tbuckley/cabot-search huggingface dataset:
Uptake and effectiveness of checkpoint inhibitor therapy among trial-ineligible patients with advanced solid malignancies.
Authors: Ravi Bharat Parikh, Eun Jeong Min, E. Paul Wileyto, Fauzia Riaz, Cary Philip Gross, Roger B. Cohen, Rebecca A. Hubbard, Qi Long, Ronac Mamtani
Journal: Journal of Clinical Oncology (2021)

e18595 Background: Immune checkpoint inhibitors (ICIs) are part of standard of care in many advanced solid malignancies. Patients (pts) with poor performance status or organ dysfunction have been usually ineligible in pivotal clinical trials of ICIs. Methods: In this retrospective cohort study, we assessed ICI uptake and effectiveness among 34,131 pts diagnosed with advanced non-targetable non-small cell lung (NSCLC), urothelial cell (UCC), renal cell (RCC), or hepatocellular (HCC) carcinoma between January 1, 2014 and December 31, 2019. Pts were identified from the Flatiron Health electronic health record-derived database, consisting of pts receiving care in 280 mostly community oncology practices in the US. 9,318 (27.3%) pts were trial-ineligible based on ECOG performance status ≥ 2 or liver (total bilirubin ≥ 3 mg/dL) or kidney (eGFR &lt; 30 ml/min/1.73m 2 ) dysfunction. The association between trial-ineligibility and ICI monotherapy uptake was assessed using inverse probability weighted logistic regression. We hypothesized that there would be no differences in overall survival between ICI and non-ICI therapies in the trial-ineligible cohort. To test this hypothesis, we used inverse probability of treatment weighted survival analyses. Because we observed non-proportional hazards, we report 12- and 36-month restricted mean survival times (RMSTs) and time-varying hazard ratios &lt; and ≥ 6 months. Results: Between 2014-2019, the proportion of pts who received ICI monotherapy rose from 0% to 30.2% among trial-ineligible pts and from 0.1% to 19.4% among trial-eligible pts. Trial-ineligible pts received ICI monotherapy more frequently than trial-eligible pts (22.5% vs 12.7%, adjusted odds ratio [aOR] relative to non-ICI therapy 1.8, 95% CI 1.7-1.9). Among trial-ineligible pts, there were no OS differences between ICI monotherapy, ICI combination therapy, and non-ICI therapy at 12 months (RMST 7.8 vs. 7.7 vs. 8.1 mos) or 36 months (15.0 vs. 13.9 vs. 14.4 mos). Relative to non-ICI therapy, ICI monotherapy was associated with early mortality (adjusted hazard ratio [aHR] within 6 months 1.19) but late benefit (aHR after 6 months 0.80) in trial-ineligible pts (Table). Conclusions: Trial-ineligible pts with advanced malignancies preferentially receive first-line ICI, despite the lack of a survival benefit and possible early mortality associated with ICI use. Positive results for ICI in phase III trials may not translate to this vulnerable population. [Table: see text]
A real-world study of camrelizumab in the treatment of hepatocellular carcinoma.
Authors: Yong-Yi Zeng, Wu-hua Guo, Zhibo Zhang, Xi Shi, Yongjie Su, Qinghe Cai, Jianyang Peng
Journal: Journal of Clinical Oncology (2021)

e16121 Background: Programmed cell death protein‐1(PD-1) targeted immunotherapy is a promising treatment strategy for advanced hepatocellular carcinoma. Anti-PD-1 inhibitor camrelizumab showed antitumour activity in phase II studies of advanced hepatocellular carcinoma, with manageable toxicities. This study evaluates safety and efficacy of camrelizumab in patients with advanced hepatocellular carcinoma. Methods: This is a multicentre, real‐world trial done at thirty-three centres in Fujian Province, China. Eligible patients were aged 18 to 75 years was diagnosed by China Liver Cancer Staging(CNLC) 2019 clinical diagnostic criteria or with a histological or cytological diagnosis of advanced hepatocellular carcinoma, unresectable or had progressed on or were intolerant to previous systemic treatment, and had an Eastern Cooperative Oncology Group performance score of 0-1. Patients were received camrelizumab 200 mg intravenously every 2 weeks plus other treatments, such as molecular targeted drug, transcatheyer artetial chemoembolization, radiotherapy and chemotherapy. The primary endpoints were progression-free survival. Safety was analysed in all treated patients. Follow-up is ongoing. Results: Between Mar 12, 2020, and Dec 25, 2020, 63 patients were screened for eligibility, of whom 41 eligible patients received camrelizumab were recruited and among whom 15 received apatinib, 16 received lenvatinib, 2 received sorafenib and 1 received regorafenib. Median followup was 5.28 months (IQR 1.63–10.20). Objective response was reported in 12 (29.3%; 95% CI 16.1–45.5) of 41 patients. Disease control was reported in 34 (82.9%; 95% CI 67.9–92.8) of 41 patients. The median PFS was not reached, and expected more than 9 months. Grade 3 or 4 treatment-related adverse events occurred in 21 (51.2%) of 41 patients; the most common were increased gamma-glutamyltransferase (15 [36.6%]) and increased aspartate aminotransferase (7 [17%]). One death was judged by the investigators to be potentially treatment-related (due to upper gastrointestinal bleeding). Conclusions: Camrelizumab showed promising efficacy and safety in pretreated Chinese patients with advanced hepatocellular carcinoma, and might represent a new treatment option for these patients. Clinical trial information: ChiCTR2000041405. Research Sponsor: Jiangsu Hengrui Medicine Co., Ltd. Clinical trial information: ChiCTR2000041405.
Triglycerides and Residual Atherosclerotic Risk
Authors: Sergio Raposeiras-Roubin, Xavier Rosselló, Belén Oliva, Leticia Fernández-Friera, José M. Mendiguren, Vicente Andrés, Héctor Bueno, Javier Sanz, Vicente Martínez de Vega, Emad Abu-Assi, Andrés Iñiguez, Antonio Fernández-Ortiz, Borja Ibáñez, Valentin Fuster
Journal: Journal of the American College of Cardiology (2021)

Even when low-density lipoprotein-cholesterol (LDL-C) levels are lower than guideline thresholds, a residual risk of atherosclerosis remains. It is unknown whether triglyceride (TG) levels are associated with subclinical atherosclerosis and vascular inflammation regardless of LDL-C. This study sought to assess the association between serum TG levels and early atherosclerosis and vascular inflammation in apparently healthy individuals. An observational, longitudinal, and prospective cohort study, including 3,754 middle-aged individuals with low to moderate cardiovascular risk from the PESA (Progression of Early Subclinical Atherosclerosis) study who were consecutively recruited between June 2010 and February 2014, was conducted. Peripheral atherosclerotic plaques were assessed by 2-dimensional vascular ultrasound, and coronary artery calcification (CAC) was assessed by noncontrast computed tomography, whereas vascular inflammation was assessed by fluorine-18 fluorodeoxyglucose uptake on positron emission tomography. Atherosclerotic plaques and CAC were observed in 58.0% and 16.8% of participants, respectively, whereas vascular inflammation was evident in 46.7% of evaluated participants. After multivariate adjustment, TG levels ≥150 mg/dl showed an association with subclinical noncoronary atherosclerosis (odds ratio [OR]: 1.35; 95% confidence interval [CI]: 1.08 to 1.68; p = 0.008). This association was significant for groups with high LDL-C (OR: 1.42; 95% CI: 1.11 to 1.80; p = 0.005) and normal LDL-C (OR: 1.85; 95% CI: 1.08 to 3.18; p = 0.008). No association was found between TG level and CAC score. TG levels ≥150 mg/dl were significantly associated with the presence of arterial inflammation (OR: 2.09; 95% CI: 1.29 to 3.40; p = 0.003). In individuals with low to moderate cardiovascular risk, hypertriglyceridemia was associated with subclinical atherosclerosis and vascular inflammation, even in participants with normal LDL-C levels. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318)
Mepolizumab targets multiple immune cells in aspirin-exacerbated respiratory disease
Authors: Kathleen M. Buchheit, Erin Lewis, Deborah Gakpo, Jonathan Hacker, Aaqib Sohail, Faith Taliaferro, Evans Berreondo Giron, Chelsea Asare, Marko Vukovic, Jillian C. Bensko, Daniel F. Dwyer, Alex K. Shalek, Jose Ordovas-Montanes, Tanya M. Laidlaw
Journal: Journal of Allergy and Clinical Immunology (2021)
Increases in Anti-infective Drug Prices, Subsequent Prescribing, and Outpatient Costs
Authors: Junsoo Lee, Heesoo Joo, Brian A. Maskery, Jonathan D. Alpern, Chanhyun Park, Michelle Weinberg, William M. Stauffer
Journal: JAMA Network Open (2021)

Outpatient costs SOC prescription drug costsPatients receiving SOC prescription drugsNumbers of patients with hookworm, pinworm, and Clostridioides difficile who were treated (and not treated) with SOC prescription drugs are as follows.For hookworm, the numbers are 267 (360) patients in 2010 to 2011, 206 (413) patients in 2012 to 2013, 156 (385) patients in 2014 to 2015, and 219 (572) patients in 2016 to 2018.For pinworm, the numbers are 4283 (1007) patients in 2010, 4915 (1286) patients in 2011, 4207 (2121) patients in 2012, 1917 (2810) patients in 2013, 1551 (3300) patients in 2014, 1322 (2849) patients in 2015, 1218 (3076) patients in 2016, 1234 (2940) patients in 2017, and 807 (2064) patients in 2018.For C difficile, the numbers are 2383 (1070) patients in 2010, 3393 (1320) patients in 2011, 4057 (1461) patients in 2012, 3663 (1418) patients in 2013, 4010 (1501) patients in 2014, 4188 (1403) patients in 2015, 4317 (1411) patients in 2016, 3625 (1136) patients in 2017, and 2502 ( 740) patients in 2018.The changes over time were tested by using the comparison between 2010 and 2018 data.Among the samples, the proportions of female patients were 52.2% for hookworm, 62.5% for pinworm, and 64.5% for C difficile.Mean ages for patients with hookworm, pinworm, and C difficile were 32.7, 13.1, and 42.0 years, respectively.Patients older than 65 years were excluded from the analysis to avoid issues with Medicare coinsurance payments, as mentioned in the eAppendix in the Supplement.Error bars denote 95% CIs.
Predictive value of topoisomerase II alpha protein for clinicopathological characteristics and prognosis in early breast cancer.
Authors: Wu Yun, Yiqun Han, Hangcheng Xu, Qing Li, Binghe Xu, Pin Zhang, Peng Yuan, Fei Ma, Yang Luo, Ying Fan, Shanshan Chen, Ruigang Cai, Qiao Li, Jiayu Wang
Journal: Journal of Clinical Oncology (2021)

e12586 Background: Topoisomerase II alpha (TOP2A) has been identified as a proliferation marker, of which the most common method for detection is immunohistochemistry (IHC). However, the optimal cut-off of TOP2A expression regarding prognostic value remains controversial. This study was to identify the optimal cut-off value of TOP2A expression and its correlation with clinicopathological variables and prognosis in early-stage breast cancer in China. Methods: Between January 2013 and January 2015, a total of 1084 early breast cancer patients were enrolled. The optimal cut-off of TOP2A expression was assessed using the minimum P value approach. Correlations between TOP2A expression and clinicopathological characteristics were explored by the Spearman’s correlation analysis, while the impact of TOP2A expression on disease free survival (DFS) and overall survival (OS) was evaluated by the Kaplan-Meier methods. Univariate and multivariate Cox regression analyses were executed to identify statistically significant prognostic factors. Results: The optimal cut-off value of TOP2A was recommended as 15%. Overall, 603 (55.6%) patients were TOP2A over-expression and 481 (44.4%) patients were TOP2A low-expression. TOP2A over-expression was in positive associations with a higher ki67 index (r = 0.83, P &lt; 0.001), HER2 positive (r = 0.24, P &lt; 0.001), a larger tumor size (r = 0.15, P &lt; 0.001), and a higher histologic grade (r = 0.59, P &lt; 0.001), and in a significantly negative correlation with hormone receptor (HR) positive expression in early breast cancer (r = -0.40, P &lt; 0.001). TOP2A over-expression significantly associated with worse DFS (P = 0.001) and OS (P &lt; 0.001) and was an independent prognostic factor for both DFS (hazard ratio [HR] = 1.71; 95% confidence interval [95%CI]: 1.13-2.59, P = 0.02) and OS (HR = 3.53; 95%CI: 1.53-8.23, P = 0.003) in stage I-II breast cancer patients. Conclusions: To our knowledge, this is the first study to recommend the optimal cut-off value of TOP2A expression in breast cancer. The TOP2A expression is significantly correlated with HER2 status, ki67 index, tumor size, histologic grade, and HR status, and could be a surrogate indicator for poor prognosis of early breast cancer.
Leveraging the electronic medical record (EMR) to predict patient reported financial hardship in cancer patients.
Authors: Sandeep Sai Voleti, Sikander Ailawadhi, Carolyn Mead-Harvey, Rahma M. Warsame, Rafael Fonseca, Joan M. Griffin, Nandita Khera
Journal: Journal of Clinical Oncology (2021)

6594 Background: Patient reported financial hardship (FH) in cancer care is a growing challenge for patients, their caregivers and healthcare providers. As treatment costs escalate, it is imperative to develop effective strategies to proactively recognize and mitigate FH within oncology practice. Using automated processes to screen and refer patients to appropriate resources is a potential option. At Mayo Clinic, screening for FH involves using a single financial strain question ‘ How hard is it for you to pay for the very basics like food, housing, medical care, and heating?’ completed by all cancer patients annually as part of the Social Determinants of Health (SDOH) assessment. In this study, we describe the prevalence and predictors for FH (denoted by the answer ‘hard and very hard’) in our patient population. Methods: Patients receiving cancer care at the three Mayo Clinic sites (Minnesota, Arizona, and Florida) who completed the FH screen at least once were included in this study. Demographics (age, gender, race/ ethnicity, insurance, employment status, marital status, and zip code) and disease state data for included patients was extracted from the EMR and Mayo Clinic Cancer Registry. Disease state was categorized by type of cancer (hematological or solid malignancy) and cancer stage. Zip code was used to derive median income, rural/urban residence and distance from the cancer center. Multivariable logistic regression models were utilized to examine factors associated with FH. Results: The final study cohort included 31,969 patients with median age 66 years (IQR 57,73), 51% females, and 76% married. Race/ethnicity composition was 93% White, 3% Black, and 4% Hispanic. 52% of patients had Medicare and 43% had commercial insurance. Other notable factors included 48% retired, 41% working/ students, 76% married, and 72% urban residents. Median time from cancer diagnosis was 1.1 year (IQR 0.1, 3.8) and median income was $64,406 (IQR 53,067, 82,038). 31% of patients had hematological malignancies, 20% of the cancers for which staging information was available were metastatic. FH was reported by 4% (n = 1194) of the patients. A significantly higher likelihood of endorsing FH (p &lt; 0.001 for all) was noted in Hispanic (OR 1.64), Black (OR 1.84), American Indian/Alaskan native (OR 2.02), below median income (OR 1.48), rural (OR 1.17), self-pay (OR 2.77), Medicaid (OR 2.29), Medicare (OR 1.43), unemployed/disabled (OR 2.39), single (OR 2.07), or divorced (OR 2.43) patients. Older age, being retired, and living farther from the cancer center were associated with significantly less likelihood of endorsing FH. Conclusions: Our study successfully leveraged the EMR to identify key sociodemographic groups more likely to report FH. An electronic trigger to flag such patients at high-risk of FH and proactively address FH is currently being developed.
Complete Heart Block after open Heart Surgery in Children with Congenital Cardiac Diseases Feasibility of more waiting time before PPM administration
Authors: Ahmad Khosroshahi
Journal: Clinical Cardiology and Cardiovascular Interventions (2021)

Introduction: Congenital cardiac disorders are the most prevalent congenital disorders which require interventional or surgical treatments. The most common causes of complete heart block (CHB) are degeneration of cardiac conduction system, acute myocardial infarction and congenital cardiac disorders. CHB after congenital heart surgery is of paramount importance which causes post-operation death and heart failure. Application of a pacemaker is a standard treatment for CHB. The purpose of this paper is to study the frequency of early postoperative CHB in patients with congenital cardiac diseases and also the need for temporary (TPM) and permanent (PPM) pacemakers. Materials and methods: This descriptive-analytical and cross-sectional study was conducted on children with congenital heart defects who had undergone open-heart surgery in Tabriz’s Shahid Madani Hospital from 2011 to 2016. Patients with early postoperative CHB were included in the study. Those who had improved on their own and those who needed TPM and PPM were identified and at the end, the frequency of CHB and the need for TPM and PPM were assessed. Results: Of the 2100 operated patients, 109 patients developed early postoperative heart block. The frequency of early CHB after open heart surgery was 5.19%. Of the 109 patients, 69 patients (63.3%) with early postoperative CHB needed TPM, 9 patients needed PPM and 22 patients improved without pacemaker. Conclusion: The prevalence of early CHB in patients operated for congenital cardiac diseases was 5.19%. The need for TPM was high and most of the patients had improved cardiac rhythm with no need for PPM or TPM.
Driver mutations to predict for poorer outcomes in non-small cell lung cancer patients treated with concurrent chemoradiation and consolidation durvalumab.
Authors: Yufei Liu, Zhe Zhang, Waree Rinsurongkawong, Xiuning Le, Carl Michael Gay, Matthew S. Ning, John Heymach, Jianjun Zhang, Steven H. Lin
Journal: Journal of Clinical Oncology (2021)

8528 Background: The use of durvalumab after chemoradiation in locally advanced non-small cell lung cancer (NSCLC) patients significantly improves overall survival. However, it is unclear whether this benefit applies to all genetic subtypes of lung cancer. We hypothesize that patients with driver mutation NSCLC may derive less benefit from consolidation durvalumab. Methods: Using the Genomic Marker-Guided Therapy Initiative (GEMINI) database at MD Anderson, we identified 134 patients who were treated with chemoradiation followed by durvalumab for NSCLC. We segregated patients with driver mutations to targetable (EGFR, ALK translocation, ROS1 fusion, MET exon 14 skipping, RET fusion, and/or BRAF) (N = 24) and those driven by canonical KRAS mutations (N = 26). The rest (N = 84) had none of these mutations. We gathered demographic, treatment, and outcome data and compared progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. We used multivariate regression analysis to account for demographic and treatment variables. Results: For our cohort, median age at diagnosis was 64.8, 52% were female (n = 70), and median follow up was 1.5 years. 86% of patients have a history of smoking (n = 115). 21% had squamous cell histology (n = 28). 2 patients had stage IIA disease, 6 had stage IIB, 48 had stage IIIA, 56 had stage IIIB, 13 had stage IIIC, and 9 had stage IV. 73 patients had progression after durvalumab and 37 patients died. Patients with driver mutations had significantly worse median PFS compared to those without driver mutations (8.9 mo vs 26.6 mo; HR 2.62 p &lt; 0.001). Patients with KRAS mutations had particularly poor PFS (Median 7.9 mo, HR 3.34, p &lt; 0.001), while patients with targetable driver mutations trended to worse PFS (Median 14.5 mo, HR 1.96, p = 0.056). The median OS for the cohort was 4.8 yrs with no significant differences based on driver mutation status. On multivariate analysis, only driver mutation status was associated with PFS, but not OS. For patients with first progression, we found the targetable driver group to have significantly improved time to second objective progression (PFS2) compared to the KRAS (HR 0.28, p = 0.011) or non-mutated group (HR 0.38, p = 0.025). All patients in the targetable driver group received targeted therapy after first progression. Conclusions: Our results suggest that patients with driver mutations have worse PFS compared to patients without these mutations after chemoradiation. However, patients with targetable oncogene driver mutations have significantly improved prognosis after initial progression compared to the other groups, likely due to targeted therapy, suggesting that these therapies, including novel approaches towards KRAS mutants, should be further explored in this setting.
Hypoxia‐Inducible Exosomes Facilitate Liver‐Tropic Premetastatic Niche in Colorectal Cancer
Authors: Hao Sun, Qingtao Meng, Chengyu Shi, Hongbao Yang, Xiaobo Li, Shenshen Wu, Giuseppe Familiari, Michela Relucenti, Michael Aschner, Xuehao Wang, Rui Chen
Journal: Hepatology (2021)

Background and Aims Liver metastasis is a frequent occurrence in patients with colorectal cancer (CRC), with 15%‐25% of CRC patients having liver metastases at the time of initial diagnosis. Specifically, some regional‐stage patients with mild symptoms (stage 1 or 2) will also advance to liver metastases rapidly, even if the CRC lesion in situ is resected in time. Nevertheless, the precise mechanism of liver metastasis is still unclear. Approach and Results Fresh tumor tissues from patients with CRC, adjacent noncancerous tissues, and colorectal adenoma tissues were subjected to microarray analysis to identify differentially expressed microRNA. Exosomes from human serum and cell culture medium were separated, quantitated, and verified by transmission electronic microscopy and Zetasizer Nano. Luciferase reporter assay, real‐time quantitative PCR, western blot, immunoprecipitation, chromatin and re‐chromatin immunoprecipitation, migration and invasion assay, PDX mouse model, flow cytometry, immunohistochemistry, and immunofluorescence staining were employed to explore the regulation among CRC liver metastases, immunosuppression, and cell adhesion. In this study, we demonstrated that the hypoxic microenvironment in primary CRC lesions boosted exosome release, selectively initiated favorable premetastatic niche formation in the liver but not in other organs. Mechanistically, Kupffer cells (KCs) can phagocytose exosomes containing highly expressed miR‐135a‐5p from the blood circulation into the liver. Exosomal miR‐135a‐5p initiated the large tumor suppressor kinase 2–yes‐associated protein–matrix metalloproteinase 7 axis to promote the occurrence of CRC liver metastasis, and cluster of differentiation 30–TNF receptor–associated factor 2–p65–mediated immunosuppression signaling also contributed to this process. Conclusions Hypoxia‐induced exosomal miR‐135a‐5p correlates with the development, clinical severity, and prognosis of CRC liver metastases through the premetastatic niche; and our findings revealed that miR‐135a‐5p might be a promising target in halting CRC liver metastases.