tbuckley/cabot-search huggingface dataset:
Trends in Diagnosis Related Groups for Inpatient Admissions and Associated Changes in Payment From 2012 to 2016
Authors: Ty J. Gluckman, Kateri J. Spinelli, Mansen Wang, Amir Yazdani, Gary Grunkemeier, Steven M. Bradley, Jason H. Wasfy, Abhinav Goyal, Andrew Oseran, Karen E. Joynt Maddox
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Hospitals are reimbursed based on Diagnosis Related Groups (DRGs), which are defined, in part, by patients having 1 or more complications or comorbidities within a given DRG family. Hospitals have made substantial investment in efforts to document these complications and comorbidities. <h3>Objective</h3> To examine temporal trends in DRGs with a major complication or comorbidity, compare these findings with 2 alternative measures of disease severity, and estimate associated changes in payment. <h3>Design, Setting, and Participants</h3> This retrospective cohort study used data from the all-payer National Inpatient Sample for admissions assigned to 1 of the top 20 reimbursed DRG families at US acute care hospitals from January 1, 2012, to December 31, 2016. Data were analyzed from July 10, 2018, to May 29, 2019. <h3>Exposures</h3> Quarter year of hospitalization. <h3>Main Outcomes and Measures</h3> The primary outcome was the proportion of DRGs with a major complication or comorbidity. Secondary outcomes were comorbidity scores, risk-adjusted mortality rates, and estimated payment. Changes in assigned DRGs, comorbidity scores, and risk-adjusted mortality rates were analyzed by linear regression. Payment changes were estimated for each DRG by calculating the Centers for Medicare &amp; Medicaid Services weighted payment using 2012 and 2016 case mix and hospitalization counts. <h3>Results</h3> Between 2012 and 2016, there were 62 167 976 hospitalizations for the 20 highest-reimbursed DRG families; the sample was 32.9% male and 66.8% White, with a median age of 57 years (interquartile range, 31-73 years). Within 15 of these DRG families (75%), the proportion of DRGs with a major complication or comorbidity increased significantly over time. Over the same period, comorbidity scores were largely stable, with a decrease in 6 DRG families (30%), no change in 10 (50%), and an increase in 4 (20%). Among 19 DRG families with a calculable mortality rate, the risk-adjusted mortality rate significantly decreased in 8 (42%), did not change in 9 (47%), and increased in 2 (11%). The observed DRG shifts were associated with at least $1.2 billion in increased payment. <h3>Conclusions and Relevance</h3> In this cohort study, between 2012 and 2016, the proportion of admissions assigned to a DRG with major complication or comorbidity increased for 15 of the top 20 reimbursed DRG families. This change was not accompanied by commensurate increases in disease severity but was associated with increased payment.
Abstract 12978: Identification of Cardiovascular Adverse Effects Associated With Midostaurin - A WHO Pharmacovigilance Database Analysis
Authors: Arrush Choudhary, Ali Manouchehri, Javid Moslehi, Joe-elie Salem
Journal: Circulation (2020)

Introduction: Midostaurin is an oral multiple tyrosine kinase inhibitor (TKI) approved for treatment of acute myeloid leukemia and systemic mastocytosis. Clinical trials have shown efficacy of midostaurin with few adverse events. Although midostaurin does cause QT-prolongation, other associated cardiovascular complications are unknown. The purpose of this study is to identify and characterize cardiovascular adverse events associated with midostaurin. Methods: We used VigiBase, WHO's global database of individual case safety reports, to evaluate the association between midostaurin and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC 025 is the lower end of the IC 95% credibility interval and an IC 025 value of more than zero is deemed significant. Results: We identified 153 adverse cardiovascular events reported in patients who received midostaurin. Midostaurin treatment was associated with higher reporting of QT prolongation (48 cases, IC 025 4.15), heart failure (38 cases, IC 025 1.90), atrial fibrillation (20 cases, IC 025 1.53), and pericardial disease (12 cases, IC 025 1.23). A majority of these adverse events occurred within 50 days of midostaurin initiation with midostaurin being the only suspected culprit medication. Fatalities occurred in 8.7%, 43.2%, and 42.1% of cases of QT prolongation, heart failure, and atrial fibrillation, respectively. Conclusions: Midostaurin can lead to severe and sometimes fatal cardiac toxicities in a subset of patients. Baseline electrocardiograms and echocardiograms would be prudent in patients starting midostaurin to characterize and monitor these adverse effects.
Abstract 12901: Novel Oral Anticoagulants Are Associated With Decreased Recurrence of Venous Thromboembolism in Patients With Cancer: An Updated Meta-Analysis
Authors: Sunil Upadhaya, Seetharamprasad Madala, Sunil Badami
Journal: Circulation (2020)

Introduction: Patients with cancer are at high risk for recurrent thromboembolic phenomenon. Use of novel oral anticoagulants (NOAC) for treatment of venous thromboembolism (VTE) in such patients is controversial. We conducted this updated meta-analysis to evaluate the pooled efficacy and safety of NOAC in patients with cancer. Methods: We did systematic search of PubMed and Cochrane library databases for randomized controlled trials comparing NOAC with low molecular weight heparin (LMWH) for VTE treatment in cancer patients till April 2020. The efficacy outcomes were recurrent VTE and all-cause mortality rates, and the primary safety outcome was incidence of major bleeding rate. Results: Four randomized controlled studies comparing NOAC with LMWH (1446 patients in NOAC group and 1448 patients in LMWH group) were included in our study. Use of NOAC lead to significant reduction in recurrent VTE rate (odds ratio (OR): 0.55 [0.36-0.84], I 2 = 45 %, p value = 0.006) (Figure 1). However, we did not find any significant difference in rate of major bleeding (OR: 1.30 [0.76-2.23], I 2 = 35%, p value = 0.34) (Figure 2) and all-cause mortality (OR: 1 [0.80 - 1.26], I 2 = 33%, p value = 0.98). Conclusions: This updated meta-analysis showed comparatively lower pooled recurrent VTE rate in patient being treated with NOAC, whereas similar rates of major bleeding and all-cause death. NOAC are more efficacious and has similar safety profile compared with LMWH.
Severe Adult Asthmas: Integrating Clinical Features, Biology, and Therapeutics to Improve Outcomes
Authors: Sally E. Wenzel
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Section:ChooseTop of pageAbstract <<DefinitionPrevalenceClinical EvaluationClinical and Molecular Bi...Biologic Implications of ...Integrating Clinical, Mol...ConclusionsReferencesCITING ARTICLES
Tumor Microenvironment‐“AND” Near‐Infrared Light‐Activated Coordination Polymer Nanoprodrug for On‐Demand CO‐Sensitized Synergistic Cancer Therapy
Authors: Panpan Sun, Le Jia, Jun Hai, Siyu Lu, Fengjuan Chen, Kun Liang, Shihao Sun, Hanwen Liu, Xu Fu, Yanhong Zhu, Baodui Wang
Journal: Advanced Healthcare Materials (2020)

Abstract Carbon monoxide (CO) as an emerging treatment holds great promise for inducing the apoptosis of cancer cells. Here coordination assembled strategy is first reported for synthesis of Cu(II)‐flavone coordination polymer (NCu‐FleCP) CO nanoprodrug that is stable in normal physiological conditions, and yet readily reduces to small size prodrug complex and releases CO on demand under glutathione (GSH) and near infrared (NIR) light. Specifically, after uptaking by cancer cells, local GSH attacked coordination bond within NCu‐FleCP, resulting in the release of Cu(I) and free Fle. The CC bond of Fle is cleavage under NIR light to release CO for gas therapy, and Cu(I) reacts with local H 2 O 2 through Fenton like reaction to generate hydroxyl radicals ( • OH) for chemodynamic therapy. Detailed in vitro and in vivo experiments demonstrate that the CO prodrug system in generating a sufficient quantity of CO and • OH offers remarkable destructive effects against cancer cells without causing toxicity to surrounding normal tissues. The study provides a solid foundation to develop smart coordination polymer CO prodrugs with on‐demand CO release, enhanced permeability and retention effect, and biodegradability for multimodal synergistic therapy.
CTNI-27. FIRST-IN-PEDIATRICS PHASE I STUDY OF GDC-0084 (PAXALISIB), A CNS-PENETRANT PI3K/mTOR INHIBITOR, IN NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) OR OTHER DIFFUSE MIDLINE GLIOMA (DMG)
Authors: Christopher Tinkle, Jie Huang, Olivia Campagne, Haitao Pan, Arzu Onar-Thomas, Jason Chiang, Paul Klimo, Rick Boop, Zoltan Patay, Barry Shulkin, John Lucas, Thomas Merchant, Santhosh Upadhyaya, Giles Robinson, Anna Vinitsky, Clinton Stewart, Amar Gajjar
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND GDC-0084 is an oral, highly selective and potent inhibitor of class I PI3K and moderate inhibitor of mTOR, with an established adult maximum tolerated dose (MTD) of 60 mg/day and evidence of brain tumor penetration in adult recurrent glioblastoma. METHODS We used a rolling-6 design to evaluate the safety and pharmacokinetic (PK) properties and establish the pediatric MTD of once-daily GDC-0084 administered after focal RT in children with newly diagnosed DIPG and histone H3 K27M-mutant DMG. Non-compartmental plasma PK analyses were performed using samples collected on cycle 1 days 1–3 after single-dose and day 28 at steady-state. RESULTS Twenty-five patients have been enrolled, 16 of whom were treated at study dosage levels of 27 mg/m2 (n=11) and 35 mg/m2 (n=5). Two dose limiting toxicities (DLTs) observed at 35 mg/m2 were grade 3 mucositis and grade 3 rash. Grade 3 hyperglycemia was the only DLT at 27 mg/m2. The most frequent grade 3 or 4 adverse events attributed to GDC-0084 were rash (5 patients), neutropenia (4), and hyperglycemia (2). After single-dose, GDC-0084 exposures (AUC0-48h) at 27 and 35 mg/m2 were 3399±1301 and 4462±2868 hr·ng/mL, respectively. Mean GDC-0084 half-life was 20.6±9.1 hr, comparable to that observed in adults. CONCLUSIONS The dosage of 27 mg/m2 has been established as the pediatric MTD of GDC-0084, which is approximately equivalent to 80% of the adult MTD. At 27 mg/m2, GDC-0084 is well tolerated in children where the spectrum of toxicities is similar to those observed in adults and consistent with this class of agents.
Regulation of FN1 degradation by the p62/SQSTM1-dependent autophagy–lysosome pathway in HNSCC
Authors: Xinchen Liu, Lin Meng, Xing Li, Daowei Li, Qilin Liu, Yumeng Chen, Xiangwei Li, Wenhuan Bu, Hongchen Sun
Journal: International Journal of Oral Science (2020)

Abstract Epithelial–mesenchymal transition (EMT) is involved in both physiological and pathological processes. EMT plays an essential role in the invasion, migration and metastasis of tumours. Autophagy has been shown to regulate EMT in a variety of cancers but not in head and neck squamous cell carcinoma (HNSCC). Herein, we investigated whether autophagy also regulates EMT in HNSCC. Analyses of clinical data from three public databases revealed that higher expression of fibronectin-1 (FN1) correlated with poorer prognosis and higher tumour pathological grade in HNSCC. Data from SCC-25 cells demonstrated that rapamycin and Earle’s balanced salt solution (EBSS) promoted autophagy, leading to increased FN1 degradation, while 3-methyladenine (3-MA), bafilomycin A1 (Baf A1) and chloroquine (CQ) inhibited autophagy, leading to decreased FN1 degradation. On the other hand, autophagic flux was blocked in BECN1 mutant HNSCC Cal-27 cells, and rapamycin did not promote autophagy in Cal-27 cells; also in addition, FN1 degradation was inhibited. Further, we identified FN1 degradation through the lysosome-dependent degradation pathway using the proteasome inhibitor MG132. Data from immunoprecipitation assays also showed that p62/SQSTM1 participated as an autophagy adapter in the autophagy–lysosome pathway of FN1 degradation. Finally, data from immunoprecipitation assays demonstrated that the interaction between p62 and FN1 was abolished in p62 mutant MCF-7 and A2780 cell lines. These results indicate that autophagy significantly promotes the degradation of FN1. Collectively, our findings clearly suggest that FN1, as a marker of EMT, has adverse effects on HNSCC and elucidate the autophagy–lysosome degradation mechanism of FN1.
MBRS-37. RECURRENT ACTIVATING MUTATIONS OF AKT GENES IN WNT-ACTIVATED MEDULLOBLASTOMAS
Authors: Julien Masliah-Planchon, Emmanuelle Lechapt-Zalcman, Jean-Baptiste Aillaud, Olivier Ayrault, Célio Pouponnot, Francois Doz, Olivier Delattre, Franck Bourdeaut
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB) can be classified into four distinct molecular subgroups (WNT group, SHH group, group 3, and group 4). Medulloblastoma of the WNT subgroup (WNT-MB) are commonly associated with favorable prognosis. Prospective molecular analysis based on a combination of CGH-array, targeted NGS and Nanostring-based subgrouping on 272 MB was conducted. Our custom targeted NGS panel of 75 genes includes genes recurrently affected in MB together with actionable genes with therapeutic purpose including some involved in the PIK3/AKT signaling pathway. Among the 272 MB analyzed, 26 cases (9.6%) belonged to the WNT subgroup based on CTNNB1 mutations, monosomy of chromosome 6 and Nanostring-based molecular subgrouping. Our targeted NGS revealed three hotspot activating mutations in AKT3 in WNT-MB and only one cases in another MB subgroup (in a group 4 MB; among the 33 cases of confirmed group 4 MB in our cohort). We subsequently performed Sanger sequencing of the hotspot Glu17 codon of AKT1, AKT2, and AKT3 in 42 additional WNT-MB. This analysis revealed six additional activating mutations of AKT genes (four AKT3 and two AKT1 hotspots mutations) in WNT-MB. Altogether, we report 9/68 (13.2%) cases of WNT-MB with AKT genes mutations (two mutations in AKT1 and seven mutations in AKT3). Our molecular analysis revealed AKT hotspot mutations that presumably activate the PIK3/AKT signaling pathway in WNT-MB. Even though WNT-MB is the subgroup of MB with the most favorable prognosis, this result emphasizes a possibility of targeted therapy that need to be further explored in vitro and in vivo.
MODL-02. TARGETING REPLICATION STRESS IN PEDIATRIC BRAIN TUMORS
Authors: Sonja Krausert, Sander Lambo, Norman Mack, Benjamin Schwalm, Stefan Pfister, Marcel Kool
Journal: Neuro-Oncology (2020)

Abstract Pediatric brain tumors harboring amplifications or high overexpression of MYC-/MYCN are often associated with poor outcome. High MYC(N) expression in these tumors leads to increased transcription, which can be in conflict with DNA replication and subsequently can cause replication stress, R-loops and DNA damage. We hypothesize that high MYC(N) expression makes them vulnerable to DNA damage response inhibitors (DDRi) and even more vulnerable to combinations of DDRi and chemotherapeutics. To test this hypothesis we performed in vitro drug experiments using Group 3 medulloblastoma (MB) and ETMR cell lines. IC50-values were evaluated of topoisomerase inhibitor Irinotecan (SN-38) and Pamiparib (BGB-290), a brain-penetrant PARP-inhibitor, in monotherapy. All cell lines were sensitive for SN-38 and showed IC50-values in the low nM-range but PARP-inhibitors were ineffective. However, a significant decrease in IC50 can be observed when SN-38 and Pamiparib are used in combination. For in vivo treatments, we injected NSG mice with luciferase labelled patient-derived xenograft- (PDX-) cells of various models (MB Group 3, MB SHH, ETMR, RELA EPN), monitored tumor growth via IVIS and randomized the mice into four groups (vehicle, BGB-290, Irinotecan and Irinotecan+Pamiparib) when a predefined threshold of tumor growth was reached. Mice were treated with Irinotecan (or vehicle) once per day i.p. and Pamiparib (or vehicle) twice per day per oral gavage. Treatment with Pamiparib did not show any survival benefit, but mice treated with Irinotecan or the combination showed a clear survival benefit. Treatments are ongoing and more results will be presented at the conference.
Bloviating and Bungling the COVID-19 Pandemic
Authors: Donald A. Redelmeier, Fizza Manzoor
Journal: JAMA Network Open (2020)

Wegwarth and coauthors 1 shed some light into why their country of Germany has fared better than the United States in handling the coronavirus disease 2019 (COVID-19) pandemic. 1As of November 1, 2020, for example, the mortality rate per million was 5 times lower in Germany than in the United States (128 vs 715, respectively). 2 Indeed, the mortality rate in Germany was lower than almost every American state, including Hawaii.This difference in mortality, morbidity, and lost quality of life is difficult to attribute to medical technology, drug therapy, underlying genetics, environmental factors, or virus characteristics.One contributing factor may be differences in public health messages intended to guide individual behaviors to mitigate the COVID-19 pandemic.Wegwarth et al 1 used a national survey of German adults (N = 2011) to test nuances in public health messaging about the COVID-19 pandemic.The nuances spanned from comprehensive
NCOG-39. PROGRESSION-FREE AND SURVIVAL RATE OF CHEMOTHERAPY IN PEDIATRICS WITH OPTIC PATHWAY GLIOMAS: A SYSTEMATIC REVIEW
Authors: Vega Pangaribuan, Jemmy Kurniawan, Doni Widyandana
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Optic pathway gliomas (OPG) are typically astrocytic neoplasms that represent 3-5% of all pediatric brain tumors. The prognosis of these tumors has often been poor. Total surgical resection of OPG is not amenable, thus the role of surgery remains limited. Chemotherapy can be considered as the main modality of treatment; it is also able to postpone the use of radiotherapy which may harm the brain growth in children. METHODS We conducted the PRISMA-guided systematic literature search from 6 electronic databases to identify studies reporting outcomes of chemotherapy in OPG patients. The inclusion criteria are literature reporting the survival outcomes of chemotherapy in OPG patients with minimum subjects of 10 patients and aged below 22 years old. RESULTS A total of 48 out of 557 studies were assessed for its full paper eligibility. Thus, we found 10 studies comprising of 451 patients that met the inclusion criteria for analysis. From 8 different regimens of chemotherapy that were reported, the most commonly used regimens are Carboplastin ± Vincristine. The 3-year, 5-year, and 10-year progression-free survival (PFS) rates were ranged from 23-70%, 34-73%, and 47.1% respectively. The 3-year, 5-year, and 10-year overall survival (OS) rate has a range of 91-95%, 70.1-97%, and 61.3%-62.3% respectively. In detail, we found that 1 study with Cisplatin with Etoposide regimens reported 0% of the 5-year PFS rate, therefore it was excluded from the analysis. There are 2 studies that reported a high rate of 5-year radiotherapy free survival with chemotherapy, ranging from 61-82%. CONCLUSION This systematic review showed that chemotherapy in patients with OPG leads to an unsatisfactory 5-year PFS rate (34-73%), however it is able to provide a high 5-year OS (91-95%). In the absence of good quality control for these studies, future prospective clinical trials with adjusted confounding factors are urgently needed.
Run or Die in the Evolution of New MicroRNAs—Testing the Red Queen Hypothesis on De Novo New Genes
Authors: Yixin Zhao, Guang-An Lu, Hao Yang, Pei Lin, Zhongqi Liufu, Tian Tang, Jin Xu
Journal: Molecular Biology and Evolution (2020)

The Red Queen hypothesis depicts evolution as the continual struggle to adapt. According to this hypothesis, new genes, especially those originating from nongenic sequences (i.e., de novo genes), are eliminated unless they evolve continually in adaptation to a changing environment. Here, we analyze two Drosophila de novo miRNAs that are expressed in a testis-specific manner with very high rates of evolution in their DNA sequence. We knocked out these miRNAs in two sibling species and investigated their contributions to different fitness components. We observed that the fitness contributions of miR-975 in Drosophila simulans seem positive, in contrast to its neutral contributions in D. melanogaster, whereas miR-983 appears to have negative contributions in both species, as the fitness of the knockout mutant increases. As predicted by the Red Queen hypothesis, the fitness difference of these de novo miRNAs indicates their different fates.
Abstract 15619: Markers of Insulin Resistance Predict Prevalent Coronary Artery Disease in Non-Diabetic Individuals Presenting for Cardiac Surgery
Authors: David Carew, Jonathan Tiong, Sarang Paleri, Karen Duve, Jane Mack, Arul Baradi, Andrew Newcomb, Andrew Wilson
Journal: Circulation (2018)

Background: We have previously shown a high rate of insulin resistance (IR) in non-diabetic patients undergoing cardiac surgery, and that this predicts post-operative dysglycemia. We hypothesised t...
Multiple Myeloma, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology
Authors: Shaji K. Kumar, Natalie S. Callander, Kehinde Adekola, Larry Anderson, Muhamed Baljevic, Erica Campagnaro, Jorge J. Castillo, Jason C. Chandler, Caitlin Costello, Yvonne Efebera, Matthew Faiman, Alfred Garfall, Kelly Godby, Jens Hillengass, Leona Holmberg, Myo Htut, Carol Ann Huff, Yubin Kang, Malin Hultcrantz, Sarah Larson, Michaela Liedtke, Thomas Martin, James Omel, Kenneth Shain, Douglas Sborov, Keith Stockerl-Goldstein, Donna Weber, Jennifer Keller, Rashmi Kumar
Journal: Journal of the National Comprehensive Cancer Network (2020)

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.