis is no longer of prognostic value at the time of enhancing recurrence. CDKN2A/B deletion status was predictive of survival from progression of IDH-mutated tumors.
Doxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A Multicenter Randomized Controlled Trial
Authors: Kai-ni Shen, Wei-jun Fu, Yu Wu, Yu-jun Dong, Zhong-xia Huang, Yong-qiang Wei, Chun-rui Li, Chun-yan Sun, Ye Chen, Hui-lei Miao, Yue-lun Zhang, Xin-xin Cao, Dao-bin Zhou, Jian Li
Journal: Circulation (2021)

Background: Doxycycline was demonstrated in a retrospective study to be associated with greater survival in patients with light chain amyloidosis. Therefore, we prospectively compared the efficacy of bortezomib-cyclophosphamide-dexamethasone (CyBorD) and CyBorD combined with doxycycline for cardiac light chain amyloidosis. Methods: This was a multicenter, open-label, randomized controlled trial. Patients with Mayo 2004 stage II to III light chain amyloidosis were included. Patients were randomized to doxycycline 100 mg twice daily along with 9 cycles of CyBorD (doxycycline group) or to 9 cycles of CyBorD alone (control group). The primary outcome was 2-year progression-free survival (PFS). PFS was defined as the time from randomization to death, hematologic progression, or organ progression (heart, kidney or liver). Hematologic progression was defined on the basis of a substantial increase in free light chain. An increase in either NT-proBNP (N-terminal pro B-type natriuretic peptide) or cardiac troponin was the main criterion for defining cardiac progression. Cardiac PFS, defined as the time from randomization to cardiac progression or death, was compared between groups in an exploratory analysis. The corresponding treatment hazard ratio was estimated with a Cox regression model. Results: One hundred forty patients underwent randomization, with 70 in each group. The median age was 61 years (range, 33–78 years) with a male:female ratio of 1.75:1. Stage II disease was present in 34 (48.6%) and 33 (47.1%) patients in the doxycycline and control groups, respectively. After a median follow-up duration of 24.4 months, 32 of 70 (45.7%) patients in the doxycycline group and 30 of 70 (42.9%) patients in the control group experienced progression. PFS was not significantly different between groups (hazard ratio, 0.97 [95% CI, 0.59–1.60]; P =0.91). Cardiac progression occurred in 29 of 70 (41.4%) patients in the doxycycline group and 26 of 70 (37.1%) patients in the control group. The death rates for both groups by the end of follow-up was the same, 25 of 70 (35.7%). No significant differences were observed for either cardiac PFS (hazard ratio, 0.91 [95% CI, 0.54–1.55]; P =0.74) or overall survival (hazard ratio, 1.04 [95% CI, 0.60–1.81]; P =0.89). Conclusions: Our trial demonstrated that doxycycline combined with CyBorD failed to prolong PFS or cardiac PFS compared with CyBorD alone in cardiac light chain amyloidosis. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03401372.
Abstract EP25: Socioeconomic Disparities In The Use Of Temporary Mechanical Circulatory Support And Outcome In Cardiogenic Shock
Authors: Kyeeun Park, Pyi Phyo Aung, Htoo Myat Nge
Journal: Circulation (2022)

Introduction: There has been limited data on impact of socioeconomic status (SES) on temporary mechanical circulation support (MCS) use and in-hospital outcome of cardiogenic shock (CS). Investigating accessibility of advanced medical device and the outcome by SES is imperative to improve public health and develop interventions to reduce healthcare disparities. Methods and Results: We conducted a retrospective analysis of the 2016 to 2018 National Inpatient Sample database and the 2018 to 2019 Nationwide Readmission Database (NRD). Study populations were selected using ICD-10 diagnosis code and ICD-10 procedure code for MCS. SES was evaluated using median household income of patient’s ZIP code and dived into quarter. Discharge-level weight analysis was used to produce a national estimate. We conducted univariate and multivariable hierarchical regression analysis to calculate odds ratio (OR) with STATA 17. During the study period, 466,350 patients were hospitalized with CS of which 30.46% were from 1 st (lowest), 26.62% from 2 nd , 23.65% from 3 rd and 19.27 from 4 th (highest) quartile. 38.58% of CS was secondary to acute coronary artery syndrome. 19.49% (90,905 of 466,350) of CS led to MCS use with IABP, Impeller, percutaneous left ventricular assist device (pLVD) and extracorporeal membrane oxygenation (ECMO) (73.87%;67,154 of 90,905, 26.05%;23,680 of 90,905, 24.35%;22,135 of 90,905 and 1.45%;1,320 of 90,905 respectively). 18.27% (25,435 of 139,235) of lowest quartile patients utilized MCS in contrast to 20.50 %(18,055 of 88,070) of highest quartile. After adjusting for age, sex and comorbid burden, there was a significant higher mortality for the lowest SES quartile as compared to the highest quartile (OR 1.18; 95%CI 1.14-1.24; p &lt; 0.0001). Similarly, the lowest SES quartile was found to be significant indicator for unplanned 30-day readmission (OR 1.16; 95%CI 1.12-1.21; p &lt; 0.0001). Furthermore, there was a lower utilization of MCS among patients from lower SES compared to higher SES (OR 0.87; 95%CI 0.83-0.91; p &lt; 0.0001). Discussion: Patients with lower SES were found to have increased in-hospital mortality, unplanned readmission and decreased utilization of MCS. Further study and public intervention needed to improve CS outcome and accessibility of MCS in low SES patients.
Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin
Authors: Jesper Bäckdahl, Lovisa Franzén, Lucas Massier, Qian Li, Jutta Jalkanen, Hui Gao, Alma Andersson, Nayanika Bhalla, Anders Thorell, Mikael Rydén, Patrik L. Ståhl, Niklas Mejhert
Journal: Cell Metabolism (2021)

Main text(Cell Metabolism 33, 1869–1882.e1–e6; September 7, 2021)In the original version of Figure 7G, the legend states that the image is from subject #2. However, the H&E image displayed in Figure 7G is from subject #5. This error has been corrected online. As this error occurred while writing the legend and not during data analysis, this error has no impact on the main results or conclusions of the publication. The authors apologize for this error and any confusion it may have caused. Main text(Cell Metabolism 33, 1869–1882.e1–e6; September 7, 2021)In the original version of Figure 7G, the legend states that the image is from subject #2. However, the H&E image displayed in Figure 7G is from subject #5. This error has been corrected online. As this error occurred while writing the legend and not during data analysis, this error has no impact on the main results or conclusions of the publication. The authors apologize for this error and any confusion it may have caused. (Cell Metabolism 33, 1869–1882.e1–e6; September 7, 2021) In the original version of Figure 7G, the legend states that the image is from subject #2. However, the H&E image displayed in Figure 7G is from subject #5. This error has been corrected online. As this error occurred while writing the legend and not during data analysis, this error has no impact on the main results or conclusions of the publication. The authors apologize for this error and any confusion it may have caused. Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulinBäckdahl et al.Cell MetabolismAugust 10, 2021In BriefTissue microarchitecture and cell composition are major determinants of organ function. Here, Bäckdahl et al. apply spatial transcriptomics to human white adipose tissue. This reveals that the tissue is more spatially defined than expected and identifies three distinct mature adipocyte subtypes with qualitatively different sensitivities to insulin stimulation in vivo. Full-Text PDF Open Access