tbuckley/cabot-search huggingface dataset:
ARC-9: Phase Ib/II study to evaluate etrumadenant (AB928)-based treatment combinations in patients with metastatic colorectal cancer (mCRC).
Authors: Michael Cecchini, Kartik Krishnan, Nick Giafis, Jennifer Scott, Cheng Seok Quah, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2021)

TPS150 Background: ATP release from dying cancer cells in response to platinum-based chemotherapy increases extracellular immunosuppressive adenosine, which binds and activates the A 2a and A 2b receptors on immune cells. Adenosine-mediated signaling impairs activation, proliferation, and cytotoxic activity of effector T cells, resulting in inhibition of antitumor activity. Concomitant adenosine receptor blockade may therefore enhance the therapeutic efficacy of chemo/immunotherapy regimens. Etrumadenant (AB928), the first clinical-stage, small-molecule, dual adenosine receptor antagonist, is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Recently, results were reported for the ARC-3 phase 1/1b study of etrumadenant + modified 5-fluorouracil + oxaliplatin (mFOLFOX-6) in patients (pts) with mCRC. In this study, etrumadenant + mFOLFOX-6 was well tolerated without significant additive toxicity. Disease control was observed in patients with RAS/BRAF mutated mCRC, as well as 3L+ disease previously treated with FOLFOX and/or FOLFIRI (PR and/or SD &gt;4 mo). Due to deep responses in 1L-3L+ pts, 6 pts had the opportunity to pursue surgery and radiotherapy with curative intent. The encouraging results from ARC-3 warrant further evaluation of etrumadenant-based combination therapy for mCRC. Methods: ARC-9 is a phase 1b/2, multicohort, open-label, randomized platform study designed to evaluate safety and clinical activity of etrumadenant (150 mg orally once daily [QD]) in combination with standard-of-care (SOC) regimens or novel therapeutics in pts with mCRC (Table). Cohort eligibility is based on prior anticancer treatment history. Pts enrolled in Cohorts A and B will be randomized (2:1) into the experimental vs SOC arms. Cohort C consists of a single arm to allow inclusion of novel agents as they become available with built in early stopping rules for futility. Pts who progress on the SOC arm of Cohort A can enroll in Cohort B; pts who progress on the SOC arm of Cohort B can crossover to the experimental arm. Primary endpoints across cohorts are shown in Table. Safety monitoring will occur throughout the trial, disease assessments will occur every 8 weeks, and correlative study pre- and on-treatment biopsies will be performed. [Table: see text]
Association of Polypharmacy and Potentially Inappropriate Medications With Physical Functional Impairments in Older Adults With Cancer
Authors: Mostafa R. Mohamed, Erika Ramsdale, Kah Poh Loh, Huiwen Xu, Amita Patil, Nikesha Gilmore, Spencer Obrecht, Megan Wells, Ginah Nightingale, Katherine M. Juba, Bryan Faller, Adedayo Onitilo, Thomas Bradley, Eva Culakova, Holly Holmes, Supriya G. Mohile
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: Polypharmacy and potentially inappropriate medications (PIMs) are prevalent in older adults with cancer, but their associations with physical function are not often studied. This study examined the associations of polypharmacy and PIMs with physical function in older adults with cancer, and determined the optimal cutoff value for the number of medications most strongly associated with physical functional impairment. Methods: This cross-sectional analysis used baseline data from a randomized study enrolling patients aged ≥70 years with advanced cancer starting a new systemic cancer treatment. We categorized PIM using 2015 American Geriatrics Society Beers Criteria. Three validated physical function measures were used to assess patient-reported impairments: activities of daily living (ADL) scale, instrumental activities of daily living (IADL) scale, and the Older Americans Resources and Services Physical Health (OARS PH) survey. Optimal cutoff value for number of medications was determined by the Youden index. Separate multivariate logistic regressions were then performed to examine associations of polypharmacy and PIMs with physical function measures. Results: Among 439 patients (mean age, 76.9 years), the Youden index identified ≥8 medications as the optimal cutoff value for polypharmacy; 43% were taking ≥8 medications and 62% were taking ≥1 PIMs. On multivariate analysis, taking ≥8 medications was associated with impairment in ADL (adjusted odds ratio [aOR], 1.64; 95% CI, 1.01–2.58) and OARS PH (aOR, 1.73; 95% CI, 1.01–2.98). PIMs were associated with impairments in IADL (aOR, 1.72; 95% CI, 1.09–2.73) and OARS PH (aOR, 1.97; 95% CI, 1.15–3.37). A cutoff of 5 medications was not associated with any of the physical function measures. Conclusions: Physical function, an important component of outcomes for older adults with cancer, is cross-sectionally associated with polypharmacy (defined as ≥8 medications) and with PIMs. Future studies should evaluate the association of polypharmacy with functional outcomes in this population in a longitudinal fashion.
Suicide-Related Internet Searches During the Early Stages of the COVID-19 Pandemic in the US
Authors: John W. Ayers, Adam Poliak, Derek C. Johnson, Eric C. Leas, Mark Dredze, Theodore Caputi, Alicia L. Nobles
Journal: JAMA Network Open (2021)

This cross-sectional study assesses trends in suicide-related internet search rates in the early stages of the COVID-19 pandemic in the US.
Use of risk assessment instruments to predict violence and antisocial behaviour in 73 samples involving 24 827 people: systematic review and meta-analysis
Journal: BMJ (2012)

Use of risk assessment instruments to predict violence and antisocial behaviour in 73 samples involving 24 827 people: systematic review and meta-analysisIn this Research paper's data supplement, the uploaded image in web figure 4 is the same as in web figure 3 (BMJ 2012;345:e4692, doi:10
Trends in Outbreak-Associated Cases of COVID-19 — Wisconsin, March–November 2020
Authors: Ian W. Pray, Anna Kocharian, Jordan Mason, Ryan Westergaard, Jonathan Meiman
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

During September 3–November 16, 2020, daily confirmed cases of coronavirus disease 2019 (COVID-19) reported to the Wisconsin Department of Health Services (WDHS) increased at a rate of 24% per week ..
Financial incentives for doctors
Authors: Marc A Rodwin
Journal: BMJ (2004)

Have their place but need to be evaluated and used to promote appropriate goals 

George Bernard Shaw put it well. “That any sane nation, having observed that you could provide for the supply of bread by giving bakers a pecuniary interest in baking for you, should go on to give a surgeon a pecuniary interest in cutting off your leg, is enough to make one despair…”1 The problem, according to Shaw, was that the profit motive and doctors' entrepreneurialism create the wrong incentives for good medical practice. The creation of the NHS solved the problem of perverse incentives. Or did it?

Certainly the NHS eliminates the need for practitioners to perform excessive medical procedures to achieve economic security. But all payment systems create incentives. They differ in strength, effect, and the activities they encourage. The NHS pays general practitioners in part by capitation to reward doctors who serve more patients. Since its creation the NHS has also provided distinction awards—salary premiums for a select group of practitioners—as a strategy to recruit and retain doctors who might otherwise choose careers …
Weight Loss and Weight Regain in Usual Clinical Practice: Results From the TARGET-NASH Observational Cohort
Authors: Miguel H. Malespin, Alfred Sidney Barritt, Stephanie E. Watkins, Cheryl Schoen, Monica A. Tincopa, Karen D. Corbin, Andrea R. Mospan, Breda Munoz, Huy N. Trinh, L. Michael Weiss, K. Rajender Reddy, Rohit Loomba, Nyingi Kemmer, Anna S. Lok
Journal: Clinical Gastroenterology and Hepatology (2021)
A lncRNA TCL6-miR-155 Interaction Regulates the Src-Akt-EMT Network to Mediate Kidney Cancer Progression and Metastasis
Authors: Priyanka Kulkarni, Pritha Dasgupta, Yutaka Hashimoto, Marisa Shiina, Varahram Shahryari, Z. Laura Tabatabai, Soichiro Yamamura, Yuichiro Tanaka, Sharanjot Saini, Rajvir Dahiya, Shahana Majid
Journal: Cancer Research (2021)

Abstract Metastasis is the leading cause of mortality from kidney cancer, and understanding the underlying mechanism of this event will provide better strategies for its management. Here we investigated the biological, functional, and clinical significance of lncTCL6 and its interacting miR-155 in clear cell renal cell carcinoma (ccRCC). We employed a comprehensive approach to investigate the lncTCL6-miR-155-Src/Akt–mediated epithelial-to-mesenchymal transition (EMT) pathway as a novel regulatory mechanism in ccRCC progression. Expression analyses revealed that lncTCL6 is downregulated in ccRCC compared with normal tissues. Overexpression of lncTCL6 in ccRCC cell lines impaired their oncogenic functions, such as cell proliferation and migration/invasion, and induced cell-cycle arrest and apoptosis; conversely, depletion of lncTCL6 rescued these phenotypic effects. Furthermore, lncTCL6 directly interacted with miR-155. Unlike lncTCL6, miR-155 was overexpressed in ccRCC. Stable knockdown of miR-155 phenocopied the effects of lncTCL6 overexpression. Conversely, reconstitution of miR-155 and suppression of lncTCL6 in noncancerous renal cell HK2 induced tumorigenic characteristics. Patients with higher expression of lncTCL6 and lower expression of miR-155 had better survival probability. When overexpressed, lncTCL6 recruited STAU1 and mediated decay of Src mRNA, followed by a marked downregulation of an integrated network of Src target genes involved in migration, invasion, and EMT. However, the interaction between miR-155 and lncTCL6 attenuated the regulatory role of lncTCL6 on Src-mediated EMT. In conclusion, this study is the first report documenting the lncTCL6-miR155-Src/Akt/EMT network as a novel regulatory mechanism in aggressive ccRCC and a promising therapeutic target to inhibit renal cancer. Significance: This study's investigation of noncoding RNA interactions in renal cell carcinoma identify miRNA-155-lncRNA TCL6-mediated regulation of the Src-Akt-EMT network as a novel mechanism of disease progression and metastasis.
Real-world data on overall survival associated with biweekly versus weekly cetuximab among metastatic colorectal cancer (mCRC) patients in the United States.
Authors: Himani Agg, Yimei Han, Zhanglin Lin Cui
Journal: Journal of Clinical Oncology (2021)

33 Background: Cetuximab 250mg/m 2 weekly (Q1W) after an initial dose of 400mg/m 2 is approved for treatment of K-Ras wild-type mCRC. In real world 29% of patients received cetuximab 500mg/m 2 biweekly (Q2W). In this study overall survival (OS) associated with Q2W vs Q1W dosing of cetuximab for mCRC in real world was compared. Methods: This study utilized Flatiron Health electronic health record-derived database to identify adult patients with stage IV or recurrent K-Ras wild-type mCRC who received cetuximab+FOLFIRI/FOLFOX/irinotecan, or cetuximab monotherapy in first, second or third-line therapy from 01/01/2013 to 12/31/2019. Patients were assigned to Q1W or Q2W cohort if they had 70% or more cetuximab infusions with a gap of 4-10 days or 11-18 days from previous infusion. Patients who did not fall into either cohort were excluded from analysis. Propensity score (PS) matching was used to balance cohorts on their baseline demographic, clinical and treatment characteristics. Kaplan-Meier methods and Cox proportional hazards regressions were used to compare OS. Results: Baseline characteristics for Q2W (N = 422) vs Q1W (N = 653) cohorts before PS matching- median age 62 vs 65 years, male 58.5% vs 59.3%, white 68.3% vs 66.5%, stage IV 56.6% vs 58.5%, ECOG PS 0/1 61.6% vs 52.1%, ECOG PS 2+ 9.2% vs 9.5%. After PS matching, baseline characteristics were balanced. Hazard ratios (HRs) comparing OS in PS-matched Q2W vs Q1W cohorts were not significant for overall or line of therapy populations (Table). Conclusions: Weekly and biweekly cetuximab had comparable effectiveness in this real-world study. [Table: see text]
Abstract 15630: Predicting Clinical Outcomes of Inpatients With Heart Failure Based on Echocardiogram Reports Using Natural Language Processing and Deep Learning Models
Authors: Talal Alzahrani, Brian Choi, Joseph Krepp, Jannet F Lewis
Journal: Circulation (2019)

Background: Statistical models have been developed in the last two decades to predict clinical outcomes for patients hospitalized with heart failure. These predictive models were developed based on...
Protein arginine methyltransferase 1 contributes to the development of allergic rhinitis by promoting the production of epithelial-derived cytokines
Authors: Ji-Yeon Park, Joo-Hee Choi, Sang-Nam Lee, Hyung-Ju Cho, Ji-Suk Ahn, Yong-Bum Kim, Do-Yong Park, Sang Chul Park, Soo-In Kim, Min-Jung Kang, Ah-Ra Jang, Jae-Hun Ahn, Tae-Sung Lee, Dong-Yeon Kim, Sung Jae Shin, Joo-Heon Yoon, Jong-Hwan Park
Journal: Journal of Allergy and Clinical Immunology (2021)

Arginine methylation is a posttranslational modification mediated by protein arginine methyltransferases (PRMTs). Although previous studies have shown that PRMT1 contributes to the severity of allergic airway inflammation or asthma, the underlying mechanism is poorly understood.
Comment on Piccinini and Bergman The Measurement of Insulin Clearance. Diabetes Care 2020;43:2296–2302
Authors: Andrea Tura, Giovanni Pacini
Journal: Diabetes Care (2021)

We found interesting the review by Piccinini and Bergman (1) about the methods for assessing insulin clearance. However, some issues deserve comment. The authors claim that single-compartment description of C-peptide kinetics may provide limited accuracy. We agree that two-compartment description is typically more appropriate, but the single-compartment approach proved to be acceptable in glucose tolerance tests characterized by low dynamics. Indeed, the study by Volund et al. (2) reported that the C-peptide single-compartment model was acceptable for insulin and C-peptide infusion experiments in dogs and that C-peptide clearance was similar in the studied dogs and in humans from previous studies. Another study in humans showed that, even for the …
Protecting the environment from plastic PPE
Authors: Elissa J Zhang, Lucy P Aitchison, Nicole Phillips, Ramon Z Shaban, Andrew W Kam
Journal: BMJ (2021)

Although measures to control covid-19 have been associated with some positive environmental effects, including decreases in global emissions of carbon dioxide, 1 the pandemic has exacerbated plastic pollution through high use of personal protective equipment (PPE).Single use items include surgical masks, gloves, and non-reusable gowns.
A multi-institutional phase Ib/II trial of first-line triplet regimen (Pembrolizumab, Trastuzumab, Chemotherapy) for HER2-positive advanced gastric and gastroesophageal junction cancer (PANTHERA Trial): Molecular profiling and clinical update.
Authors: Sun Young Rha, Choong-kun Lee, Hyo Song Kim, Beodeul Kang, Minkyu Jung, Woo Sun Kwon, Woo Kyun Bae, Dong-Hoe Koo, Su-Jin Shin, Hei-Cheul Jeung, Dae Young Zang, Hyun Cheol Chung
Journal: Journal of Clinical Oncology (2021)

218 Background: We report the updated clinical data and molecular profiling results of a multi-institutional phase Ib/II trial of triple combination (pembrolizumab, trastuzumab, and chempotherapy) as first line therapy for HER2 positive advanced gastric and gastroesophageal junction (AGC/GEJ) cancer. (PANTHERA trial; NCT02901301). Methods: Pembrolizumab 200mg IV D1, Trastuzumab 6mg/kg (after 8mg/kg load) D1, Capecitabine 1000mg/m 2 bid D1-14, and Cisplatin 80mg/m 2 D1 every 3 weeks was selected as recommended phase II dose. The primary endpoint for phase II was ORR per RECIST v1.1. Secondary endpoints included PFS, OS, DOR, safety, and predictive biomarker analysis by targeted NGS. Results: At the time of data lock on Aug 31, 2020, total of 43 patients were treated with median follow up of 18.2 months, and 3 patients remained on the treatment, and 6 patients finished 2-year treatment without progression. ORR was 76.7% (CR 16.3%, PR 60.5%, conversion surgery 4.6%) with 26 pts (56.6%) showing more than 50% of tumor burden reduction. Median PFS was 8.6 months (95% CI 7.2-16.5) and median OS was 19.3 months (95% CI 16.5-NR). There were no MSI-H/dMMR or EBV-positive pts. No patient discontinued pembrolizumab because of immune-related adverse events. Clinical features including PD-L1 status (55.3% of pts ≥ CPS 1 and 13.2% of pts ≥ CPS 10 among available 38 pts), metastatic organ or baseline tumor burden was not related to the survival. Ninety-eight tumor tissues from 39 pts (paired tumor tissues from 22 pts) were analyzed with targeted NGS. Although every pts were HER2 IHC-positive, baseline HER2 amplification by NGS was related to the survival ( HER2 amp (n=8) vs HER2 non-amp (n=23); mPFS, not reached vs 7.7 months, P=0.0178; mOS, not reached vs 17.9 months, P=0.044) but no other signaling pathways predicted pts’ survival. HER2 mutations including L869R or D769H were related to the acquired resistance. High TMB showed a tendency toward better survival (mPFS; High (n=7) vs Low (n=24) TMB, 22.0 vs 8.2, P=0.2835) due to small number of patients. Updated immune markers and serial NGS analyses will be presented. Conclusions: First-line triplet regimen (Pembrolizumab, Trastuzumab, and Chemotherapy) showed promising efficacy based on HER2 amplification by NGS regardless of PD-L1 status in AGC/GEJ cancer. Correlative biomarkers found from NGS study need to be validated through on-going phase III Keynote-811 study. Clinical trial information: NCT02901301. [Table: see text]
OP0066 Effects of tnf blockade with infliximab in patients with primary sjÖgren’s syndrome: an open pilot study
Authors: SD Steinfeld, P Demols, V Gangji, T Appelboom
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Tumour necrosis factor α (TNFα) is a proinflammatory cytokine involved in the pathogenesis of Sjögren’s syndrome (SS), and blockade of TNFα may reduce the activity of the disease. <h3>Objectives</h3> This study evaluated the safety and potential efficacy of infliximab, a chimeric human-mouse anti-TNFα monoclonal antibody, in patients with active primary SS. <h3>Methods</h3> This was a monocentre, open-label pilot study. Sixteen patients with active primary SS (ESR &gt; 25 mm/h and hyperIgG) received three infusions of 3 mg/kg infliximab (at weeks 0, 2 and 6). Standard clinical assessment, complete ophtalmological testing and functional evaluation. <h3>Results</h3> All the patients completed the study. There was a statistically significant improvement in all clinical and functional parameters. They included global assessments (p &lt; 0.01) for patient global assessment, patient pain, physician global assessment, erythrocyte sedimentation rate (p &lt; 0.05), salivary flow rate (p &lt; 0.001), Schirmer I test (p &lt; 0.01), lissamine green staining (p &lt; 0.05), tender joint count (p &lt; 0.01), fatigue score (p &lt; 0.001), dry eyes and dry mouth (p &lt; 0.01). This clinical benefit was observed at week 2 and was maintained throughout the study and the 2 months follow-up period. The treatment was well tolerated in all patients and no significant adverse events were seen. No lupus-like syndrome and no anti-dsDNA antibodies were observed. <h3>Conclusion</h3> In patients with active primary SS, a loading dose regimen of three infusions of infliximab provided a fast and significant clinical benefit without major adverse reaction. It was possible to maintain statistically significant improvement up to 8 weeks after the third infusion.
THU0206 Clinical significance of qtc dispersion and ejection fraction of the left ventricle in patients with rheumatoid arthritis
Authors: BV Obradovic-Tomasevic, L Radunovic, K Cobeljic, V Obradovic
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> QTc dispersion (QTc-d) is an indicator of imbalanced ventricular activity and represents a useful prediction for the appearance of ventricular arrhythmias. The longer QTc-d is more frequent in the patients with the duration of rheumatoid arthritis (RA). Echocardiographically estimated systolic function by ejaction fraction (EF%) has a clinical and therapeutical significance. <h3>Objectives</h3> The objective of the research was to examine two groups of patients with RA as regards the duration of the disease to 5 and 10 years. It was necessary to establish in which group ventricular arrhythmias were more frequent in relation to QTc-d and in relation to EF% as well. <h3>Methods</h3> 50 patients were examined, 30 females and 20 females, whose average age of 58 ± 3. All the patients were divided into two groups. The first group included 28 patients with the duration of the diseases to 5 years, and the second group consisted of 22 patients with the duration of the disease from 5 to 10 years. On 12-leed ECG Qtc-d was measured as a difference QTc max – Qtc min and it was corrected by Bazett's formula. All the measures were done in sinus rhythm. Echocardiographic estimation of the systolic function was determined from EF%, 2-D-Echocardiograpphy. <h3>Results</h3> The values of QTc-d in the first group were 50.5 ± 2.5 msec, whereas EF% was 48% ± 3.5. In the second group QTc-d was 78.5 msec ± 3.2 and EF% was 39% ± 2.5. The longer QTc-d and lower EF% were noted in all examined patients. However, in the second group of the patients, these values were considerably changed, which indicates that the duration of the disease is important. In the second group the ventricular arrhythmias were more frequent and they are very important in prognosis and treatment of those patients. <h3>Conclusion</h3> Exanimated showed that the longer QTc-d was considerably longer in the second group of the patients. EF% was considerably lower in the second group. The longer QTc-d and low EF% were in good correlation with the ventricular arrhythmias. <h3>References</h3> Goldeli O, Dursun E, Komsuoglu B. Dispersion of ventricular repolarization: a new marker of ventricular arrhythmias in patients with rheumatoid arthritis. J Rheunatol. 1998;25(3):447–50 Crawford M, DiMarco J, <i>et al</i>. <i>Cardiology</i>. Mosby, 2001; section 8:5.1‑10