tbuckley/cabot-search huggingface dataset:
Validation of the lung immune prognostic index (LIPI) in patients with metastatic renal cell carcinoma treated with nivolumab in the GETUG-AFU 26 NIVOREN trial.
Authors: Pernelle Lavaud, Cécile Dalban, Sylvie Negrier, Christine Chevreau, Gwenaelle Gravis, Stephane Oudard, Brigitte Laguerre, Philippe Barthelemy, Delphine Borchiellini, Marine Gross Goupil, Lionnel Geoffrois, Frederic Rolland, Antoine Thiery-Vuillemin, Florence Joly, Sylvain Ladoire, Florence Tantot, Laura Mezquita, Bernard Escudier, Laurence Albiges
Journal: Journal of Clinical Oncology (2020)

735 Background: The Lung Immune Prognostic Index (LIPI) is a prognostic score combining pretreatment dNLR (neutrophils/ (leucocytes-neutrophils) and LDH correlated to immune checkpoint inhibitors (ICI) benefit in several advanced cancers. We aimed to correlate LIPI score with Nivolumab (N) benefit in metastatic clear cell renal cell carcinoma (mccRCC) patients. Methods: We investigated the LIPI score in the GETUG-AFU 26 NIVOREN phase II trial assessing the activity and safety of N after failure of upfront VEGF-targeted therapies. A dNLR ≥ 3 and LDH ≥ upper superior limit were analyzed for the LIPI, and patients were stratified into 3 groups (good (GG), intermediate (IG) and poor (PG)) (Mezquita et al, JAMA Oncol 2018). The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and objective response rate (ORR). Results: Overall, 619 pts were included. Median age was 64 years old, 22.1% pts had received more than 2 previous lines and IMDC risk groups were 18.3%, 56.5% and 25.0% for good/intermediate and poor risk respectively. Median (m) follow up was 23.7 months (mo). The mPFS with N was 4.0 mo and mOS was not reach. LIPI classified 364 pts (58.8%) as GG, 216 pts (34.9%) as IG and 39 pts (6.3%) as PG. The PFS and OS results are summarized in the Table. In multivariate analysis, LIPI score remains an independent prognostic factor after adjustment for sex, age, ECOG PS and IMDC. ORR did not seem to be influenced by the LIPI groups. Conclusions: We report for the first time that LIPI score is associated with PFS and OS in patients treated with N for mccRCC. LIPI score appears as an independent prognostic factor even after adjustment for established risk factors. External validation in a VEGF-targeted therapy cohort is ongoing and will contribute to evaluate the predictive value of LIPI in mccRCC.[Table: see text]
State and Territorial Laws Prohibiting Sales of Tobacco Products to Persons Aged &lt;21 Years — United States, December 20, 2019
Authors: Kristy Marynak, Margaret Mahoney, Kisha-Ann S. Williams, Michael A. Tynan, Elizabeth Reimels, Brian A. King
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Raising the minimum legal sales age (MLSA) for tobacco products to 21 years (T21) is a strategy to help prevent and delay the initiation of tobacco product use (1). On December 20, 2019, Congress raised the federal MLSA for tobacco products from 18 to 21 years. Before enactment of the federal T21 law, localities, states, and territories were increasingly adopting their own T21 laws as part of a comprehensive approach to prevent youth initiation of tobacco products, particularly in response to recent increases in use of e-cigarettes among youths (2). Nearly all tobacco product use begins during adolescence, and minors have cited social sources such as older peers and siblings as a common source of access to tobacco products (1,3). State and territorial T21 laws vary widely and can include provisions that might not benefit the public's health, including penalties to youths for purchase, use, or possession of tobacco products; exemptions for military populations; phase-in periods; and preemption of local laws. To understand the landscape of U.S. state and territorial T21 laws before enactment of the federal law, CDC assessed state and territorial laws prohibiting sales of all tobacco products to persons aged <21 years. As of December 20, 2019, 19 states, the District of Columbia (DC), Guam, and Palau had enacted T21 laws, including 13 enacted in 2019. Compared with T21 laws enacted during 2013-2018, more laws enacted in 2019 have purchase, use, or possession penalties; military exemptions; phase-in periods of 1 year or more; and preemption of local laws related to tobacco product sales. T21 laws could help prevent and reduce youth tobacco product use when implemented as part of a comprehensive approach that includes evidence-based, population-based tobacco control strategies such as smoke-free laws and pricing strategies (1,4).
Abstract 412: Galectin-3 Promotes Pro-Hypertrophic Communication Between Fibroblasts and Cardiomyocytes
Authors: Mario Bustamante, Ingrid Oyarzun, Georthan Mancilla, Clara Quiroga, Hugo E Verdejo, Pablo Castro
Journal: Circulation Research (2017)

Galectin-3 (gal-3) is a β-galactoside-binding protein used as a prognostic biomarker in chronic heart failure (CHF) patients. Genetic and pharmacologic studies show that gal-3 is required for cardiac remodeling in animal models of CHF, suggesting an active role for gal-3 in the progression of the disease, but the mechanism involved is largely unknown. We assessed the hypothesis that gal-3 induces cardiac remodeling, causing both cardiomyocyte hypertrophy and fibroblasts activation through a mechanism involving intercellular communication. As a model, we used neonatal rat ventricular cardiomyocytes (NRVM), and fibroblasts (NRVF) stimulated with recombinant gal-3. We assessed cell death and proliferation by flow cytometry and MTT assays. To elucidate the signaling pathways involved, we quantified relative changes in protein levels by Western blot. To determine cell size and sarcomerization, we used confocal microscopy. Changes in mRNA and microRNA expression were analyzed by qPCR. Our results show that gal-3 does not induce hypertrophy or sarcomerization on isolated NRVM culture. On the other hand, NRVF treated with gal-3 exhibit an increase in ERK1/2 (n=3, p&lt;0.05) and AKT (n=3, p&lt;0.05) phosphorylation, as well as a marked increase in cell proliferation (n=4, p&lt;0.05), without changes in αSMA and collagen. Interestingly, gal-3 increased tgfb1 expression in cardiac fibroblasts (n=5, p&lt;0.05) and induced an increase of miR-21 and miR-23a levels in the culture media (15- and 6-folds over basal, respectively, n=4, p&lt;0.05). To test a possible paracrine communication between cardiomyocytes and fibroblasts, we stimulated NRVM with fibroblast-derived, gal-3-stimmulated conditioned medium. Our results show that in this condition there is an increase in both cardiac remodeling markers (Nppa and Myh7), as well as cardiomyocyte area. In conclusion, gal-3 activates pro-survival and proliferation signaling pathways in cardiac fibroblasts without a direct effect on cardiomyocytes. However, gal-3 can induce cardiomyocyte hypertrophy by a mechanism involving paracrine communication between fibroblasts and myocytes, which likely includes TGFβ1 and the hypertrophy-related miR-21 and miR-23a.
Treatment compliance and early toxicity in SAKK 01/10: Single-dose carboplatin and involved-node radiotherapy for treatment of stage IIA/B seminoma.
Authors: Alexandros Papachristofilou, Jens Bedke, Stefanie Hayoz, Natalie Fischer, Xaver Schiel, Ulrich Schratzenstaller, Susanne Krege, Anja Lorch, Daniel M. Aebersold, Paul-Martin Putora, Dominik R. Berthold, Deborah Zihler, Ngwa C. Azinwi, Friedemann Zengerling, Annette Dieing, Arndt-Christian Mueller, Richard Cathomas
Journal: Journal of Clinical Oncology (2020)

405 Background: Standard treatment options for stage IIA/B seminoma include either extensive paraaortal/pelvic radiotherapy or intensive chemotherapy with 3x BEP or 4x EP. Both treatment modalities are associated with excellent efficacy but also a high rate of acute and late toxicities. Therefore, de-escalation strategies appear warranted for this patient group aiming to minimize acute and long-term toxicities while maintaining efficacy. SAKK 01/10 is a joint project of the Swiss Group for Clinical Cancer Research and the German Testicular Cancer Study Group. Methods: Patients with stage IIA/B seminoma (de novo or relapse on active surveillance) were eligible for participation in this single arm phase II trial. A repeat scan was advised in patients with equivocal lymph node enlargement. Treatment consisted of one cycle carboplatin AUC7 followed by involved-node radiotherapy with 30 Gy in stage IIA and 36 Gy in stage IIB disease. The primary endpoint of the trial is 3-year progression free survival. We report on treatment compliance and early toxicity during treatment and within 30 days. Results: 120 patients with stage IIA/B seminoma were recruited from 10/12 until 06/18 in 20 study centers in Switzerland and Germany. 116 patients were eligible and initiated treatment per protocol (40% stage IIA, 60% stage IIB). All patients received chemotherapy (CT) with a median applied dose of 984 mg (range: 560-1920 mg). The median planning target volume (PTV) for radiotherapy (RT) was 297 cm 3 (range: 24-1047 cm 3 ). RT was delayed/interrupted in two patients due to adverse events. During CT, grade 2 and grade 3 adverse events were seen in 21% and 2% of all patients respectively (most common grade 2 events: neutropenia 6%, nausea 5%). During RT, grade 2 and grade 3 adverse events were seen in 26% and 6% of all patients respectively (most common grade 2 events: neutropenia 15%, nausea 6%). One case of transient creatinine increase was reported as a severe adverse event, resolving without sequelae. Conclusions: Treatment with one cycle carboplatin AUC7 and 30-36 Gy involved-node radiotherapy for stage IIA/B seminoma is feasible and demonstrates a very favorable early toxicity profile. Clinical trial information: NCT01593241.
Determination of the Effects of Active Seasonal Allergic Rhinitis Symptoms (Nasal Edema and Congestion) on the Absorption of Intranasal (IN) epinephrine Administered as ARS-1
Authors: Michael Kaliner, F. Estelle Simons, Richard Lockey, Phillip Lieberman, Sarina Tanimoto, Richard Lowenthal
Journal: Journal of Allergy and Clinical Immunology (2020)
A systematic review and network meta-analysis of FDA approved treatment options in men with nonmetastatic, castration-resistant prostate cancer (M0CRPC).
Authors: Irbaz Bin Riaz, Noureen Asghar, Daenielle K. Lang, Yuan Yao, Anum Riaz, Abdulaali Almutairi, Zhen Wang, Ivo Abraham, M. Hassan Murad, Manish Kohli
Journal: Journal of Clinical Oncology (2020)

335 Background: Network meta-analysis can provide useful evidence for relative efficacy and toxicity of different treatment options in absence of head-to-head trials. Previously, we reported no difference in efficacy between Apalutamide (APA) and Enzalutamide (ENZA). In this analysis, we provide updated indirect comparisons of all FDA approved agents (APA,ENZA, Darolutamide(DARO) for the treatment of M0CRPC with rapid PSA doubling time. Methods: MEDLINE, EMBASE and Cochrane Library were searched to identify relevant clinical trials. Hazard ratios (HR) and 95% confidence interval (CI) for Metastasis Free Survival (MFS), Overall Survival (OS) and data on grade 3 or higher AEs were abstracted. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparisons. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: Three RCTs (SPARTAN, PROSPER and ARAMIS) compared APA, ENZA and DARO respectively in combination with ADT to ADT alone. A total of 4117 patients were included in efficacy analysis (2694 received novel hormonal agents and 1423 received ADT and placebo). There were no statistically significant differences in MFS (HR 0.97, 95% CrI 0.74 - 1.30) between APA and ENZA; however, both APA 0.69 (95% CI 0.52 -0.92) and ENZA 0.71 (95% CrI 0.53, 0.92) significantly improved MFS as compared to DARO. There were no statistically significant differences in OS between these drugs. DARO had fewer grade 3 or higher adverse events of fatigue (HR 0.09, 95% CrI 0.01 – 0.51) compared to ENZA. However other common adverse events such as hypertension, falls, coronary artery disease/myocardial infarction and diarrhea were not significantly different between treatment groups. There was low risk of bias amongst included studies. Conclusions: APNA and ENZA provide significant improved in MFS as compared to DARO in patients with M0CRPC. The drugs have similar toxicity profile except that DARO was associated with lower incidence of fatigue compared to ENZA. Cost effective analysis of these drugs will be reported separately.
Presumed Asymptomatic Carrier Transmission of COVID-19
Authors: Yan Bai, Lingsheng Yao, Tao Wei, Fei Tian, Dong-Yan Jin, Lijuan Chen, Meiyun Wang
Journal: JAMA (2020)

This study describes possible transmission of novel coronavirus disease 2019 (COVID-19) from an asymptomatic Wuhan resident to 5 family members in Anyang, a Chinese city in the neighboring province of Hubei.
TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline <i>BRCA</i> Carriers With HER2-Negative Breast Cancer (the INFORM trial)
Authors: Nadine Tung, Banu Arun, Michele R. Hacker, Erin Hofstatter, Deborah L. Toppmeyer, Steven J. Isakoff, Virginia Borges, Robert D. Legare, Claudine Isaacs, Antonio C. Wolff, Paul Kelly Marcom, Erica L. Mayer, Paulina B. Lange, Andrew J. Goss, Colby Jenkins, Ian E. Krop, Eric P. Winer, Stuart J. Schnitt, Judy E. Garber
Journal: Journal of Clinical Oncology (2020)

Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline BRCA mutation carriers (BRCA carriers). Limited data exist for estrogen receptor (ER)-positive (+) breast cancer among BRCA carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in BRCA carriers with stage I-III human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC.BRCA carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m2 every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review.A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were BRCA1+, 30% were BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities.pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.
Prognostic factors that affect survival outcomes in men with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223.
Authors: Esmail Mutahar Al-Ezzi, Husam Alqaisi, Sarah Picardo, Marco Iafolla, Srikala S. Sridhar, Adrian G. Sacher, Nazanin Fallah-Rad, Charles Catton, Padraig Warde, Robert James Hamilton, Neil Eric Fleshner, Alexandre Zlotta, Aaron Richard Hansen
Journal: Journal of Clinical Oncology (2020)

225 Background: Radium-223 (Ra-223) improved overall survival (OS) in men with mCRPC with predominantly bone metastases. We analyzed their survival outcomes to identify factors associated with prognosis for men treated with Ra-223. Methods: This was a retrospective study of men with mCRPC at Princess Margaret Cancer Centre treated with Ra-223. Demographics, disease characteristics, number of bone metastasis [ &lt; 6, 6-20, &gt; 20], laboratory results, number of Ra-223 doses, systemic treatment lines after radium-223, use of bone protecting agents (BPA) and survival outcomes were collected. OS and progression-free survival (PFS) were estimated by Kaplan-Meier (log-rank) analysis. Uni- (UVA) and multi-variate (MVA) analysis (Cox-regression) were used to evaluate patient and disease characteristics, number of Ra-223 doses and overall survival. Results: 114 men received Ra-223 between May 2015 and May 2018 with median age 75 years (range 53-93). Median radium doses was 5 (68 [59.6%] received &gt; 4 doses, 46 [40.4%] received ≤4 doses). Median baseline ALP 113.5 U/L (31-1121), median baseline Hb 118 g/L (69-153), median baseline PSA 70.2 ug/L (0.15-5275), median LDH 242 UL (82-1426). 58% had 6-20 bone metastases and 28% had &gt; 20 bone metastases. The median OS and PFS for men who received ≤4 doses vs &gt; 4 doses was 4.56 vs 19.8 months (HR = 8.4; 95%CI: 4.861-14.62; p≤ 0.0001) and 2.9 vs 7.45 months (HR = 4.6; 95%CI: 2.837 to 7.537; p≤ 0.0001) respectively. The baseline median ALP was (154 vs 98; p = 0.03) for men who received ≤4 doses vs &gt; 4 doses Ra-223. On UVA, ECOG 0-1 (HR = 0.33; p = 0.0003), baseline PSA &lt; 70 ug/L (HR = 0.51; p = 0.0023), LDH &lt; 250 U/L (HR 0.55; p = 0.0082), Hb &gt; 120 g/L(HR 0.46; p = 0.0004), ALP &lt; 150 U/l(HR 0.38; p ≤ 0.0001) and receipt of subsequent treatment after Ra-223 (HR = 0.33; p &lt; 0.0001) were associated with improved OS. On MVA, receipt of subsequent treatment, administration &gt; 4 cycles of Ra-223 and baseline ALP &lt; 150 U/L were associated with improved OS. Conclusions: Men who receive &gt; 4 cycles of Ra-223 have significantly better OS than those who receive ≤4 doses. Baseline ALP was independently associated with better OS and could be used to identify patients most likely to benefit from Ra-223.
QTc Prolongation and Psychotropic Medications
Authors: Margo C. Funk, Scott R. Beach, Jolene R. Bostwick, Chris Celano, Mehrul Hasnain, Ananda Pandurangi, Abhisek C. Khandai, Adrienne Taylor, James L. Levenson, Michelle Riba, Richard J. Kovacs
Journal: American Journal of Psychiatry (2020)

Council on Consultation-Liaison Psychiatry's Work Group on QTcProlongation and Psychotropic Medications.The Work Group had been charged to develop a set of clinical considerations to guide psychiatrists on best practice prescription and monitoring of psychotropic medications that may prolong the QTc interval or increase the risk of torsades de pointes.The Resource Document was supported by and received the official endorsement of the American College of Cardiology.The following summarizes the Work Group report.Over the past decade, there has been increased attention from the medical community about the role of QTc monitoring in the prescription of psychotropic medications.Psychiatrists frequently prescribe psychotropic drugs that may prolong cardiac repolarization, thereby increasing the risk for torsades de pointes (TdP), a potentially fatal cardiac arrhythmia.The corrected QT interval (QTc) on the electrocardiogram (ECG) is the most widely used and accepted marker of TdP risk by drug safety boards; however, there is not unanimity in the guidelines and warnings among the Food and Drug Administration (FDA) in the United States and analogous bodies in other countries.There is a paucity of strong evidence to guide clinicians, and to date there are no practice guidelines endorsed by the American Psychiatric Association (APA) or the American College of Cardiology (ACC).This resource document is not intended to be a practice guideline, rather an educational tool for clinicians to use when prescribing psychotropic medications.Well-established risk factors for TdP include medications that prolong cardiac repolarization, bradycardia, female sex, increased age, hypokalemia, hypomagnesemia, congenital long-QT syndrome, personal history of structural heart disease, previous history of acquired QTcprolongation, family history of sudden cardiac death, concurrent use of other QTc-prolonging medications, pharmacodynamic and pharmacokinetic drug interactions, drug toxicity, hepatic and/or renal dysfunction, and acute illness.It is essential to be aware of these risk factors to assess and monitor patients accordingly if a drug with a risk to prolong QTc interval is being considered or prescribed.
Responding to Unprofessional Behavior by Trainees — A “Just Culture” Framework
Authors: Jason A. Wasserman, Michael Redinger, Tyler Gibb
Journal: New England Journal of Medicine (2020)

Professionalism lapses by trainees can be addressed productively if viewed through a lens of medical error, drawing on "just culture" principles. With this approach, educators can promote a formative learning environment while fairly addressing problematic behaviors.
Prostate-directed radiation therapy and overall survival for men with M1a prostate cancer.
Authors: David Dewei Yang, Santino Butler, Vinayak Muralidhar, Brandon Arvin Virgil Mahal, Neil E. Martin, Kent William Mouw, Paul L. Nguyen, Martin T. King, Peter F. Orio
Journal: Journal of Clinical Oncology (2020)

101 Background: A recent randomized controlled trial demonstrated that radiation therapy to the prostate improves overall survival for men with newly diagnosed metastatic prostate cancer with a low metastatic burden. Most patients in this trial had bony metastases (stage M1b). The benefit of prostate-directed radiation therapy for men with metastases limited to non-regional lymph nodes (stage M1a) is unknown. We investigated the association between prostate-directed radiation therapy and overall survival for men with M1a prostate cancer. Methods: We identified 2,079 men from the National Cancer Database who were newly diagnosed with M1a prostate adenocarcinoma from 2004 through 2014 and had data on the use of androgen deprivation therapy, chemotherapy, and radiation therapy. Median follow-up was estimated using the reverse Kaplan-Meier method. The association between radiation therapy to the prostate and overall survival was examined using multivariable Cox proportional hazards regression analysis. Results: Overall, 12.7% (264) of patients received radiation therapy to the prostate. Median follow-up was 4.6 years (95% confidence interval 4.3-4.8 years). On multivariable analysis, when accounting for the use of androgen deprivation therapy and chemotherapy, Gleason grade group, clinical tumor and nodal stage, and prostate-specific antigen level at diagnosis, the use of radiation therapy to the prostate was associated with a significant improvement in overall survival (adjusted hazard ratio 0.60, 95% confidence interval 0.49-0.74, P&lt;0.001). Adjusted median overall survival was 3.3 years for patients who did not receive radiation therapy to the prostate compared to 5.5 years for patients who did. Conclusions: Similar to newly diagnosed M1b prostate cancer with a low metastatic burden, patients with M1a prostate cancer may also derive a significant overall survival benefit from receiving radiation therapy to the primary prostate tumor. The use of prostate-directed radiation therapy for M1a patients should be further investigated.
Abstract 16113: The Impact of Dementia on Heart Failure Mortality: A National Study of 5.2 Million People
Authors: Jane A Cannon, Chih M Wong, Pardeep S Jhund, Jonathan R Dalzell, Terence J Quinn, Niall M Broomfield, Matthew R Walters, John J McMurray
Journal: Circulation (2014)

Background: Due to ageing of the general population, the incidence of heart failure (HF) and dementia are both rising. We assessed the hypothesis that a co-morbidity of dementia has an impact upon ...