tbuckley/cabot-search huggingface dataset:
Pharmaceutical Industry Payments and Oncologists’ Selection of Targeted Cancer Therapies in Medicare Beneficiaries
Authors: Aaron P. Mitchell, Aaron N. Winn, Stacie B. Dusetzina
Journal: JAMA Internal Medicine (2018)

ters with patients who were nonwhite (eg, African American [OR, 0.88; 95% CI, 0.83-0.93],or Medicaid or Medicare insured [OR, 0.80; 95% CI, 0.68-0.95and 0.75; 95% CI, 0.69-0.81,respectively]), had medical history of diabetes (OR, 0.73; 95% CI, 0.67-0.79)and/or osteoporosis (OR, 0.88; 95% CI, 0.79-0.98),had been seen by a PA (OR, 0.78; 95% CI, 0.71-0.86),and with a visit diagnosis of pneumonia (OR, 0.55; 95% CI, 0.46-0.64)(Table 2).We observed substantial clinician variation with 17% never using steroid injections and 13% of clinicians using an injection more than 40% of the time (data not shown).Conclusions | Adverse effects of systemic steroids, even for shortterm use, are well documented.Future research is needed to further explore regional and national trends in use of corticosteroids for patients with ARTIs, as it likely represents high-cost, potentially harmful care.This study revealed high rates of systemic corticosteroid use among patients with ARTIs in Louisiana and nationally.Study limitations include possible inclusion of encounters for exacerbation of chronic respiratory illnesses such as asthma or COPD and discordance in corticosteroid outcomes measured (injection vs oral).This hypothesis-generating study highlights the need to further examine use of systemic corticosteroid for ARTIs and associated safety issues.
Dose-exposure-response relationship between AZD6738 and peripheral monocytes.
Authors: Andrew Pierce, Alienor Berges, S Y Amy Cheung, Nathan Standifer, Graham Ross, Simon Smith, Simon J Hollingsworth, Matthew Krebs, Sophie Postel-Vinay, Yung-Jue Bang, Anthony B. El-Khoueiry, Wassim Abida, Raghav Sundar, Louise Carter, Eduardo Castanon-Alvarez, Seock-Ah Im, Juanita Suzanne Lopez, Timothy Anthony Yap, Kevin Harrington, Jean-Charles Soria
Journal: Journal of Clinical Oncology (2017)

e14063 Background: AZD6738 is a potent, selective inhibitor of the ataxia telangiectasia and Rad3-related (ATR) serine/threonine-specific protein kinase with good selectivity against other phosphatidylinositol 3-kinase-related kinase (PIKK) family members. To support dose/schedule guidance through mathematical modelling of clinical pharmacokinetic/pharmacodynamic relationships, we sought to determine quantitative pharmacodynamic effects of AZD6738 in peripheral blood with respect to drug exposure. Methods: We assessed peripheral blood cell subpopulations in clinical studies of AZD6738 used either as a monotherapy, a combination with the PARP-1 inhibitor olaparib and in combination with the PD-L1 inhibitor durvalumab through both blood analyser and flow cytometry characterization. Peripheral pharmacokinetics of AZD6738 were also assessed. Results: Levels of peripheral monocytes were suppressed in a dose-dependent manner for the duration of AZD6738 dosing resulting in a decrease of up to 80% within the first 7 consecutive days of AZD6738 treatment; these results were consistent across studies. Upon cessation of an AZD6738 dosing interval monocyte levels return to baseline values within 14 days; in combination with durvalumab there is a trend for the rebound in monocyte counts to surpass baseline levels by up to 20%. Monocyte suppression is specific to AZD6738 and not found with either single agent olaparib or single agent durvalumab, possibly attributable to defective base excision repair in monocytes and lack of PARP-1. Monocytes were found to be the most sensitive cell type to AZD6738 treatment compared with neutrophils, platelets, haemoglobin or lymphocytes. Conclusions: This drug effect of AZD6738 is consistent with natural clearance of peripheral monocytes under suppression of monocyte precursor proliferation in the bone marrow, suggestive of a change in the equilibrium between production and elimination of peripheral monocytes. Used as a surrogate marker of target inhibition, a mathematical model of the AZD6738/monocyte dose-exposure-response relationship is described and has been used to inform AZD6738 Phase 2 dose and schedule.
Effect of exogenous interferon-gamma (IFN-gamma) on peripheral blood immune markers as part of a phase I clinical trial of combined IFN-gamma with nivolumab (Nivo) in patients (pts) with select solid tumors.
Authors: Matthew R. Zibelman, Alexander Macfarlane, R. Katherine Alpaugh, Essel Dulaimi, Kim Costello, John O'Neill, Hossein Borghaei, Crystal Shereen Denlinger, Daniel M. Geynisman, Efrat Dotan, Angela Jain, Lainie P. Martin, Elias Obeid, Jeffery A. Nieves, David Crouteau, Amy Y. Grahn, Kerry Campbell, Elizabeth R. Plimack
Journal: Journal of Clinical Oncology (2017)

97 Background: IFN-gamma is a known activator of PD-L1 expression and plays a key role in immune activation. We present initial correlative peripheral blood findings after the first 2 cohorts of pts enrolled in a phase I trial of combined IFN-gamma/Nivo in pts with various solid tumors. Methods: Pts with advanced solid tumors who had progressed after at least 1 prior therapy were recruited. An induction phase of IFN-gamma (50 or 75 mcg/m2 subq every other day for 1 week) preceded the combination of Nivo (3 mg/kg IV every 2 weeks) with continuation of IFN-gamma at same dose and schedule for 3 months. Pts with clinical benefit could remain on Nivo alone for up to 1 year. Peripheral blood was analyzed via flow cytometry at baseline, after IFN-gamma induction (prior to Nivo start), and after 6 weeks of combo treatment. Results: 13 pts have been accrued. Pre and post induction samples were collected on all pts. Nine pts had available on-treatment samples at time of data analysis. Comparing blood collections from baseline to post-IFN-gamma induction revealed a substantial expansion of the CD14 high , CD16 + monocyte population (p=0.001) and a statistically significant increase in MHC class II expression on all monocyte populations (p≤ 0.002 for all types). Natural killer (NK) cells demonstrated greater numbers of cells per ml of blood (p=0.03) and increased NKp30 expression, an important receptor mediating tumor cell lysis (p= 0.005 for CD56 dim ; p= 0.03 for CD56 bright ). With the addition of Nivo, evidence for activation of CD56 dim NK cells was detected as increased CD69 expression compared to post-induction (p=0.02). PD-1 expression on T-cells showed reduced expression in most comparators after initiation of Nivo (p=0.055 CD8 + ; p=0.008 CD4 + ). Conclusions: Early correlative peripheral blood data demonstrate expected systemic IFN-gamma effect as measured by monocyte activation and increased MHC II expression. Evidence of NK cell activation and proliferation was also observed. Decreased PD-1 expression on T-cells may reflect down-regulation in response to PD-1 blockade. Correlations with biopsy specimens and clinical response are planned. Clinical trial information: NCT02614456.
Incidence and average cost per toxicity in patients treated with nivolumab.
Authors: Neil Thomas Mason, Nikhil I. Khushalani, Scott Joseph Antonia, Howard L. McLeod
Journal: Journal of Clinical Oncology (2017)

93 Background: Recently approved PD-1 inhibitors such as nivolumab have demonstrated clear efficacy in metastatic melanoma and other cancers, but also come at a high cost and with the potential for severe side effects. However, most of the data available comes from clinical trials rather than patients treated in clinical practice as standard-of-care. This study reports the incidence of severe toxicities in a number of cancer types and estimates the per patient cost of managing these toxicities. Methods: Patients with metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, and Hodgkin’s lymphoma treated with nivolumab between January 1, 2014 through April 30, 2016 were identified at Moffitt Cancer Center (N=74). Toxicities occurring during treatment or within 2 months of stopping treatment were identified by a chart review and each toxicity graded using the CTCAE 4.0 criteria. A cost of care analysis was performed to estimate the cost of serious toxicities (Grade 3-5) compared to a control group who experienced no or minor adverse events (Grade 0-2). Billing data was used to estimate the mean cost of care for each group. Costs were subcategorized by service line, e.g., pharmacy costs, radiology, laboratory services. Results: The most common severe toxicities were anemia, dyspnea, renal failure, colitis, fatigue, and pneumonitis (Table 1). The average cost of care for patients experiencing grade 3-5 toxicities was $2,036 higher than those without toxicity. Conclusions: The incidence of toxicity in our population was similar to that reported in clinical trials. Costs were higher for patients with toxicities, driven by additional outpatient care (19% higher cost per patient) as well as additional pharmacy costs (22% higher per patient). Though small in comparison to the cost of nivolumab, over $6,000 per dose, these costs should not be dismissed, particularly when performing cost effectiveness and value research. [Table: see text]
New insights into long noncoding RNAs and their roles in glioma
Authors: Zixuan Peng, Changhong Liu, Minghua Wu
Journal: Molecular Cancer (2018)

Glioma is one of the most prevalent types of primary intracranial carcinoma with varying malignancy grades I–IV and histological subtypes, including astrocytomas, glioblastoma multiform (GBM), oligodendrogliomas and mixed tumors. Glioma is characterized by rapid cell proliferation and angiogenesis, and the WHO grade IV glioblastoma, which is highly malignant with poor prognosis because GBM stem-like cells (GSCs) are resistant to conventional therapy and easily recrudescent, accounts for the majority of gliomas. Consequently, investigations exploring the accurate molecular mechanisms and reliable therapeutic targets for gliomas have drawn extensive attention. Based on the increasing amount of functional lncRNAs aberrantly expressed in glioma tissues and cell lines, lncRNAs might be critical for glioma initiation, progression and other malignant phenotypes. This review summarizes the latest insights into the lncRNA field and their functional roles in glioma, therefore evaluating the potential clinical applications of lncRNAs as prospective novel biomarkers and therapeutic targets.
Favorable outcome of patients with lung adenocarcinoma harboring POLE mutations and expressing high PD-L1
Authors: Liang Liu, Jimmy Ruiz, Stacey S. O’Neill, Stefan C. Grant, W. Jeffrey Petty, Meng Yang, Kexin Chen, Umit Topaloglu, Boris Pasche, Wei Zhang
Journal: Molecular Cancer (2018)

Mutations in polymerase ε (POLE) confer favorable prognosis and outcomes in various cancer types, but their role in non-small cell lung cancer (NSCLC) is unknown. Utilizing the data of 513 patients with adenocarcinoma (LUAD) and 497 patients with squamous cell carcinoma (LUSC) from The Cancer Genome Atlas (TCGA) cohort, we tested the prognostic value of POLE mutations and programmed cell death ligand 1 (PD-L1) expression in the two main subtypes of NSCLC. POLE mutation is a favorable biomarker for the improved overall survival (OS) of the LUSC patients (P = 0.033, 28 mutant vs. 469 wildtype patients), but not that of the LUAD patients (P = 0.12, 31 mutant vs. 482 wildtype patients). POLE-mutant LUAD patients with high expression of PD-L1 (Mut-High, n = 6) exhibited improved OS (P = 0.024) when compared to POLE-mutant patients with low PD-L1 expression (Mut-Low, n = 24) and other patients without POLE mutation (n = 476). This benefit was not due to the high content of the tumor infiltrating lymphocytes. Instead, the antitumor immune response was activated in Mut-High patients so that these patients were likely responding more effectively to immuno-oncology (IO) treatments; whereas genes involved with metabolic pathways were enriched in Mut-Low group, which may cause the decreased OS of these patients. Our study sheds light on the molecular basis of NSCLC and adds to our understanding of responses to chemotherapy and IO therapy.
Sputum proteomics and airway cell transcripts of current and ex-smokers with severe asthma in U-BIOPRED: an exploratory analysis
Authors: Kentaro Takahashi, Stelios Pavlidis, Francois Ng Kee Kwong, Uruj Hoda, Christos Rossios, Kai Sun, Matthew Loza, Fred Baribaud, Pascal Chanez, Steve J. Fowler, Ildiko Horvath, Paolo Montuschi, Florian Singer, Jacek Musial, Barbro Dahlen, Sven-Eric Dahlen, Norbert Krug, Thomas Sandstrom, Dominic E. Shaw, Rene Lutter, Per Bakke, Louise J. Fleming, Peter H. Howarth, Massimo Caruso, Ana R. Sousa, Julie Corfield, Charles Auffray, Bertrand De Meulder, Diane Lefaudeux, Ratko Djukanovic, Peter J. Sterk, Yike Guo, Ian M. Adcock, Kian Fan Chung
Journal: European Respiratory Journal (2018)

Severe asthma patients with a significant smoking history have airflow obstruction with reported neutrophilia. We hypothesise that multi-omic analysis will enable the definition of smoking and ex-smoking severe asthma molecular phenotypes. The U-BIOPRED cohort of severe asthma patients, containing current-smokers (CSA), ex-smokers (ESA), nonsmokers and healthy nonsmokers was examined. Blood and sputum cell counts, fractional exhaled nitric oxide and spirometry were obtained. Exploratory proteomic analysis of sputum supernatants and transcriptomic analysis of bronchial brushings, biopsies and sputum cells was performed. Colony-stimulating factor (CSF)2 protein levels were increased in CSA sputum supernatants, with azurocidin 1, neutrophil elastase and CXCL8 upregulated in ESA. Phagocytosis and innate immune pathways were associated with neutrophilic inflammation in ESA. Gene set variation analysis of bronchial epithelial cell transcriptome from CSA showed enrichment of xenobiotic metabolism, oxidative stress and endoplasmic reticulum stress compared to other groups. CXCL5 and matrix metallopeptidase 12 genes were upregulated in ESA and the epithelial protective genes, mucin 2 and cystatin SN, were downregulated. Despite little difference in clinical characteristics, CSA were distinguishable from ESA subjects at the sputum proteomic level, with CSA patients having increased CSF2 expression and ESA patients showing sustained loss of epithelial barrier processes.
Survival of neuroblastoma patients treated by long-term infusion of anti-GD<sub>2</sub> antibody ch14.18/CHO and killer-cell Ig-like receptor (KIR) genotypes and Fcγ-receptor polymorphisms.
Authors: Holger N. Lode, Hans Loibner, Sascha Troschke-Meurer, Dominique Valteau Couanet, Alberto Garaventa, Juliet Gray, Victoria Castel, Isaac Yaniv, Nikolai Siebert, Christin Eger, Madlen Juettner, Silke Kietz, Karoline Ehlert, Evelyne Janzek, Ina Mueller, Ruth Ladenstein
Journal: Journal of Clinical Oncology (2017)

111 Background: Receptors expressed on natural killer (NK) cells and their ligands on target cells involved in antibody-dependent cell-mediated cytotoxicity (ADCC) may influence outcome in patients (pts) with high-risk relapsed/refractory neuroblastoma (NB) treated by long-term infusion (LTI) of anti-GD 2 antibody ch14.18/CHO Methods: 53 pts received 6x10 6 IU/m 2 sc IL-2 (d1-5; 8-12), LTI of 100 mg/m 2 ch14.18/CHO (d8-17) and 160 mg/m 2 oral 13-cis-RA (d19-32) in a closed single center program (53 pts) (APN311-303). Polymorphisms in Fcγ-receptor genes 2A (H131R), -3A (V158F) and -3B (NA1/NA2), and KIR- as well as KIR ligand expression (HLA-C1; HLA-C2; HLA-Bw4+) were determined by real-time PCR. Results: The survival update of the APN311-303 cohort revealed a 5-y OS of 56.4±7.1% (mean OS 4.35y [0.3-6.2y]) and a 5-y PFS of 29.1±6.3% (mean PFS 2.4y [0.1 - 5.9y]). Median TTP/PFS was 1.35 y (95% CI: 0.21-2.48 y). This result is clearly superior to historical controls not treated with ch14.18/CHO with a 5-y OS of 14.8±6.8% (p &lt; 0.005), indicating clinical efficacy of the treatment. In this cohort, we identified 26/53 pts with the NK- stimulatory KIR haplotype (2DS2+) who had superior OS- and PFS-rates compared to 18/53 pts with an inhibitory haplotype and KIR/KIR-ligand match (2DS2-, 3DL1+, Bw4+) (p &lt; 0.02). Similarly, we found 33/53 pts with low affinity FCGR alleles (FCGR2A-H131R/R and/or FCGRA3A-V158 F/F). These patients showed lower PFS rates compared to 20/53 patients with high affinity FCGR polymorphisms (p &lt; 0.01). ADCC analysis on day 15 of cycle 1 showed higher levels in the pt group with NK- stimulatory versus NK- inhibitory KIR/KIR ligand haplotypes (23±6 % vs. 6±2%, p &lt; 0.01). A similar effect was observed in pts with high affinity FCGR polymorphisms with an ADCC increase of 20±6% compared to 11±2% in the low affinity FCGR control. Conclusions: KIR-haplotypes and FCGR- polymorphisms correlated with the functional immune parameter ADCC and clinical outcome, and thus support the relevance of ADCC for clinical efficacy of ch14.18/CHO in neuroblastoma.
Personal Genomics and Cryptocurrency Team Up
Authors: Jennifer Abbasi
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Duodenal fistula: The most lethal surgical complication in a case series of radical gastrectomy
Authors: Marcus Fernando Kodama Pertille Ramos, Marina Alessandra Pereira, Leandro Cardoso Barchi, Osmar Kenji Yagi, Andre Roncon Dias, Daniel Jose Szor, Bruno Zilberstein, Ulysses Ribeiro-Júnior, Ivan Cecconello
Journal: International Journal of Surgery (2018)
Antibody Concentrations Decrease 14-Fold in Children With Celiac Disease on a Gluten-Free Diet but Remain High at 3 Months
Authors: David Petroff, Johannes Wolf, Thomas Richter, Marcus K.H. Auth, Holm H. Uhlig, Martin W. Laass, Peter Lauenstein, Andreas Krahl, Norman Händel, Jan de Laffolie, Almuthe C. Hauer, Matthias Heiduk, Gunter Flemming, Antje Schmidt, Dirk Hasenclever, Thomas Mothes
Journal: Clinical Gastroenterology and Hepatology (2018)

Background & AimsCeliac disease can be identified by a serologic test for IgA against tissue transglutaminase (IgA-TTG) in a large proportion of children. However, the increased concentrations of antibody rarely normalize within the months after children are placed on a gluten-free diet (GFD). Early serologic predictors of sufficient adherence to GFD are required for optimal treatment.MethodsIn a prospective study, we observed the response to a GFD in 345 pediatric patients (67% girls; mean age, 8.4 y) who underwent duodenal biopsy to confirm or refute celiac disease from October 2012 through December 2015. Baseline serum samples were tested centrally for IgA-TTG and IgG against deamidated gliadin. Follow-up serologic analyses of children on a GFD were performed about 3 months later.ResultsThe geometric mean concentration of IgA-TTG decreased from 72.4-fold to 5.2-fold the upper limit of normal (ULN), or by a factor of 14.0 (95% CI, 12.0–16.4). A substantial response (defined as a larger change than the typical variation in patients not on a GFD) was observed in 80.6% of the children. Only 28.1% of patients had a substantial response in the concentration of IgG against deamidated gliadin. Concentration of IgA-TTG remained above 1-fold the ULN in 83.8% of patients, and above 10-fold the ULN in 26.6% of patients with a substantial response.ConclusionsSerum concentration of IgA-TTG decreases substantially in most children with celiac disease within 3 months after they are placed on a GFD, but does not normalize in most. This information on changes in antibody concentrations can be used to assess patient response to the diet at short-term follow-up evaluations. Patients with a substantial response to a GFD often still have high antibody levels after 3 months. German Clinical Trials Registry no. DRKS00003854.
88P Feasibility of outpatient dinutuximab (D) and irinotecan (I) for second-line treatment of relapsed or refractory small cell lung cancer (RR SCLC): Part 1 of an open-label, randomized, phase 2/3 study
Authors: M.J. Edelman, O. Juan, A. Navarro, G. Golden, A. Saunders
Journal: Journal of Thoracic Oncology (2018)
127TiP Phase I study of neo-adjuvant Stereotactic Body Radiotherapy (SBRT) in operable patients with borderline resectable locally advanced NSCLC (LA-NSCLC) (LINNEARRE I STUDY: NCT02433574)
Authors: T. Tsakiridis, N. Isfahanian, N. Nguyen, J. Wright, W. Hanna, A. Swaminath, Y. Shargal, J. Agzaraian, M. Wierzbicki, T. Chow
Journal: Journal of Thoracic Oncology (2018)
190P Are neutrophil-to-lymphocyte ratio (NLR) and neutrophil count percentage (NCP) predictors of nivolumab outcome and toxicity in NSCLC?
Authors: J. Rogado, V. Pacheco Barcia, P. Toquero, B. Vera, R. Mondejar, N. Romero Laorden, A.I. Ballesteros Garcia, O. Donnay, R. Colomer Bosch, J.M. Sánchez-Torres
Journal: Journal of Thoracic Oncology (2018)
Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis
Authors: Dirk J. van der Windt, Vikas Sud, Hongji Zhang, Patrick R. Varley, Julie Goswami, Hamza O. Yazdani, Samer Tohme, Patricia Loughran, Robert M. O'Doherty, Marta I. Minervini, Hai Huang, Richard L. Simmons, Allan Tsung
Journal: Hepatology (2018)

Nonalcoholic steatohepatitis (NASH) is a progressive, inflammatory form of fatty liver disease. It is the most rapidly rising risk factor for the development of hepatocellular carcinoma (HCC), which can arise in NASH with or without cirrhosis. The inflammatory signals promoting the progression of NASH to HCC remain largely unknown. The propensity of neutrophils to expel decondensed chromatin embedded with inflammatory proteins, known as neutrophil extracellular traps (NETs), has been shown to be important in chronic inflammatory conditions and in cancer progression. In this study, we asked whether NET formation occurs in NASH and contributes to the progression of HCC. We found elevated levels of a NET marker in serum of patients with NASH. In livers from STAM mice (NASH induced by neonatal streptozotocin and high-fat diet), early neutrophil infiltration and NET formation were seen, followed by an influx of monocyte-derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with deoxyribonuclease (DNase) or using mice knocked out for peptidyl arginine deaminase type IV (PAD4-/- ), did not affect the development of a fatty liver but altered the consequent pattern of liver inflammation, which ultimately resulted in decreased tumor growth. Mechanistically, we found that commonly elevated free fatty acids stimulate NET formation in vitro.Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (Hepatology 2018).