tbuckley/cabot-search huggingface dataset:
Modifiable Lifestyle and Medical Risk Factors Associated With Myeloproliferative Neoplasms
Authors: Andrew S. Duncombe, Lesley A. Anderson, Glen James, Frank de Vocht, Lin Fritschi, Ruben Mesa, Mike Clarke, Mary Frances McMullin
Journal: HemaSphere (2020)

Despite the identification of acquired genetic mutations associated with Myeloproliferative Neoplasms (MPNs) there is a paucity of information relating to modifiable risk factors that may lead to these mutations. The MOSAICC Study was an exploratory case-control study of polycythemia vera (PV), essential thrombocythemia (ET), and Myelofibrosis (MF). MPN patients and population controls (identified by General Practitioners) and non-blood relative/friend controls were recruited from 2 large UK centers. Participants completed a telephone-based questionnaire analyzed by unconditional logistic regression analysis adjusting for potential confounders. Risk factors for MPNs identified included increasing childhood household density [odds ratio (OR) 2.55, 95% confidence interval (CI) 1.16-5.62], low childhood socioeconomic status (OR 2.30, 95%CI 1.02-5.18) and high pack years smoking (OR 2.19, 95%CI 1.03-4.66) and current smoking restricted to JAK2 positive PV cases (OR 3.73, 95%CI 1.06-13.15). Obesity was linked with ET (OR 2.59, 95%CI 1.02-6.58) confirming results in previous cohort studies. Receipt of multiple CT scans was associated with a strongly increased risk of MPN although with wide confidence intervals (OR 5.38, 95%CI 1.67-17.3). Alcohol intake was inversely associated with risk of PV (OR 0.41, 95%CI 0.19-0.92) and ET (OR 0.48, 95%CI 0.24-0.98). The associations with childhood household density, high pack years smoking and alcohol were also seen in multivariate analysis. This is the largest case control study in MPNs to date and confirms the previously reported associations with obesity and cigarette smoking from cohort studies in addition to novel associations. In particular, the role of smoking and JAK2 mutation cases merits further evaluation.
Neoadjuvant chemotherapy (TPF regimen) followed with robotic surgery and its impact on outcome in management of esophageal cancers: Indian experience.
Authors: S.P. Somashekhar, Rohit Kumar C., Ashwin K. Rajgopal, Amit Rauthan, Poonam Patil
Journal: Journal of Clinical Oncology (2020)

407 Background: Neo-adjuvant chemotherapy coupled with robotic three stage esophagectomy have shown promising results in esophageal cancer. Methods: 136 patients diagnosed with squamous cell cancer esophagus were included to analyze the benefit of NACT with DCF (docetaxel 75mg/m 2 day 1, cisplatin 75mg/m 2 day 1, 5-FU 750mg/m 2 per day 1-4) regimen 3 cycles followed by three stage robotic esophagectomy. Esophagus, assessed by EUS and PET-CT scan, pre-chemo and post-chemo, in biopsy proven Squamous cell Carcinoma Oesophagus. All the data pertaining to chemotherapy and surgery were prospectively maintained in a data base. Results: Median age 62.7 years, male to female 5.9:4.1. T2 4%, T3 90% &amp; T4 6%. N0 10% &amp; N+90%. Post NACT, Partial response of 50.8%, and a complete pathological response of 27.6% was observed with response rate of 66.3%. 20 pts. had mucositis, but none had grade 3 toxicity, neutropenia in 24 pts. and febrile neutropenia in 7 pt., vomiting and fatigue in 35 pts. Mean blood loss 256.5±85.8ml, duration of surgery 322.4±28.4min, ICU stay 1.5±0.8-day, hospital stay 10.5±2.1 day. Proximal and distal margin was negative for all whereas only 2 patients had a positive CRM. Mean Lymph node yield was 22.4±3.5 nodes. All patients had complete robotic surgery with no conversions and major intraoperative complication. Post-operatively Minor complication was noted in 5 patients temporary vocal cord palsy, 10 delayed gastric emptying, wound infection in 3 and minor lung infection 9. Major complication in form of leak (3), stenosis (5), chylous leak (4) was noted. 30-day mortality 4.5%. With the longest follow up of 50 months, 3 year DFS and OS was 75.4% &amp; 68% respectively. Conclusions: Neoadjuvant chemotheraphy with TPF regimen showed excellent response rates with minimal G3 toxicity and is well tolerated in Indian patients. Combination of NACT with robotic esophagectomy has excellent outcome with low morbidity &amp; mortality.
Pattern of progression in advanced HCC treated with ramucirumab/placebo: Results from two randomized phase III trials (REACH/REACH-2).
Authors: Maria Reig, Peter R. Galle, Masatoshi Kudo, Richard S. Finn, Josep M. Llovet, William R. Schelman, Kun Liang, Chunxiao Wang, Ryan C. Widau, Paolo Abada, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2020)

544 Background: REACH (NCT01140347) and REACH-2 (NCT02435433) studied ramucirumab (RAM) in pts with advanced hepatocellular carcinoma (HCC) following sorafenib; REACH-2 enrolled pts with baseline alpha-fetoprotein (AFP) ≥400 ng/mL, and met its primary endpoint of overall survival (OS) for RAM vs placebo. This post-hoc analysis examined radiological progression patterns (RPP) incidence every 6 weeks per RECIST v1.1, and if RPP were related to OS and post-progression survival (PPS). Methods: Pts with advanced HCC, Child-Pugh A, and ECOG PS 0-1 with prior sorafenib were randomized (REACH 1:1; REACH-2 2:1) to receive RAM 8 mg/kg or placebo Q2W. Among pts with ≥1 RPP (new extrahepatic lesion [NEH], new intrahepatic lesion [NIH], extrahepatic growth [EHG], or intrahepatic growth [IHG]), results were analyzed by trial and for pooled individual patient data of REACH-2 and REACH (AFP ≥400 ng/mL). Cox models evaluated treatment effect of RPP on OS, and prognostic implications of RPP on OS (adjusting baseline ECOG PS, AFP, macrovascular invasion, arm) and on PPS (adjusting ECOG PS, AFP at progression). Results: RPP incidence in the pooled population was: NEH 39%; NIH 24%; EHG 39%; IHG 37%. When examining NEH vs other RPP, PPS was worse among those with NEH in REACH (HR 2.33, 95% CI 1.51, 3.60), REACH-2 (HR 1.49, 95% CI 0.72, 3.08), and the pooled data (HR 1.75, 95% CI 1.12, 2.74). Use of post-discontinuation therapy may have influenced results. OS was also significantly reduced in those with NEH across studies (Table). RAM provided OS benefit in the pooled population, including pts with NEH (HR 0.56, 95% CI 0.39, 0.80). Conclusions: Acknowledging limitations of post-randomization RPP analysis, the emergence of NEH on RAM or placebo may be an independent poor prognostic factor for PPS. The impact of RAM on OS was consistent across all RPP subgroups. Clinical trial information: NCT01140347 and NCT02435433. [Table: see text]
The effect of assessing genetic risk of prostate cancer on the use of PSA tests in primary care: A cluster randomized controlled trial
Authors: Jacob Fredsøe, Jan Koetsenruyter, Peter Vedsted, Pia Kirkegaard, Michael Væth, Adrian Edwards, Torben F. Ørntoft, Karina D. Sørensen, Flemming Bro
Journal: PLoS Medicine (2020)

Background Assessing genetic lifetime risk for prostate cancer has been proposed as a means of risk stratification to identify those for whom prostate-specific antigen (PSA) testing is likely to be most valuable. This project aimed to test the effect of introducing a genetic test for lifetime risk of prostate cancer in general practice on future PSA testing. Methods and findings We performed a cluster randomized controlled trial with randomization at the level of general practices (73 in each of two arms) in the Central Region (Region Midtjylland) of Denmark. In intervention practices, men were offered a genetic test (based on genotyping of 33 risk-associated single nucleotide polymorphisms) in addition to the standard PSA test that informed them about lifetime genetic risk of prostate cancer and distinguished between "normal" and "high" risk. The primary outcome was the proportion of men having a repeated PSA test within 2 years. A multilevel logistic regression model was used to test the association. After applying the exclusion criteria, 3,558 men were recruited in intervention practices, with 1,235 (34.7%) receiving the genetic test, and 4,242 men were recruited in control practices. Men with high genetic risk had a higher propensity for repeated PSA testing within 2 years than men with normal genetic risk (odds ratio [OR] = 8.94, p < 0.01). The study was conducted in routine practice and had some selection bias, which is evidenced by the relatively large proportion of younger and higher income participants taking the genetic test. Conclusions Providing general practitioners (GPs) with access to a genetic test to assess lifetime risk of prostate cancer did not reduce the overall number of future PSA tests. However, among men who had a genetic test, knowledge of genetic risk significantly influenced future PSA testing. Trial registration This study is registered with ClinicalTrials.gov, number NCT01739062.
Risk of Cirrhosis and Hepatocellular Cancer in Patients With NAFLD and Normal Liver Enzymes
Authors: Yamini Natarajan, Jennifer R. Kramer, Xian Yu, Liang Li, Aaron P. Thrift, Hashem B. El‐Serag, Fasiha Kanwal
Journal: Hepatology (2020)

The long-term risk of disease for patients with nonalcoholic fatty liver disease (NAFLD) in the absence of elevated enzymes is unclear. We conducted a retrospective cohort study using the Corporate Data Warehouse of the Veterans Health Administration.We classified patients into three groups: patients with steatosis/normal alanine aminotransferase (ALT), steatosis/elevated ALT, and no steatosis/normal ALT. We examined incidence rates for cirrhosis and hepatocellular carcinoma (HCC) and conducted cause-specific hazard models to evaluate the risk of cirrhosis and HCC. We identified 3,522 patients with steatosis/normal ALT, 15,419 patients with steatosis/elevated ALT, and 9,267 patients with no steatosis/normal ALT. The mean age in each group was 58.9, 54.7 and 59.3 years, respectively; over 90% were men. Compared to patients with hepatic steatosis/normal ALT, those with steatosis/elevated ALT were younger and more likely to be obese (both P < 0.01). In patients with steatosis/normal ALT, the incidence rates of cirrhosis and HCC were 1.22 (95% confidence interval [CI]: 0.83-1.74) and 0.20 (95% CI: 0.06-0.46) per 1,000 person-years, respectively; this was lower than in patients with steatosis/elevated ALT (cirrhosis: 3.85; 95% CI: 3.50-4.23, and HCC: 0.37; 95% CI: 0.26-0.49). Patients with steatosis/elevated ALT had a higher risk of developing cirrhosis (adjusted hazard ratio: 3.37; 95% CI: 2.34-4.86; P < 0.01) than patients with steatosis/normal ALT; they also had a higher risk of HCC, although it did not reach statistical significance (hazard ratio: 2.07; 95% CI: 0.82-5.28; P = 0.13). The risk of cirrhosis and HCC in patients with steatosis/normal ALT and those without steatosis was not significantly different.Patients with hepatic steatosis with persistently normal ALT are at lower risk for cirrhosis compared to those with steatosis and elevated ALT and not different from the risk in a clinical cohort without hepatic steatosis.
Dissemination and Implementation of Palliative Care in Oncology
Authors: Betty R. Ferrell, Vincent Chung, Marianna Koczywas, Thomas J. Smith
Journal: Journal of Clinical Oncology (2020)

Palliative care began in academic centers with specialty consultation services, and its value to patients, families, and health systems has been evident. The demand for palliative care to be integrated throughout the cancer trajectory, combined with a limited palliative care workforce, means that new models of care are needed. This review discusses evidence regarding the need for integration of palliative care into routine oncology care and describes best practices recognized for dissemination of palliative care. The available evidence suggests that palliative care be widely adopted by clinicians in all oncology settings to benefit patients with cancer and their families. Efforts are needed to adapt and integrate palliative care into community practice. Limitations of these models are discussed, as are future directions to continue implementation efforts. The benefits of palliative care can only be realized through effective dissemination of these principles of care, with more primary palliative care delivered by oncology clinicians.
DeepCPI: A Deep Learning-Based Framework for Large-Scale <i>in Silico</i> Drug Screening
Authors: Fangping Wan, Yue Zhu, Hailin Hu, Antao Dai, Xiaoqing Cai, Ligong Chen, Haipeng Gong, Tian Xia, Dehua Yang, Ming-Wei Wang, Jianyang Zeng
Journal: Genomics Proteomics & Bioinformatics (2019)

Abstract Accurate identification of compound–protein interactions (CPIs) in silico may deepen our understanding of the underlying mechanisms of drug action and thus remarkably facilitate drug discovery and development. Conventional similarity- or docking-based computational methods for predicting CPIs rarely exploit latent features from currently available large-scale unlabeled compound and protein data and often limit their usage to relatively small-scale datasets. In the present study, we propose DeepCPI, a novel general and scalable computational framework that combines effective feature embedding (a technique of representation learning) with powerful deep learning methods to accurately predict CPIs at a large scale. DeepCPI automatically learns the implicit yet expressive low-dimensional features of compounds and proteins from a massive amount of unlabeled data. Evaluations of the measured CPIs in large-scale databases, such as ChEMBL and BindingDB, as well as of the known drug–target interactions from DrugBank, demonstrated the superior predictive performance of DeepCPI. Furthermore, several interactions among small-molecule compounds and three G protein-coupled receptor targets (glucagon-like peptide-1 receptor, glucagon receptor, and vasoactive intestinal peptide receptor) predicted using DeepCPI were experimentally validated. The present study suggests that DeepCPI is a useful and powerful tool for drug discovery and repositioning. The source code of DeepCPI can be downloaded from https://github.com/FangpingWan/DeepCPI.
Real-world treatment patterns and survival in patients (pts) with hepatocellular carcinoma in the United States.
Authors: Michael Morse, Anne-Marie Meyer, Marcus Lawrance, Marta Pereira, Shivani K. Mhatre, Vincent Gaillard, Farshid Dayyani
Journal: Journal of Clinical Oncology (2020)

519 Background: Outcomes in pts with hepatocellular carcinoma (HCC) vary by epidemiology, degree of hepatic dysfunction and tx. We analyzed the relationship between tx patterns and outcomes to help characterize emerging clinical data in the context of contemporary disease management. Methods: Retrospective observational study of the Flatiron Health de-identified electronic health record–derived database to analyze the relationship between first recorded tx (1tx) and overall survival (OS) in pts diagnosed with HCC (any stage) Jan 2011 to Nov 2018. Tx categories included transplant, resection/SBRT/RFA, TACE/TARE/TAE, tyrosine kinase inhibitor (TKI), cancer immunotherapy (CIT), and others. Descriptive statistics were used to summarize tx distribution and pt characteristics; Kaplan-Meier method was used to estimate OS by tx category. Results: A total of 2134 pts with HCC were categorized by 1tx: transplant (n = 35), resection/SBRT/RFA (n = 408), TACE/TARE/TAE (n = 830), TKI (n = 751), and CIT (n = 20). Pt demographics were generally similar across txs (Table). Overall, pts with HCC had a median OS of 16.6 mo; varying from 71.5 mo in pts receiving transplant to 5.0 mo in pts treated with TKI. Conclusions: Pts receiving systemic tx for HCC have poor prognoses in clinical practice. Despite the limitations of data availability, this study showed a substantial unmet need for more effective HCC tx options. [Table: see text]
Apurinic/apyrimidinic endonuclease-1 and hepatocellular carcinoma.
Authors: Nicholas James Skill, Mary Alice Maluccio
Journal: Journal of Clinical Oncology (2020)

563 Background: The enzyme apurinic/apyrimidinic endonuclease-1 (APE1) is associated with protection against DNA damage and oxidative damage congruent with cancer. The purpose of this study is to investigate hepatic APE1 levels in association with hepatocellular carcinoma (HCC) in order to better stratify patients with underlying liver disease for the development of HCC and identify novel targets for therapy. Methods: Hepatic APE1 levels were determined by immunohistochemistry staining and ELISA within liver and tumor samples from patients with HepC±HCC. Hepatic APE1 staining was semi-quantitated using a scale of 0-100. Serum APE1 levels were determined by ELISA. In addition, APE1 staining was quantified in hepatic paraffin embedded sections from MDR2 −/− mice with HCC and within MDR2 −/+ mice controls that do not develop HCC. Results: Hepatocyte APE1 staining was lower in livers from patients with HepC and HCC when compared to patients with HepC without HCC. In a similar manner, hepatic APE1 levels were significantly lower in patients with HepC and HCC patients when compared to HepC controls. In contrast, serum APE1 level was greater in patients with HepC and HCC when compared to patients with HepC and no HCC. Moreover, APE1 levels were greater in HCC tumors when compared to non-malignant liver tissue. Hepatocyte APE1 staining in MDR −/− mice with HCC was lower when compared to MDR2 −/+ mice that do not develop HCC. In addition, cytosolic APE1 staining was increased in HCC tumor of MDR2 −/− mice when compared to controls. Conclusions: Increased APE1 is a potential biomarker of HCC risk in patients with underlying liver disease and is a novel target for therapy in patients with underlying liver disease whom have a higher risk of developing HCC. Consequently, targeted APE1 inhibition may increase chemotherapy response by reducing tolerance to DNA damage. Additional studies are required to better understand the role of APE1 inhibition in HCC in the face of reduced background hepatic APE1 levels.
Causal modeling of TCGA, NSCLC, and HNSCC data to identify network drivers of tumor immune subtypes.
Authors: Rahul K Das, Raymond T. Yan, Craig B. Davis, Mateusz Maciejewski, Xinmeng Jasmine Mu, Aishwarya Krishnakumar, Bruce W. Church, Iya Khalil
Journal: Journal of Clinical Oncology (2020)

68 Background: Immune checkpoint inhibitors have achieved unprecedented success in several cancer types, yet only a subset of patients derives clinical benefit. Better understanding of tumor-immune interactions is imperative to improve clinical outcomes. Bayesian causal machine learning was applied on real world data to elucidate the molecular drivers of immune subtypes of tumors. Methods: Using a Reverse Engineering Forward Simulation (REFS) platform, ensembles of causal models were built on genomics, transcriptomics, and clinical data from 681 non-small cell lung carcinoma (NSCLC), 328 lung adeno (LUAD) and 353 lung squamous cell (LUSC), and 413 head and neck squamous cell carcinoma (HNSCC) patients from TCGA. The outcomes modeled were six tumor immune subtypes (Thorsson et al., 2018): wound-healing, IFNγ dominant, inflammatory, lymphocyte-depleted, immunologically quiet, and TGFβ dominant. Causal drivers of immune subtypes were identified from average causal effect (ACE) of the variables, as computed from the counterfactual simulations. ACE was defined as median of posterior distribution of odds ratio (1 vs 0 for discrete; 95th vs. 5th %ile for continuous variables). Results: The models showed impressive k-fold cross validation predictive performance (AUC ~ 0.8-0.9) for the most prevalent immune subtypes in TCGA: wound-healing and IFNg dominant in both LUAD and HNSCC, as well as inflammatory in LUAD. The potential causal drivers of the tumor immune subtypes and their ACE are listed in Table. The findings suggest that macrophage activation and polarization, which is driven in part by metabolic reprogramming, is a primary driver of tumor immune subtypes. Conclusions: Bayesian causal modeling revealed literature-supported hypotheses regarding predictors of response (CXCL13) and resistance (STK11 mutation, mTOR pathway) to PD-(L)1 blockade therapy. The additional target pathways such as AKT1/mTOR may be actionable for altering immunogenicity of tumors. [Table: see text]
Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis
Authors: Andreas Kerschbaumer, Alexandre Sepriano, Josef S Smolen, Désirée van der Heijde, Maxime Dougados, Ronald van Vollenhoven, Iain B McInnes, Johannes W J Bijlsma, Gerd R Burmester, Maarten de Wit, Louise Falzon, Robert Landewé
Journal: Annals of the Rheumatic Diseases (2020)

Objectives To inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA). Methods A systematic literature research (SLR) to investigate the efficacy of any disease-modifying antirheumatic drug (DMARD) (conventional synthetic (cs)DMARD, biological (b) and biosimilar DMARD, targeted synthetic (ts)DMARD) or glucocorticoid (GC) therapy in patients with RA was done by searching MEDLINE, Embase and the Cochrane Library for articles published between 2016 and 8 March 2019. Results 234 abstracts were selected for detailed assessment, with 136 finally included. They comprised the efficacy of bDMARDs versus placebo or other bDMARDs, efficacy of Janus kinase (JAK) inhibitors (JAKi) across different patient populations and head-to-head of different bDMARDs versus JAKi or other bDMARDs. Switching of bDMARDs to other bDMARDs or tsDMARDs, strategic trials and tapering studies of bDMARDs, csDMARDs and JAKi were assessed. The drugs evaluated included abatacept, adalimumab, ABT-122, baricitinib, certolizumab pegol, SBI-087, CNTO6785, decernotinib, etanercept, filgotinib, golimumab, GCs, GS-9876, guselkumab, hydroxychloroquine, infliximab, leflunomide, mavrilimumab, methotrexate, olokizumab, otilimab, peficitinib, rituximab, sarilumab, salazopyrine, secukinumab, sirukumab, tacrolimus, tocilizumab, tofacitinib, tregalizumab, upadacitinib, ustekinumab and vobarilizumab. The efficacy of many bDMARDs and tsDMARDs was shown. Switching to another tumour necrosis factor inhibitor (TNFi) or non-TNFi bDMARDs after TNFi treatment failure is efficacious. Tapering of DMARDs is possible in patients achieving long-standing stringent clinical remission; in patients with residual disease activity (including patients in LDA) the risk of flares is increased during the tapering. Biosimilars are non-inferior to their reference products. Conclusion This SLR informed the task force regarding the evidence base of various therapeutic regimen for the development of the update of EULAR’s RA management recommendation.
Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis
Authors: Takeshi Tsuda, Masayuki Nishide, Yohei Maeda, Yoshitomo Hayama, Shohei Koyama, Satoshi Nojima, Hyota Takamatsu, Daisuke Okuzaki, Takayoshi Morita, Takeshi Nakatani, Yasuhiro Kato, Yoshimitsu Nakanishi, Yu Futami, Yasuhiko Suga, Yujiro Naito, Hachiro Konaka, Shingo Satoh, Maiko Naito, Mayuko Izumi, Sho Obata, Ayaka Nakatani, Takashi Shikina, Kazuya Takeda, Masaki Hayama, Hidenori Inohara, Atsushi Kumanogoh
Journal: Journal of Allergy and Clinical Immunology (2020)