tbuckley/cabot-search huggingface dataset:
HSR19-090: Changes in Adherence to Tyrosine Kinase Inhibitor Treatment Patterns Among Patients With Chronic Myeloid Leukemia and the Impact on Costs: 2001–2017
Authors: Henry J. Henk, Lena E. Winestone, Jennifer J. Wilkes, Laura Becker, Pamela Morin, Gary H. Lyman, Eric J. Chow
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Chronic myeloid leukemia (CML) treatment improved considerably after introduction of oral tyrosine kinase inhibitors (TKI). As a result, the number of patients living with CML may reach 250,000 by 2040. We track changes in TKI treatment adherence since 2001 and provide an early assessment of treatment costs following the availability of second-generation TKIs and generic imatinib. Methods: A retrospective cohort from the OptumLabs Data Warehouse, which includes claims data for privately insured and Medicare Advantage (MA) enrollees in a large private U.S. health plan with medical and pharmacy benefits, was used. Patients with CML initiated TKI treatment between May 2001 and October 2016 and were continuously enrolled in the health plan 6 months prior through 12 months following TKI start. Adherence was defined by medication possession ratio (MPR 1 =total days’ supply of imatinib in 1st year divided by 365, 1=perfect adherence). Total health care costs include medical and prescription medication benefits. MPR 1 was modeled using ordinary least squares regression. The association between MPR 1 and healthcare costs was estimated using a generalized linear model specified with a gamma error distribution and a log link. Results: We identified 1,793 eligible patients. First-line TKI has changed over time (dasatinib and nilotinib represent 45% of all 2016 starts; imatinib 55%). From 2001 to 2016, adherence increased (Table 1). MPR 1 was higher in men and increased with age until age ∼62 after which it declined. MPR 1 was lower for patients with more comorbid conditions prior to treatment. Overall, MPR 1 was inversely associated with total health care costs (medical and pharmacy) among privately insured ( P &lt;.001) but not MA enrollees. The net impact of MPR 1 on total healthcare costs diminished over time ( P &lt;.001) where a 10% point decrease in MPR 1 was associated with 12% and 4% lower total costs, prior to and following availability of 2nd generation TKIs, respectively. When examining medical costs only, MPR 1 was inversely associated with medical costs for both privately insured ( P &lt;.001) and MA enrollees ( P =.016). Conclusions: We found that adherence to TKI treatment increased over time. While imatinib is still used more frequently than other TKIs as first-line therapy, second-generation TKIs are becoming increasingly used as first-line agents. Possible cost-offsets are decreasing over time but it may be too early to formally evaluate the impact of generic imatinib.
Patient-reported outcomes in patients with resected, high-risk melanoma with BRAFV600E or BRAFV600K mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): a randomised, placebo-controlled, phase 3 trial
Authors: Dirk Schadendorf, Axel Hauschild, Mario Santinami, Victoria Atkinson, Mario Mandalà, Vanna Chiarion-Sileni, James Larkin, Marta Nyakas, Caroline Dutriaux, Andrew Haydon, Caroline Robert, Laurent Mortier, Thierry Lesimple, Ruth Plummer, Jacob Schachter, Kohinoor Dasgupta, Stephanie Manson, Roy Koruth, Bijoyesh Mookerjee, Richard Kefford, Reinhard Dummer, John M Kirkwood, Georgina V Long
Journal: The Lancet Oncology (2019)
Dominant factor explaining missed GP appointments is largely ignored
Authors: Stephen Black
Journal: BMJ (2019)

Oliver is right to challenge the dominant narrative surrounding the newly released data on GP appointments and the number of missed appointments.1

He (rightly) opposes the knee jerk reaction of many commentators that sought to put the blame on feckless patients. He argues that many patients may have good reasons to miss appointments. But, in looking at the justifiable reasons why patients might miss …
The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study
Authors: Marta Di Forti, Diego Quattrone, Tom P Freeman, Giada Tripoli, Charlotte Gayer-Anderson, Harriet Quigley, Victoria Rodriguez, Hannah E Jongsma, Laura Ferraro, Caterina La Cascia, Daniele La Barbera, Ilaria Tarricone, Domenico Berardi, Andrei Szöke, Celso Arango, Andrea Tortelli, Eva Velthorst, Miguel Bernardo, Cristina Marta Del-Ben, Paulo Rossi Menezes, Jean-Paul Selten, Peter B Jones, James B Kirkbride, Bart PF Rutten, Lieuwe de Haan, Pak C Sham, Jim van Os, Cathryn M Lewis, Michael Lynskey, Craig Morgan, Robin M Murray, Silvia Amoretti, Manuel Arrojo, Grégoire Baudin, Stephanie Beards, Miquel Bernardo, Julio Bobes, Chiara Bonetto, Bibiana Cabrera, Angel Carracedo, Thomas Charpeaud, Javier Costas, Doriana Cristofalo, Pedro Cuadrado, Covadonga M Díaz-Caneja, Aziz Ferchiou, Nathalie Franke, Flora Frijda, Enrique García Bernardo, Paz Garcia-Portilla, Emiliano González, Kathryn Hubbard, Stéphane Jamain, Estela Jiménez-López, Marion Leboyer, Gonzalo López Montoya, Esther Lorente-Rovira, Camila Marcelino Loureiro, Giovanna Marrazzo, Covadonga Martínez, Mario Matteis, Elles Messchaart, Ma Dolores Moltó, Juan Nacher, Ma Soledad Olmeda, Mara Parellada, Javier González Peñas, Baptiste Pignon, Marta Rapado, Jean-Romain Richard, José Juan Rodríguez Solano, Laura Roldán Díaz, Mirella Ruggeri, Pilar A. Sáiz, Emilio Sánchez, Julio Sanjuán, Crocettarachele Sartorio, Franck Schürhoff, Fabio Seminerio, Rosana Shuhama, Lucia Sideli, Simona A Stilo, Fabian Termorshuizen, Sarah Tosato, Anne-Marie Tronche, Daniella van Dam, Elsje van der Ven
Journal: The Lancet Psychiatry (2019)

Cannabis use is associated with increased risk of later psychotic disorder but whether it affects incidence of the disorder remains unclear. We aimed to identify patterns of cannabis use with the strongest effect on odds of psychotic disorder across Europe and explore whether differences in such patterns contribute to variations in the incidence rates of psychotic disorder.
The IAP antagonist birinapant potentiates bortezomib anti-myeloma activity in vitro and in vivo
Authors: Liang Zhou, Yu Zhang, Yun Leng, Yun Dai, Maciej Kmieciak, Lora Kramer, Kanika Sharma, Yan Wang, William Craun, Steven Grant
Journal: Journal of Hematology & Oncology (2019)

Mechanisms by which Smac mimetics (SMs) interact with proteasome inhibitors (e.g., bortezomib) are largely unknown, particularly in multiple myeloma (MM), a disease in which bortezomib represents a mainstay of therapy. Interactions between the clinically relevant IAP (inhibitor of apoptosis protein) antagonist birinapant (TL32711) and the proteasome inhibitor bortezomib were investigated in multiple myeloma (MM) cell lines and primary cells, as well as in vivo models. Induction of apoptosis and changes in gene and protein expression were monitored using MM cell lines and confirmed in primary MM cell populations. Genetically modified cells (e.g., exhibiting shRNA knockdown or ectopic expression) were employed to evaluate the functional significance of birinapant/bortezomib-induced changes in protein levels. A MM xenograft model was used to evaluate the in vivo activity of the birinapant/bortezomib regimen. Birinapant and bortezomib synergistically induced apoptosis in diverse cell lines, including bortezomib-resistant cells (PS-R). The regimen robustly downregulated cIAP1/2 but not the canonical NF-κB pathway, reflected by p65 phosphorylation and nuclear accumulation. In contrast, the bortezomib/birinapant regimen upregulated TRAF3, downregulated TRAF2, and diminished p52 processing and BCL-XL expression, consistent with disruption of the non-canonical NF-κB pathway. TRAF3 knockdown, ectopic TRAF2, or BCL-XL expression significantly diminished birinapant/bortezomib toxicity. The regimen sharply increased extrinsic apoptotic pathway activation, and cells expressing dominant-negative FADD or caspase-8 displayed markedly reduced birinapant/bortezomib sensitivity. Primary CD138+ (n = 43) and primitive MM populations (CD138−/19+/20+/27+; n = 31) but not normal CD34+ cells exhibited significantly enhanced toxicity with combined treatment (P < 0.0001). The regimen was also fully active in the presence of HS-5 stromal cells or growth factors (e.g., IL-6 and VEGF). Finally, the regimen was well tolerated and significantly increased survival (P < 0.05 and P < 0.001) compared to single agents in a MM xenograft model. Combined treatment also downregulated cIAP1/2 and p52 while increasing PARP cleavage in MM cells in vivo. Our data suggest that birinapant and bortezomib interact synergistically in MM cells, including those resistant to bortezomib, through inactivation of the non-canonical NF-κB and activation of the extrinsic apoptotic pathway both in vitro and in vivo. They also argue that a strategy combining cIAP antagonists and proteasome inhibitors warrants attention in MM.
HSR19-105: The Role of Chemotherapy in Elderly Colorectal Cancer Survivors: An Observational Study
Authors: Pamala A. Pawloski, Gabriela Vazquez-Benitez, Jeanette Y. Ziegenfuss, Terese A. DeFor, Elisabeth M. Seburg
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Older patients diagnosed with colorectal cancer are not routinely included in clinical trials and are frequently treated with less aggressive chemotherapy. To identify factors associated with treatment initiation in older adults, we conducted an observational study of patients diagnosed with stage I–IV colon or rectal cancer at 65 years and older between 2010 and 2014 across 6 integrated health care systems. Methods: Data were obtained from cancer registries based on chart abstraction and medical records. Time from diagnosis to surgery, chemotherapy, and radiation was measured in weeks and censored when disenrollment, death, or the end of the study period occurred. We assessed patient factors associated with time to chemotherapy initiation using survival analysis methods. Results: Among 8,088 patients diagnosed after the age of 65 with colon cancer, the mean age at diagnosis was 76 years (SD 7.7), 4,150 (51%) were female, and 34% were stage 3 or greater. More than half, 55% (n=4,434) of colon cancers were right-sided (RCC), 23% (n=1833) were left-sided (LCC), and 19% (n=1,559) were rectal cancers. Two-thirds (n=5,201) had moderately differentiated disease. Most (57%) received surgery within 4 weeks and 89% within 6 months of diagnosis (median, 3.4 weeks). At 6 months following diagnosis, 33% of patients had received chemotherapy, and only 4% received radiation. Factors associated with the receipt of chemotherapy were assessed in a multivariable survival model that included age, gender, stage, and site. Patients of older age were less likely to receive chemotherapy (HR, 0.49; 95%CI, 0.45–.53 for 75–79 vs 65–69 years), and more likely for advanced stage, and rectal site. No difference was observed between men and women. Refusal of chemotherapy was reported for only 6% of patients and was associated with age, stage, and site. Six month mortality was 13.3%. Conclusions: Factors associated with the receipt of treatment among older cancer survivors are similar to those in the general population.
Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis
Authors: Allison F. McCague, Karen S. Raraigh, Matthew J. Pellicore, Emily F. Davis-Marcisak, Taylor A. Evans, Sangwoo T. Han, Zhongzhou Lu, Anya T. Joynt, Neeraj Sharma, Carlo Castellani, Joseph M. Collaco, Mary Corey, Michelle H. Lewis, Chris M. Penland, Johanna M. Rommens, Anne L. Stephenson, Patrick R. Sosnay, Garry R. Cutting
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: The advent of precision treatment for cystic fibrosis using small-molecule therapeutics has created a need to estimate potential clinical improvements attributable to increases in cystic fibrosis transmembrane conductance regulator (CFTR) function. Objectives: To derive CFTR function of a variety of CFTR genotypes and correlate with key clinical features (sweat chloride concentration, pancreatic exocrine status, and lung function) to develop benchmarks for assessing response to CFTR modulators. Methods: CFTR function assigned to 226 unique CFTR genotypes was correlated with the clinical data of 54,671 individuals enrolled in the Clinical and Functional Translation of CFTR (CFTR2) project. Cross-sectional FEV1% predicted measurements were plotted by age at which measurement was obtained. Shifts in sweat chloride concentration and lung function reported in CFTR modulator trials were compared with function-phenotype correlations to assess potential efficacy of therapies. Measurements and Main Results: CFTR genotype function exhibited a logarithmic relationship with each clinical feature. Modest increases in CFTR function related to differing genotypes were associated with clinically relevant improvements in cross-sectional FEV1% predicted over a range of ages (6-82 yr). Therapeutic responses to modulators corresponded closely to predictions from the CFTR2-derived relationship between CFTR genotype function and phenotype. Conclusions: Increasing CFTR function in individuals with severe disease will have a proportionally greater effect on outcomes than similar increases in CFTR function in individuals with mild disease and should reverse a substantial fraction of the disease process. This study provides reference standards for clinical outcomes that may be achieved by increasing CFTR function.
Gene Expression Does Not Support the Developmental Hourglass Model in Three Animals with Spiralian Development
Authors: Longjun Wu, Kailey E Ferger, J David Lambert
Journal: Molecular Biology and Evolution (2019)

Abstract It has been proposed that animals have a pattern of developmental evolution resembling an hourglass because the most conserved development stage—often called the phylotypic stage—is always in midembryonic development. Although the topic has been debated for decades, recent studies using molecular data such as RNA-seq gene expression data sets have largely supported the existence of periods of relative evolutionary conservation in middevelopment, consistent with the phylotypic stage and the hourglass concepts. However, so far this approach has only been applied to a limited number of taxa across the tree of life. Here, using established phylotranscriptomic approaches, we found a surprising reverse hourglass pattern in two molluscs and a polychaete annelid, representatives of the Spiralia, an understudied group that contains a large fraction of metazoan body plan diversity. These results suggest that spiralians have a divergent midembryonic stage, with more conserved early and late development, which is the inverse of the pattern seen in almost all other organisms where these phylotranscriptomic approaches have been reported. We discuss our findings in light of proposed reasons for the phylotypic stage and hourglass model in other systems.
Quick Uptakes
Authors: Rebecca Voelker
Journal: JAMA (2019)

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The Caspase-3/PKCδ/Akt/VEGF-A Signaling Pathway Mediates Tumor Repopulation during Radiotherapy
Authors: Jin Cheng, Sijia He, Min Wang, Ling Zhou, Zhengxiang Zhang, Xiao Feng, Yang Yu, Jingjing Ma, Chenyun Dai, Shengping Zhang, Lianhui Sun, Yanping Gong, Yiwei Wang, Minghui Zhao, Yuntao Luo, Xinjian Liu, Ling Tian, Chuanyuan Li, Qian Huang
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Tumor repopulation is known as a major cause of treatment failure and/or tumor recurrence after radiotherapy. The underlying mechanism remains unclear. Our previous study demonstrated that irradiated apoptotic cells mediated tumor repopulation, in which caspase-3 played an important role. Herein, we investigated downstream effectors of caspase-3 involved in this process. Experimental Design: A dominant-negative protein kinase Cδ (DN_PKCδ) mutant that could not be cleaved by caspase-3 and therefore could not be activated by irradiation-induced apoptosis was constructed. DN_PKCδ stably transduced tumor cells were compared with wild-type tumor cells for their growth stimulation effects in in vitro and in vivo tumor repopulation models. Downstream effectors of caspase-3 and PKCδ were investigated. The role of PKCδ was further verified in human colorectal tumor specimens. Results: Inactivation of caspase-3 or caspase-7 attenuated tumor repopulation and weakened PKCδ cleavage. Both DN_PKCδ and PKCδ inhibitors restrained tumor repopulation both in vitro and in vivo. Phosphorylated Akt was attenuated in caspase-3–, caspase-7–, or PKCδ-inactivated tumor cells. Furthermore, expression of vascular endothelial growth factor (VEGF)-A but not hypoxia-inducible factor 1α (HIF1α) was decreased in PKCδ- or Akt-inactivated tumor cells. In addition, inhibition of p-Akt, HIF1α, VEGF-A, or VEGF-A receptor reduced tumor repopulation significantly. Finally, increased nuclear translocation of PKCδ in colorectal tumor specimens was associated with worse patient prognosis. Conclusions: The caspase-3/PKCδ/Akt/VEGF-A axis is involved in tumor repopulation and could be exploited as a potential target to enhance the efficacy of radiotherapy.
Evaluating digital medicine ingestion data from seriously mentally ill patients with a Bayesian Hybrid Model
Authors: Jonathan Knights, Zahra Heidary, Timothy Peters-Strickland, Murali Ramanathan
Journal: npj Digital Medicine (2019)

The objective of this work was to adapt and evaluate the performance of a Bayesian hybrid model to characterize objective temporal medication ingestion parameters from two clinical studies in patients with serious mental illness (SMI) receiving treatment with a digital medicine system. This system provides a signal from an ingested sensor contained in the dosage form to a patient-worn patch and transmits this signal via the patient's mobile device. A previously developed hybrid Markov-von Mises model was used to obtain maximum-likelihood estimates for medication ingestion behavior parameters for individual patients. The individual parameter estimates were modeled to obtain distribution parameters of priors implemented in a Markov chain-Monte Carlo framework. Clinical and demographic covariates associated with model ingestion parameters were also assessed. We obtained individual estimates of overall observed ingestion percent (median:75.9%, range:18.2-98.3%, IQR:32.9%), rate of excess dosing events (median:0%, range:0-14.3%, IQR:3.0%) and observed ingestion duration. The modeling also provided estimates of the Markov-dependence probabilities of dosing success following a dosing success or failure. The ingestion-timing deviations were modeled with the von Mises distribution. A subset of 17 patients (22.1%) were identified as prompt correctors based on Markov-dependence probability of a dosing failure followed by a dosing success of unity. The prompt corrector sub-group had a better overall digital medicine ingestion parameter profile compared to those who were not prompt correctors. Our results demonstrate the potential utility of a Bayesian Hybrid Markov-von Mises model for characterizing digital medicine ingestion patterns in patients with SMI.
Incidentally Detected Oropharyngeal Squamous Cell Carcinoma on 18F-Fluciclovine PET/CT
Authors: Kesav Raghavan, Kwun Wah Wen, Eric J. Small, Patrick Ha, Robert R. Flavell
Journal: Clinical Nuclear Medicine (2019)

We present a case of oropharyngeal squamous cell carcinoma (SCC) of the tongue base incidentally detected on F-fluciclovine PET/CT. A 79-year-old man with history of locally advanced prostate cancer (Gleason score 4 + 5 = 9; cT2cN1M0) previously treated with androgen deprivation therapy (luprolide + bicalutamide) presented with a slowly rising serum prostate-specific antigen over 3 years, concerning for recurrent disease. F-fluciclovine PET/CT, obtained to identify potential sites of recurrence, demonstrated prostate bed uptake with possible left seminal vesicle involvement. Additionally, an exophytic, tracer-avid right tongue base mass was incidentally noted and later confirmed to be p16+ SCC on biopsy.
Abstract 14806: The Glucagon-Like Peptide-1 Receptor Agonists Liraglutide and Semaglutide Improve Cardiovascular and Renal Outcomes Across Most Body Mass Index Categories in Type 2 Diabetes: Results of the LEADER and SUSTAIN 6 Trials
Authors: Subodh Verma, Stephen Bain, Deepak L Bhatt, Lawrence A Leiter, C David Mazer, Darren K McGuire, Richard Pratley, Bernard Zinman, Søre Lindberg, Søren Rasmussen, Hrvoje Vrazic, John Buse
Journal: Circulation (2018)

Objective: Whether cardiorenal benefits of liraglutide and semaglutide are consistent across body mass index (BMI) categories is unknown. We performed post hoc analyses on LEADER and SUSTAIN 6 data...