tbuckley/cabot-search huggingface dataset:
Impact of the 2017 ACC/AHA Guideline for High Blood Pressure on Evaluating Gestational Hypertension–Associated Risks for Newborns and Mothers
Authors: Jie Hu, Yuanyuan Li, Bin Zhang, Tongzhang Zheng, Jun Li, Yang Peng, Aifen Zhou, Stephen L. Buka, Simin Liu, Yiming Zhang, Kunchong Shi, Wei Xia, Kathryn M. Rexrode, Shunqing Xu
Journal: Circulation Research (2019)

In 2017, the American College of Cardiology (ACC)/American Heart Association (AHA) released a new hypertension guideline for nonpregnant adults, using lower blood pressure values to identify hypertension. However, the impact of this new guideline on the diagnosis of gestational hypertension and the associated maternal and neonatal risks are unknown. To estimate the impact of adopting the 2017 ACC/AHA guideline on detecting gestational blood pressure elevations and the relationship with maternal and neonatal risk in the perinatal period using a retrospective cohort design. This study included 16 345 women from China. Systolic and diastolic blood pressures of each woman were measured at up to 22 prenatal care visits across different stages of pregnancy. Logistic and linear regressions were used to estimate associations of blood pressure categories with the risk of preterm delivery, early-term delivery, and small for gestational age, and indicators of maternal liver, renal, and coagulation functions during pregnancy. We identified 4100 (25.1%) women with gestational hypertension using the 2017 ACC/AHA guideline, compared with 4.2% using the former definition. Gestational hypertension, but not elevated blood pressure (subclinical blood pressure elevation), was significantly associated with altered indicators of liver, renal, and coagulation functions during pregnancy for mothers and increased risk of adverse birth outcomes for newborns; adjusted odds ratios (95% CIs) for gestational hypertension stage 2 were 2.23 (1.18-4.24) for preterm delivery, 2.05 (1.67-2.53) for early-term delivery, and 1.43 (1.13-1.81) for small for gestational age. Adopting the 2017 ACC/AHA guideline would result in a substantial increase in the prevalence of gestational hypertension; subclinical blood pressure elevations during late pregnancy were not associated with increased maternal and neonatal risk in this cohort. Therefore, the 2017 ACC/AHA guideline may improve the detection of high blood pressure during pregnancy and the efforts to reduce maternal and neonatal risk. Replications in other populations are required.
Immune-related adverse event (irAE) education, self-efficacy, and potential irAE experiences in patients treated with immunotherapy for non-small cell lung cancer (NSCLC).
Authors: Urvi Mujumdar, Huifen Wang, Elizabeth Lawler, Victoria Lanzarini, Maria Lowe, Nataliya Trunova, Alyssa B. Klein, Cathy Emmas
Journal: Journal of Clinical Oncology (2019)

76 Background: Immunotherapy presents new challenges for effective patient engagement to ensure that irAEs are reported and treated appropriately. This study directly assesses how NSCLC patients in an online community perceived their irAE education and experience of potential irAEs. Methods: PatientsLikeMe is an online community for patients to track and share their experiences with the goal of improving health outcomes across all conditions. For this study, US residents ≥ 18, with self-reported immunotherapy treatment for NSCLC were invited to a baseline survey at enrollment and follow-up survey after 3 months (Dec 2017-Aug 2018). Quantitative and qualitative analyses were performed. Results: Respondents (N = 72) were female (69%), white (94%), and mean age of 64.3 (SD 9.3). Current immunotherapy use was reported by 60 (83%) patients and prior use by 12. Most (66 [92%]) reported that a healthcare provider (HCP) shared information about irAEs before they started treatment and 47 (71%) sought additional information. 43 (60%) reported experiencing a potential irAE while on treatment, 34 (79%) of whom indicated reporting this to a HCP. Free-text responses revealed a need for more clarity on side effects and severity, and that lapses in patient-provider communication sometimes occurred. The 3-month follow-up survey was completed by 39/72 patients; 28 (72%) remained on immunotherapy, and 8 (21%) had stopped since baseline. Of the 20 patients (51%) who reported experiencing a potential irAE in the past 3 months, 15 had also reported this at baseline, and 13 reported this to a HCP. Free-text responses revealed that many patients opted to wait until the next scheduled appointment to report irAEs or they self-managed minor side effects. Conclusions: Patients reported satisfaction with information received and responded appropriately to potential irAEs, but also suggested a need to improve information and communication with care teams. As patients become more accustomed to their treatment, there may be changes in reporting of irAEs. As this data is from a self-selected convenience sample of patients, results may be limited in generalizability.
Outcomes based on Albumin‐Bilirubin (ALBI) grade in the phase 3 CELESTIAL trial of cabozantinib versus placebo in patients with advanced hepatocellular carcinoma (HCC)
Authors: R. Miksad, I. Cicin, Y. Chen, H. Klumpen, S. Kim, Z. Lin, J. Youkstetter, S. Sen, A. Cheng, T. Meyer, R. Kelley, G. Abou-Alfa
Journal: Annals of Oncology (2019)
Hafnium oxide nanoparticles activated by SABR in combination with PD-1 inhibitors for the treatment of patients with advanced HNSCC or NSCLC: A phase I/II trial.
Authors: Tanguy Y. Seiwert, Corey Christian Foster, Christophe Le Tourneau, Valentin Calugaru, Sylvie Bonvalot
Journal: Journal of Clinical Oncology (2019)

TPS23 Background: Despite proven efficacy, a limited number of patients (pts) with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or metastatic non-small cell lung cancer (NSCLC) benefit from anti-PD-1 treatment. Indeed, most pts do not respond to initial therapy due to intrinsic resistance to checkpoint inhibition. There is thus an important unmet medical need for a curative treatment in these pts and converting the local immune microenvironment to a “hot” phenotype may help to overcome therapeutic resistance. Hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose deposit within cancer cells compared to RT alone. Recently, a phase II/III randomized trial of NBTXR3 in locally advanced soft tissue sarcoma (STS) met primary and main secondary endpoints with significant superiority compared to RT alone. Furthermore NBTXR3+RT demonstrated an immunogenic cell death-mediated abscopal effect in a pre-clinical setting, and immune cell infiltration was observed in some tumors from STS pts treated with NBTXR3+RT but not in tumors from pts treated with RT alone. NBTXR3 is currently being evaluated in 7 clinical trials, including a phase I/II study in elderly frail patients with locally advanced HNSCC. To date, no early dose limiting toxicities (DLTs) have been observed. Methods: Overall, these results have led us to evaluate NBTXR3 activated by stereotactic ablative radiotherapy (SABR) in combination with an approved anti-PD-1 antibody in an open label phase I/II, non-randomized clinical trial in pts with more advanced diseases: locoregionally recurrent or metastatic HNSCC, metastatic NSCLC, and liver metastasis pts. The phase I primary objectives are to determine NBTXR3 maximum tolerated dose(s), incidence of early DLTs and recommended dose(s). The phase II primary objectives are Complete Response Rate of target lesions and Objective Response Rate for the locoregional recurrent and the metastatic group respectively by RECIST 1.1, and safety/tolerability of treatment at the recommended dose(s). [NCT02379845] [NCT01946867]. Clinical trial information: NCT03589339.
A Metallomic Approach to Assess Associations of Serum Metal Levels With Gallstones and Gallbladder Cancer
Authors: Mei‐Hsuan Lee, Yu‐Tang Gao, Yu‐Han Huang, Emma E. McGee, Tram Lam, Bingsheng Wang, Ming‐Chang Shen, Asif Rashid, Ruth M. Pfeiffer, Ann W. Hsing, Jill Koshiol
Journal: Hepatology (2019)

Exposure to metals may promote the risk for cancers. We evaluated the associations of a broad spectrum of metals with gallbladder cancer (GBC) and gallstones.A total of 259 patients with GBC, 701 patients with gallstones, and 851 population-based controls were enrolled in Shanghai, China. A metallome panel was used to simultaneously detect 18 metals in serum through inductively coupled plasma-mass spectrometry. Logistic regression models were used to estimate crude or adjusted odds ratios (ORadj ) with 95% confidence intervals (CIs) for the association between metal levels and gallbladder disease. Among the 18 metals tested, 12 were significantly associated with GBC and six with gallstones (Pcorrected < 0.002). Boron, lithium, molybdenum, and arsenic levels were associated with GBC compared to gallstones as well as with gallstones compared to population-based controls. Elevated levels of cadmium, chromium, copper, molybdenum, and vanadium were positively associated with GBC versus gallstones; and the ORadj for the highest tertile (T3) compared to the lowest tertile (T1) ranged from 1.80 to 7.28, with evidence of dose-response trends (P < 0.05). Arsenic, boron, iron, lithium, magnesium, selenium, and sulfur were inversely associated with GBC, with the T3 versus T1 ORadj ranging from 0.20 to 0.69. Arsenic, boron, calcium, lithium, molybdenum, and phosphorus were negatively associated with gallstones, with the T3 versus T1 ORadj ranging from 0.50 to 0.75 (P < 0.05).Metals were associated with both GBC and gallstones, providing cross-sectional evidence of association across the natural history of disease. Longitudinal studies are needed to evaluate the temporality of metal exposure and gallbladder diseases and to investigate the mechanisms of disease pathogenesis.
Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival
Authors: Wei Tang, Vasanta Putluri, Chandrashekar R. Ambati, Tiffany H. Dorsey, Nagireddy Putluri, Stefan Ambs
Journal: Clinical Cancer Research (2019)

Metabolomics is a discovery tool for novel associations of metabolites with disease. Here, we interrogated the metabolome of human breast tumors to describe metabolites whose accumulation affects tumor biology.We applied large-scale metabolomics followed by absolute quantification and machine learning-based feature selection using LASSO to identify metabolites that show a robust association with tumor biology and disease outcome. Key observations were validated with the analysis of an independent dataset and cell culture experiments.LASSO-based feature selection revealed an association of tumor glycochenodeoxycholate levels with improved breast cancer survival, which was confirmed using a Cox proportional hazards model. Absolute quantification of four bile acids, including glycochenodeoxycholate and microbiome-derived deoxycholate, corroborated the accumulation of bile acids in breast tumors. Levels of glycochenodeoxycholate and other bile acids showed an inverse association with the proliferation score in tumors and the expression of cell-cycle and G2-M checkpoint genes, which was corroborated with cell culture experiments. Moreover, tumor levels of these bile acids markedly correlated with metabolites in the steroid metabolism pathway and increased expression of key genes in this pathway, suggesting that bile acids may interfere with hormonal pathways in the breast. Finally, a proteome analysis identified the complement and coagulation cascade as being upregulated in glycochenodeoxycholate-high tumors.We describe the unexpected accumulation of liver- and microbiome-derived bile acids in breast tumors. Tumors with increased bile acids show decreased proliferation, thus fall into a good prognosis category, and exhibit significant changes in steroid metabolism.
Targeted sequencing of plasma cell-free DNA to predict response to PD1 inhibitors in advanced non-small cell lung cancer.
Authors: Nicolas Guibert, Greg Jones, John F. Beeler, Clive D. Morris, Vincent Plagnol, Jean Mourlanette, Myriam Delaunay, Isabelle Rouquette, Gilles Favre, Anne Pradines, Julien Mazieres
Journal: Journal of Clinical Oncology (2019)

103 Background: Tumor mutational burden is an emerging biomarker of response to immune checkpoint inhibitors (ICI), whose clinical adoption is challenging, especially in liquid biopsies. We hypothesized that targeting limited but relevant genetic alterations in plasma cell-free DNA with next generation sequencing (NGS) along with early monitoring may represent a non-invasive approach to predict response to ICI. Methods: Plasma samples from responders (PFS &gt; 6 months) and non-responders (progressive disease at first evaluation) patients collected before nivolumab (second line) initiation and at 1 month were tested using tagged amplicon sequencing of hotspots and coding regions from 36 genes, blinded to clinical outcomes and tumor genotype. Molecular profile of ctDNA, and its early kinetics (1 month) were analyzed as potential early indicators of response. Results: 98 patients were analyzed, of which 86 (39 responders, 47 non-responders) were evaluable for response. Alterations in ctDNA were detectable in 67/86 baseline samples (78%). The detection of a targetable oncogenic driver (5 EGFR, 1 ALK) was associated with progressive disease on the first CT-scan The presence of a PTEN and/or STK11 mutations (b-PS(+)) was correlated with poor outcomes (median PFS 1.5 months vs. 8 months in b-PS(-)) patients, p = 0.0007), while the presence of transversion mutations in KRAS and/or TP53 (b-KP-Tv(+)) predicted good outcomes (median PFS 11 months vs. 2 months in b-KP-Tv(-) patients, p = 0.0088). Combining these results, patients with a low “immune score” (driver and/or b-PS(+) and/or b-KP-Tv(-)) derived poor outcomes (PFS 2 months), compared with patients with a high immune score (no driver, b-PS(-) and b-KP-Tv(+), PFS 14 months, p = 0.0001, HR 2.96). Studying early changes in 65 specimens, molecular response was correlated with clinical outcomes (14 months PFS in patients with early ctDNA decrease compared to 2 months in patients with increase, p &lt; 0.0001; HR 2.7). Using cut-off of 30% and 50% of plasma response increased the ability of ctDNA to predict response (HR 4 and 4.17, respectively). Conclusions: Targeted sequencing of plasma ctDNA and its early variations can predict response to anti-PD-1. Clinical trial information: NCT02827344.
Low molecular weight heparin (LMWH) enhances immunotherapy (I) activity in pancreatic cancer cells.
Authors: Michalis Karamouzis, Alexandros Bokas, Georgia Kyriakopoulou, Evangelos Koustas, Panagiotis Sarantis, Pavlos Papakotoulas, Dimitrios Schizas, Alexandros Papalampros, Evangelos Felekouras, Theodoros Liakakos, Athanasios G. Papavassiliou
Journal: Journal of Clinical Oncology (2019)

50 Background: The aim is to investigate the effect of LMWH in combination with chemotherapy (C) and I in PC. Methods: BxPC-3, PANC-1, MIA PACA-2 cell lines were exposed in Tinzaparin (T) (0.5, 0.7, 0.9 μΜ) and/or 1 μΜ Nab-Paclitaxel (A) and/or 1 μΜ Gemcitabine (G) and/or 1 μΜ Nivolumab (NI), 1 μΜ, Pembrolizumab (PE) and 1 μΜ ipilimumab (IPI). Protein levels of VEGFR2, p-ERK1/2, p-AKT detected by Western blotting. Cells viability was measured through MTT assay. Results: Increasing protein levels of VEGFR2 was observed in all PC cell lines exposed to a constant dose of T and/or A,G. NI and PE +/- with IPI increased VEGFR2. In NI/PE+IPI+T scheme VEGFR2 levels were decreased (0.1-0.7 folds) in a dose dependent way in mtKRAS cells (PANC1, MIAPACA2). C (G or A) + I decreased VEGFR2 protein levels in mtKRAS cells PANC1 (0.1-0.4 folds), MIAPACA2 (0.1-0.6 folds) in double scheme. T+G/A+NI/PE+IPI scheme increased VEGFR2 in all PC cells. PANC-1 cells were decreased 40% in 0,7T+IPI+(NI or PE) after 48hours. The effect of these schemes on signaling pathways (MEK/EKR, AKT/mTOR) and apoptosis was identified through pERK1/2, pAKT, PARP, cl. caspase-3. Conclusions: These results identify the different effect of I alone or in combination with T and C in PC cells bearing mutant or wild type KRAS. Double or triple combination reduced VEGFR2 protein levels in mtKRAS and not in wtKRAS PC cells. The 0,7T+IPI+(NI or PE) combination decreases cell viability of PC cells through apoptosis. Testing of the combinatorial scheme T+chemo+IPI+(NI or PE) with PANC-1 PC in scid mice is ongoing and will be presented. NC:not changed, -:&lt;20% protein vs control, +:&gt;20% protein vs control, ++:&gt;40% protein vs control. [Table: see text]
Thymic Tuberculosis Shown on FDG PET/CT Despite Coexisting Pulmonary Tuberculosis With No Increased FDG Activity
Authors: Hongyan Li, Yu Long, Fuqiang Shao, Xiaoli Lan
Journal: Clinical Nuclear Medicine (2019)

Abstract Extrapulmonary tuberculosis could involve multiple organs. However, thymic tuberculosis is relatively rare. We report a 21-year-old man who was referred for an 18 F-FDG PET/CT imaging to assess his newly detected pulmonary nodule. The images showed the pulmonary nodule had minimal activity uptake. Unexpectedly, the thymus with elevated FDG accumulation was noted. The pulmonary nodule and thymic lesion were confirmed as tuberculosis by pathology.
Access to Primary Care Clinics for Patients With Chronic Pain Receiving Opioids
Authors: Pooja A. Lagisetty, Nathaniel Healy, Claire Garpestad, Mary Jannausch, Renuka Tipirneni, Amy S. B. Bohnert
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Opioid-prescribing policies and guidelines aimed at reducing inappropriate opioid prescribing may lead physicians to stop prescribing opioids. Patients may thus encounter difficulties finding primary care practitioners willing to care for them if they take opioids. <h3>Objectives</h3> To assess practitioner willingness to accept and continue prescribing opioids to new patients with pain and whether this willingness differs across payer types. <h3>Design, Setting, and Participants</h3> This survey study used a simulated patient call audit method. A brief telephone survey was administered to all clinics followed by a call using a patient script simulating an adult patient with chronic pain who was taking long-term opioids. The patient had Medicaid or private insurance. Calls were made between June 22 and October 30, 2018, to 667 primary care clinics that served a general adult population in Michigan. Clinics that accepted both Medicaid and private insurance, took new patient appointments, and were successfully recontacted for the simulated call were eligible for the study. <h3>Main Outcomes and Measures</h3> Prevalence of clinics' acceptance of new patients receiving prescription opioids overall and by clinic characteristics and insurance type. <h3>Results</h3> Of the 194 eligible clinics, 94 (48.4%) were randomized according to insurance type to receive calls from research assistants posing as children of patients with Medicaid and 100 (51.5%) to receive calls from those with private insurance. Overall, 79 (40.7%) stated that their practitioners would not prescribe opioids to the simulated patient. Thirty-three clinics (17.0%) requested more information before making a decision. Compared with single-practitioner clinics, clinics with more than 3 practitioners were more likely (odds ratio [OR], 2.99; 95% CI, 1.48-6.04) to accept new patients currently taking opioids. No difference was found in access based on insurance status (OR, 0.92; 95% CI, 0.52-1.64) or whether the clinic offered medications for opioid use disorders (OR, 1.10; 95% CI, 0.45-2.69). <h3>Conclusions and Relevance</h3> The findings suggest that access to primary care may be reduced for patients taking prescription opioids, which could lead to unintended consequences, such as conversion to illicit substances or reduced management of other medical comorbidities.
The phase 3 KEYNOTE-181 study: pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer
Authors: J. Metges, E. François, M. Shah, A. Adenis, P. Enzinger, T. Kojima, K. Muro, J. Bennouna, C. Hsu, T. Moriwaki, S. Kim, S. Lee, K. Kato, L. Shen, S. Qin, P. Ferreira, R. Wang, P. Bhagia, S. Kang, T. Doi
Journal: Annals of Oncology (2019)
Molecular Profiling Establishes Genetic Features Predictive of the Efficacy of the p110β Inhibitor KIN-193
Authors: Isha Sethi, Zhenying Cai, Thomas M. Roberts, Guo-Cheng Yuan
Journal: Cancer Research (2019)

Aberrant activation of the PI3K pathway is a common alteration in human cancers. Therapeutic intervention targeting the PI3K pathway has achieved limited success due to the intricate balance of its different components and isoforms. Here, we systematically investigated the genomic and transcriptomic signatures associated with response to KIN-193, a compound specifically targeting the p110β isoform. By integrating genomic, transcriptomic, and drug response profiles from the Genomics of Drug Sensitivity in Cancer database, we identified mutational and transcriptomic signatures associated with KIN-193 and further created statistical models to predict the treatment effect of KIN-193 in cell lines, which may eventually be clinically valuable. These predictions were validated by analysis of the external Cancer Cell Line Encyclopedia dataset. These results may assist precise therapeutic intervention targeting the PI3K pathway. SIGNIFICANCE: These findings provide new insights into molecular signatures associated with sensitivity of the p110β inhibitor KIN-193, which may provide a useful guide for developing precise treatment methods for cancer.
Cell proliferation as a biomarker for response to immune checkpoint inhibitors in PD-L1 negative renal cell carcinoma.
Authors: Sean T. Glenn, Sarabjot Pabla, Jason Zhu, Matthew Labriola, Rajan Gupta, Daniel J. George, Shannon McCall, Edwin Yau, Jeffrey M. Conroy, Mary Nesline, Antonios Papanicolau-Sengos, Blake Burgher, Felicia L. Lenzo, Tian Zhang, Carl Morrison
Journal: Journal of Clinical Oncology (2019)

62 Background: Cell proliferation is an important marker of survival in many tumors, and we hypothesized that this attribute could be related to response to immune checkpoint inhibitors (ICIs) in RCC. Previously we reported (SITC 2018) that moderately proliferative lung cancer have a much higher response rate than either poorly or highly proliferative tumors. Methods: 69 FFPE RCC tumor samples were evaluated by RNA-seq to measure transcript levels of 394 immune related genes. Cell proliferation was defined as the mean mRNA expression of 10 genes (BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, TOP2A) which was evaluated for association with ORR to ICIs by RECIST v1.1 criteria for both PD-L1 IHC positive and negative cases. Cell proliferation for each case was split into 3 tertiles of poorly ( &lt; 33), moderately (33-66) and highly ( &gt; 66) proliferative versus a reference population. Poorly and highly proliferative were grouped for comparison to moderately proliferative tumors. PD-L1 IHC was performed using DAKO 22C3 antibody and scored by FDA guidelines and considered positive if TPS ≥1% and negative if &lt; 1%. Results: In our cohort of 69 patients, the overall ORR was 18.8. The majority, 91% of tumors were PD-L1 negative, with ORR of 14.8%, as opposed to ORR of 50% in PD-L1 positive cases. 62.2% of tumors were poorly proliferative, 8.7% were highly proliferative, and 29% were moderately proliferative. ORR in moderately proliferative tumors was 30% and 14.2% in poorly/highly proliferative tumors. In PD-L1 negative tumors the ORR in moderately proliferative tumors was 20% and 13% in poorly/highly proliferative tumors. For the 5 moderately proliferative, PD-L1 positive tumors, there were 2 PR and 1 CR, and in the 3 poorly/highly proliferative tumors there was 1 PR. Conclusions: Cell proliferation may play a crucial role in distinguishing RCC patients who may have a clinical benefit to ICI, including the important subgroup of PD-L1 negative tumors. Moderately proliferative tumors have a higher ORR than their poorly/highly counterparts.