tbuckley/cabot-search huggingface dataset:
Association Between Benzodiazepine or Z-Drug Prescriptions and Drug-Related Poisonings Among Patients Receiving Buprenorphine Maintenance: A Case-Crossover Analysis
Authors: Kevin Y. Xu, Jacob T. Borodovsky, Ned Presnall, Carrie M. Mintz, Sarah M. Hartz, Laura J. Bierut, Richard A. Grucza
Journal: American Journal of Psychiatry (2021)

Objective: Persons with opioid use disorder who take benzodiazepines are at high risk for overdose. The objective of this study was to evaluate the association of benzodiazepine and Z-drug use with drug-related poisonings among patients receiving buprenorphine maintenance treatment. Methods: A case-crossover study design was used to analyze prescription claims among persons ages 12–64 with opioid use disorder who had buprenorphine prescriptions and had claims data in the IBM MarketScan databases (2006–2016), encompassing 14,213,075 person-days of observation time for 23,036 individuals who experienced drug-related poisoning. The exposures were buprenorphine prescriptions and benzodiazepine or Z-drug prescriptions, standardized as daily diazepam-equivalent milligram doses and separated by pharmacologic properties (short-acting or long-acting benzodiazepines, Z-drugs). The outcome of interest was nonfatal drug-related poisoning. Conditional logistic regression was used to evaluate variation in benzodiazepine or Z-drug and buprenorphine use between poisoning and nonpoisoning days. Results: Buprenorphine treatment days were associated with a nearly 40% reduction in the risk of poisoning events (odds ratio=0.63, 95% CI=0.60, 0.66) compared with nontreatment days, whereas benzodiazepine or Z-drug treatment days were associated with an 88% increase in the risk of such events (95% CI=1.78, 1.98). In stratified analyses by dose, we observed a 78% (95% CI=1.67, 1.88) and 122% (95% CI=2.03, 2.43) increase in poisonings associated with low-dose and high-dose benzodiazepine or Z-drug treatment days, respectively. High-dose, but not low-dose, benzodiazepine or Z-drug treatment was associated with increased poisonings in combination with buprenorphine cotreatment (odds ratio=1.64, 95% CI=1.39, 1.93), but this was lower than the odds risk associated with benzodiazepine or Z-drug treatment in the absence of buprenorphine (low-dose: odds ratio=1.69, 95% CI=1.60, 1.79; high-dose: odds ratio=2.23, 95% CI=2.04, 2.45). Conclusions: Increased risk of nonfatal drug-related poisoning is associated with benzodiazepine or Z-drug treatment in patients with opioid use disorder, but this risk is partially mitigated by buprenorphine treatment. Dose reduction of benzodiazepines or Z-drugs while maintaining buprenorphine treatment may provide the advantage of lowering drug-related poisoning risk.
Mayo Clinic experience with 1123 adults with acute myeloid leukemia
Authors: Kebede H. Begna, Walid Ali, None Naseema Gangat, Michelle A. Elliott, Aref Al-Kali, Mark R. Litzow, C. Christopher Hook, Alexandra P. Wolanskyj-Spinner, William J. Hogan, Mrinal M. Patnaik, Animesh Pardanani, Darci L. Zblewski, Dong Chen, Rong He, David Viswanatha, Curtis A. Hanson, Rhett P. Ketterling, Ayalew Tefferi
Journal: Blood Cancer Journal (2021)

Abstract Between 2004 and 2017, a total of 1123 adult patients (median age 65 years; 61% males) with newly diagnosed acute myeloid leukemia (AML), not including acute promyelocytic leukemia, were seen at the Mayo Clinic. Treatment included intensive ( n = 766) or lower intensity ( n = 144) chemotherapy or supportive care ( n = 213), with respective median survivals of 22, 9, and 2 months ( p &lt; 0.01). Intensive chemotherapy resulted in complete remission (CR) and CR with incomplete count recovery (CRi) rates of 44 and 33%, respectively, with no difference in survival outcome between the two ( p = 0.4). Allogeneic hematopoietic stem cell transplant (AHSCT) was documented in 259 patients and provided the best survival rate (median 55 months; p &lt; 0.01). After a median follow-up of 13 months, 841 (75%) deaths were recorded. Multivariate analysis identified age &gt;60 years (HR 2.2, 1.9–2.6), adverse karyotype (HR 2.9, 1.9–4.9), intermediate-risk karyotype (HR 1.6, 1.02–2.6), post-myeloproliferative neoplasm AML (HR 1.9, 1.5–2.4), and other secondary AML (HR 1.3 (1.1–1.6) as risk factors for shortened survival. These risk factors retained their significance after inclusion of FLT3/NPM1 mutational status in 392 informative cases: FLT3 + NPM1 − (HR 2.8, 1.4–5.6), FLT3 +/ NPM + (HR 2.6 (1.3–5.2), and FLT3 − NPM1 − (HR 1.8, 1.0–3.0).
Lower risk of prostate cancer in patients with sedentary occupations presenting for a prostate biopsy: Analysis of a Veterans Affairs cohort.
Authors: Rimaz M. Khadir, Rashid K. Sayyid, Martha K. Terris
Journal: Journal of Clinical Oncology (2021)

257 Background: Sedentary behavior has been associated with increased serum prostate-specific antigen (PSA) levels. It is currently unknown whether this correlates with an increased risk of underlying prostate cancer (PCa). Our objective was to determine whether patients with sedentary occupations presenting for a prostate biopsy were at increased risk of PCa diagnosis. Methods: A prospectively collected registry of patients undergoing a prostate biopsy between July 1995 and June 2016 at the Veterans Affairs Medical Center in Augusta, GA was utilized. The occupation was classified as sedentary if it was associated with prolonged periods of sitting (i.e. &gt;50% work hours). This was determined via patient reported history at time of biopsy. The associations between a sedentary lifestyle and risk of a positive prostate biopsy, high grade cancer (i.e. Gleason score 8 or higher), and high volume cancer (i.e. at least 50% of total cores were positive) were evaluated using multivariable logistic regression analyses, controlling for age, race, body mass index, PSA level, free PSA ratio, clinical stage, prostate volume, and family history of prostate cancer. Statistical significance was set at p&lt;0.05. All statistical analyses were performed using R version 3.6.1. Results: Our cohort included 1,914 patients. 271 (14.2%) patients had sedentary jobs. Median patient age was 61.0 years (Interquartile range [IQR] 57.0 – 66.0). Median PSA at time of biopsy was 5.7 ng/ml (IQR 4.4 – 8.2). Of the 1,914 initial biopsies performed, 974 (50.9%) were positive for malignancy. Of patients diagnosed with PCa, 229 (23.5%) had high-grade disease and 316 (32.4%) had high volume disease. On multivariable analysis, patients with a sedentary job had a significantly decreased risk of PCa diagnosis (Odds ratio [OR] 0.43, 95% confidence interval [CI] 0.18-1.03, p= 0.058), but no difference in odds of high grade (OR 0.63, 95% CI 0.089-2.99, p= 0.60) or high volume disease (OR 1.07, 95% CI 0.93-1.21, p= 0.89). Conclusions: Patients with sedentary occupations presenting for a prostate biopsy are at a lower apparent risk for a positive prostate biopsy. These results suggest that the serum PSA levels in such patients may be artificially elevated secondary to increased recumbence with no corresponding increase in risk of malignancy. [Table: see text]
Phase II trial of opaganib in patients with metastatic castration-resistant prostate cancer progressing on abiraterone or enzalutamide (NCT04207255).
Authors: Omer Kucuk, Charles Smith, Terry Plasse, Besim Ogretmen, Shikhar Mehrotra, Theodore Stewart Gourdin, Mehmet Asim Bilen, Bradley Curtis Carthon, Bassel Nazha, Jamie Goldman, Michael B. Lilly
Journal: Journal of Clinical Oncology (2021)

TPS191 Background: Opaganib (Yeliva, ABC294640) is a first-in-class, sphingosine kinase-2 (SK2) selective inhibitor, with anticancer, anti-inflammatory and anti-viral activities. SK2, a lipid kinase catalyzes formation of the lipid signaling molecule sphingosine 1-phosphate (S1P). S1P promotes cancer growth, and proliferation and pathological inflammation, including inflammatory cytokine production. Specifically, by inhibiting the SK2 enzyme, opaganib blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and are also involved in immune-modulation and suppression of innate immune responses from T cells. Opaganib is a sphingosine-competitive inhibitor of SK2 and also inhibits dihydroceramide desaturase. Opaganib has antitumor activity against human and murine prostate cancer cell lines, and in xenograft (LNCaP) and syngeneic (MycCAP, TRAMP-C1) murine tumor models. In addition to its target effect of reducing sphingosine-1-phosphate, opaganib reduces both MYC and AR proteins through its kinase-blocking and desaturase-inhibiting properties, respectively. Methods: The study is open to patients with mCRPC who have been treated with at least one newer androgen antagonist (abiraterone or enzalutamide) and no prior chemotherapy for castration-resistant disease. Patients who are failing either abiraterone or enzalutamide may enroll, with the addition of opaganib. The trial design includes brief safety lead-in cohort 1a (abiraterone + opaganib 250 mg Q 12hr, 3/3 enrolled) and 1b (enzalutamide + opaganib 250 mg Q 12hr, 3/3 enrolled). These cohorts have been completed without any DLTs. We are now enrolling cohort 2 (abiraterone + opaganib 500 mg Q 12hr, 0/27 enrolled) and cohort 3 (enzalutamide + opaganib 500 mg Q 12hr, 8/27 enrolled). A total of 60 patients will be enrolled and response will be evaluated after 4 cycles (28 days/cycle) using a composite metric based on PSA, bone scan and RECIST measurements per PCWG3 criteria. Safety and tolerability will be monitored, and dose modifications will be allowed. Primary endpoint is disease control (stable disease or better) after 4 cycles. Secondary endpoints include overall survival, radiographic progression-free survival and PSA progression-free survival. Correlative studies include assessment of quality of life (QOL), circulating MDSCs, immune cells and clones with amplified AR or MYC. Supported by NIH grant P01 CA203628. Clinical trial information: NCT04207255.
Targeted delivery of protein arginine deiminase-4 inhibitors to limit arterial intimal NETosis and preserve endothelial integrity
Authors: Roberto Molinaro, Mikyung Yu, Grasiele Sausen, Colette A Bichsel, Claudia Corbo, Eduardo J Folco, Gha Young Lee, Yuan Liu, Yevgenia Tesmenitsky, Eugenia Shvartz, Galina K Sukhova, Frederik Kloss, Kevin J Croce, Omid C Farokhzad, Jinjun Shi, Peter Libby
Journal: Cardiovascular Research (2021)

Abstract Aims Recent evidence suggests that ‘vulnerable plaques’, which have received intense attention as underlying mechanism of acute coronary syndromes over the decades, actually rarely rupture and cause clinical events. Superficial plaque erosion has emerged as a growing cause of residual thrombotic complications of atherosclerosis in an era of increased preventive measures including lipid lowering, antihypertensive therapy, and smoking cessation. The mechanisms of plaque erosion remain poorly understood, and we currently lack validated effective diagnostics or therapeutics for superficial erosion. Eroded plaques have a rich extracellular matrix, an intact fibrous cap, sparse lipid, and few mononuclear cells, but do harbour neutrophil extracellular traps (NETs). We recently reported that NETs amplify and propagate the endothelial damage at the site of arterial lesions that recapitulate superficial erosion in mice. We showed that genetic loss of protein arginine deiminase (PAD)-4 function inhibited NETosis and preserved endothelial integrity. The current study used systemic administration of targeted nanoparticles to deliver an agent that limits NETs formation to probe mechanisms of and demonstrate a novel therapeutic approach to plaque erosion that limits endothelial damage. Methods and results We developed Collagen IV-targeted nanoparticles (Col IV NP) to deliver PAD4 inhibitors selectively to regions of endothelial cell sloughing and collagen IV-rich basement membrane exposure. We assessed the binding capability of the targeting ligand in vitro and evaluated Col IV NP targeting to areas of denuded endothelium in vivo in a mouse preparation that recapitulates features of superficial erosion. Delivery of the PAD4 inhibitor GSK484 reduced NET accumulation at sites of intimal injury and preserved endothelial continuity. Conclusions NPs directed to Col IV show selective uptake and delivery of their payload to experimentally eroded regions, illustrating their translational potential. Our results further support the role of PAD4 and NETs in superficial erosion.
Abstract 16844: Effect of Canagliflozin on Gene Expression and CD34+ Function on Type 2 Diabetes Subjects
Authors: Hassan Awal, Seshagiri Rao Nandula, Nabanita KUNDU, Mona Fakhri, Beda Brichacek, Adrian Elzarki, Nikhila Aimalla, Bethany Batistich, Richard Amdur, Sabyasachi Sen
Journal: Circulation (2020)

Introduction: CD34 +ve Endothelial progenitor cells (EPCs) has been shown to be dysfunctional in subjects with type 2 diabetes mellitus (T2DM) leading to poor endothelial cell function (ECF). Hypothesis: Canagliflozin, an SGLT2 inhibitor when added to other oral antidiabetic medication such Metformin, Insulin, GLP1-agonists, DPP-IV inhibitor, or sulfonylureas, may improve the cardiovascular risk by improving CD34+ EPCs function such as migration, colony formation and maturation towards endothelium. Methods: 29 subjects were enrolled in this 16 weeks, double-blind, two-arm, randomized placebo matched trial, with 100 mg Canagliflozin (Cana, low dose) compared to placebo. T2DM (30-70 years old), HbA1c of 6.5-10%, and all stages of CKD were included. Peripheral blood derived CD34+ cell number, migratory function, mRNA gene expression along with cardiometabolic parameters such as arterial stiffness, biochemistry, resting energy expenditure, and body composition were measured. Data were collected at weeks 0, 8, and 16. A mixed model regression analysis was done with a p-value &lt;0.05 considered significant. Results: We found a statistically significant reduction in systolic (p=0.008) and diastolic (p=0.038) blood pressure. There was a reduction in blood glucose level (p=0.0047) and HbA1c (p=0.03). There was a statistically significant increase in adiponectin (p=0.0062) and trend level reduction in IL6 (p=0.16), indicating an anti-inflammatory effect of canagliflozin. There is also an increase in mRNA expression of genes associated with endothelial function in CD34+ cells such as VEGFA (p=0.049), VEGF receptor KDR (p=0.13), PECAM-1, a mature endothelial marker was also upregulated (p=0.002) and NOS3 (or eNOS) was also upregulated. There were no significant changes in CD34+ numbers by direct counting and parameters tested. We also tested for serum ketones bodies and found no difference at the dose tested. Data on urine podocyte specific exosome is pending Conclusions: Our study indicates that Canagliflozin improves several components of ECF by improving adiponectin, reducing inflammatory cytokines, and by increasing expression of endothelium specific genes.
Impact of <i>FGFR2/3</i> activating genomic alterations on response to enfortumab vedotin in metastatic urothelial carcinoma (mUC).
Authors: Elio Adib, Rohit K. Jain, William Paul Skelton, Dory Freeman, Catherine Curran, Elie W. Akl, Amin Nassar, Praful Ravi, Charlene Mantia, Jaime R. Merchan, Winston Tan, Trisha M. Plastini, Toni K. Choueiri, Guru Sonpavde
Journal: Journal of Clinical Oncology (2021)

472 Background: Enfortumab Vedotin (EV), an antibody-drug conjugate that targets nectin-4, is approved for metastatic urothelial carcinoma (mUC) progressing post-platinum and PD1/L1 inhibitor therapy. Erdafitinib is approved in patients for post-platinum mUC with activating genomic alterations in FGFR2/3, but the activity of EV in this subset is unclear. We investigated the activity of EV in patients (pts) with mUC based on FGFR2/3 genotype to inform management. Methods: In this multi-center, retrospective analysis, we assessed the objective response rate (ORR) to EV in mUC pts with and without FGFR2/3 genomic alterations detected by targeted panel next-generation sequencing. Activating gene fusions and known hotspots mutations in the two genes were considered. Descriptive analysis of ORR and patient characteristics was performed. Fisher’s exact test and binomial test with two-tailed p-value were used. Results: 40 pts were available from 4 institutions. Most pts were male (31/40, 78%) and the median age at start of EV was 74.1 (range 49 – 90) years. Ten patients (25%) had upper tract urothelial carcinoma (UTUC), and 33 (82%) had baseline ECOG performance status of 0-1. 31 of 39 patients had received both platinum-based chemotherapy and PD1/L1 inhibitors. Seven patients had confirmed activating hotspot FGFR3 mutations (p.S249C or p.Y373C). One pt had FGFR2 high-level amplification (HA), and one had FGFR3 HA. Of 36 patients evaluable for ORR, 18 had partial response (PR), 12 had stable disease (SD) and 6 had progressive disease (PD). Patients with FGFR2/3 activating mutations exhibited an ORR that was not statistically different compared to patients without no mutations: 2/7 (29%; 90% CI: 5 – 66%) vs. 16/29 (55%; 90% CI: 38 – 71%) respectively ( p-value = 0.4). 3/7 patients with FGFR3 hotspot mutations received an FGFR2/3 inhibitor and none responded; one of them had a sequential response to EV. Conclusions: In this multi-center retrospective cohort, FGFR2/3 activating genomic alterations did not appear to compromise response to EV in mUC. Larger studies are required to confirm our findings and optimal sequencing of EV and erdafitinib in mUC pts with FGFR2/3 genomic alterations requires further assessment.
Landscape of genomic alterations of circulating tumor DNA in advanced genitourinary cancer patients: SCRUM-Japan MONSTAR SCREEN Project.
Authors: Nobuaki Matsubara, Taigo Kato, Takao Fujisawa, Masaki Shiota, Masatoshi Eto, Takahiro Osawa, Takashige Abe, Nobuo Shinohara, Yota Yasumizu, Nobuyuki Tanaka, Mototsugu Oya, Koshiro Nishimoto, Satoshi Horasawa, Naomi Kuramoto, Yoshiaki Nakamura, Hiroya Taniguchi, Takayuki Yoshino, Norio Nonomura
Journal: Journal of Clinical Oncology (2021)

152 Background: Circulating tumor DNA in plasma (ctDNA) is an emerging resource for detecting genomic alterations in various cancers. However, the characteristics and clinical utility of ctDNA are not fully elucidated, especially in patients with genitourinary (GU) cancers. Methods: In April 2019, SCRUM-Japan started the MONSTAR-SCREEN project, which evaluates the ctDNA from patients with various advanced solid tumors. We collected plasma and tumor samples from patients with advanced prostate cancer (PC), urothelial carcinoma (UC), and renal cell carcinoma (RCC). Plasma ctDNA and tissue genomic DNA were analyzed using NGS-based cell-free DNA assay, a modified version of FoundationOne Liquid (F1L) including blood tumor mutational burden (TMB) analysis, and tissue-based panel, FoundationOne CDx (F1CDx), respectively. Success rate of ctDNA was defined as the percentage of patients whose sample quality control status was “pass” or “qualified”. Level of ctDNA was defined as the maximum allele fraction (AF) for all known somatic alterations detected. Results: As of June 18, 2020, ctDNA analysis results were available for 470 of 540 patients with advanced solid tumors. Among them, we analyzed 70 advanced GU cancers (35 PC, 17 UC, and 18 RCC) and 400 non-GU cancers. The success rate of ctDNA was significantly lower in GU cancers than in non-GU cancers (81.4% vs. 91.5%, P = 0.016). The levels of ctDNA in PC and UC were similar to those in non-GU cancers. RCC had the second lowest ctDNA level (median 0.13%) after that in malignant melanoma. The median TMB, as estimated by ctDNA, was 4.40, 0.88 and 0.44 mutations/Mb in UC, PC and RCC, respectively. The most frequently altered genes were TP53 (34%), AR (11%), BRCA2 (11%), ATM (8.6%), and CDK12 (8.6%) in PC, TP53 (59%), TERT (41%), and CHEK2 (18%) in UC, and TP53 (22%), ATM (11%), and MTOR (11%) in RCC. The mutation rate in genes related to DNA damage response (DDR) pathways was significantly higher in GU cancers compared to that in non-GU cancers (30.0% vs. 18.0%, P = 0.033). However, other pathways were less frequently altered in GU cancers versus non-GU cancers, including Wnt (5.7% vs. 16.8%, P = 0.017), PI3K (8.6% vs. 19.0%, P = 0.039) and RAS/MAPK (8.6% vs. 29.5%, P &lt; 0.001). Conclusions: Our results reveal the genomic landscape of ctDNA in several advanced solid tumors, and highlight the differences between tumor types. Comprehensive analysis of ctDNA using the F1L assay reveled alterations in DDR-associated genes were significantly more frequent in GU cancers than in non-GU cancers. Clinical trial information: UMIN000036749.
Collecting Data About COVID-19–Related Brain Symptoms: The Journal of the American Medical Association
Authors: Rita M. A. Rubin
Journal: JAMA (2021)

The National Institutes of Health (NIH) is planning to launch a new database and biobank to collect information from clinicians about neurological problems associated with coronavirus disease 2019 (COVID-19)  COVID-19-related neurological problems include headaches, fatigue, cognitive difficulties, stroke, pain, and sleep disorders, Karp noted  Long-haulers, who often had mild or moderate COVID-19 symptoms early in their disease, have reported experiencing brain fog, crushing fatigue, and other neurological symptoms for months after they were infected  One goal of the NeuroCOVID Project is to gain insight into how common these problems are;another is to assess these problems among pregnant women and their infants
Combining Machine Learning Predictive Algorithms With Behavioral Nudges to Increase Rates of Serious Illness Conversations in Patients With Cancer
Authors: Qi Zhi Clayton Yang
Journal: JAMA Oncology (2021)

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