tbuckley/cabot-search huggingface dataset:
Risk assessment in pulmonary arterial hypertension
Authors: Marius M. Hoeper, David Pittrow, Christian Opitz, J. Simon R. Gibbs, Stephan Rosenkranz, Ekkehard Grünig, Karen M. Olsson, Doerte Huscher
Journal: European Respiratory Journal (2018)

In its August 2017 issue, the European Respiratory Journal published two papers on risk assessment in pulmonary arterial hypertension (PAH), one coming from the French registry [1], the other from COMPERA, a European pulmonary hypertension (PH) registry [2]. Both groups utilised abbreviated versions of the risk assessment strategy proposed in the current European PH guidelines [3, 4] and both included basically the same variables, i.e. World Health Organization functional class (FC), 6-min walking distance (6MWD), cardiac index, right atrial pressure and serum levels of brain natriuretic peptide (BNP) or the N-terminal fragment of its propeptide (NT-proBNP). In both studies, the cut-off values used to determine risk were those proposed in the European guidelines [3, 4]. However, the strategy to determine individual risk differed in the two studies: COMPERA calculated the average individual risk by assigning a score of 1, 2 or 3 to each criterion (1: low risk; 2; intermediate risk; 3: high risk) and rounding to the mean of the available variables, as had been previously proposed by a group from Sweden [5]. The French group, in contrast, looked at the number of variables that met the low-risk criteria. Despite these differences, the main results of both studies were similar, especially 1) that the risk stratification tool proposed by the European guidelines adequately predicted mortality, 2) that follow-up risk assessment on treatment was a more reliable predictor of survival than the initial risk assessment at the time of diagnosis, and 3) that FC, 6MWD and BNP/NT-proBNP at follow-up were independent predictors of outcome. However, there also were important differences in the two analyses: in the French study, 19% of the patients with idiopathic PAH (IPAH) met all three noninvasive low-risk criteria at follow-up, i.e. FC I or II, 6MWD >440 m, BNP <50 ng·L−1 or NT-proBNP <300 ng·L−1; these patients had a 1-year survival of 100% and a 5-year survival of 97%. In COMPERA, 21% of the IPAH patients were classified as low risk at follow-up; these patients had a 1-year survival of 96% but the 5-year survival of these patients was only 72% (data available in the online supplement of [2]). We wondered whether the differences in long-term survival were due to the fact that the low-risk definition was less strict with the COMPERA strategy than with the French strategy or whether differences in the two patient cohorts were responsible for these findings (patients in French cohort were younger than the patients in COMPERA and combinations of PAH drugs were used more frequently in the French series than in the COMPERA cohort). PAH patients reaching a low risk profile with targeted therapies have an excellent long-term survival <http://ow.ly/RBjo30i6N57> The authors are indebted to the COMPERA investigators.
Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies
Authors: Rodrigo A. Toledo, Elena Garralda, Maria Mitsi, Tirso Pons, Jorge Monsech, Estela Vega, Álvaro Otero, Maria I. Albarran, Natalia Baños, Yolanda Durán, Victoria Bonilla, Francesca Sarno, Marta Camacho-Artacho, Tania Sanchez-Perez, Sofia Perea, Rafael Álvarez, Alba De Martino, Daniel Lietha, Carmen Blanco-Aparicio, Antonio Cubillo, Orlando Domínguez, Jorge L. Martínez-Torrecuadrada, Manuel Hidalgo
Journal: Clinical Cancer Research (2018)

Purpose: Despite the wide use of antiangiogenic drugs in the clinical setting, predictive biomarkers of response to these drugs are still unknown.Experimental Design: We applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens, including inhibitors to the VEGF:VEGFR2 pathway. We performed extensive functional experiments, including ectopic expression of VEGFR2 mutants in different cell lines, kinase and drug sensitivity assays, and cell- and patient-derived xenografts.Results: WES-cfDNA yielded a 77% concordance rate with tumor exome sequencing and enabled the identification of the KDR/VEGFR2 L840F clonal, somatic mutation as the cause of therapy refractoriness in our patient. In addition, we found that 1% to 3% of samples from cancer sequencing projects harbor KDR somatic mutations located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK. Our in vitro and in vivo functional assays confirmed that L840F causes strong resistance to antiangiogenic drugs, whereas the KDR hot-spot mutant R1032Q confers sensitivity to strong VEGFR2 inhibitors. Moreover, we showed that the D717V, G800D, G800R, L840F, G843D, S925F, R1022Q, R1032Q, and S1100F VEGFR2 mutants promote tumor growth in mice.Conclusions: Our study supports WES-cfDNA as a powerful platform for portraying the somatic mutation landscape of cancer and discovery of new resistance mechanisms to cancer therapies. Importantly, we discovered that VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs. Clin Cancer Res; 24(15); 3550-9. ©2018 AACR.
Randomized Trial Comparing EUS and Surgery for Pancreatic Pseuodocyst Drainage
Authors: Varadarajulu Shyam
Journal: Endoscopy (2011)

Background: Although EUS-guided cystogastrostomy is increasingly performed, surgery is still considered the gold standard technique for management of pancreatic pseudocysts (PC). AIM: Compare treatment outcomes, quality of life (QOL) and costs between EUS and surgery for pancreatic cystogastrostomy.
EUS-GUIDED GASTROJEJUNAL ANASTOMOSES WITH AXIOS® STENT FOR ANASTOMOTIC AFFERENT LOOP OBSTRUCTION A ABOUT 5 CASES WITH VIDEOS
Authors: JM Gonzalez, D Lorenzo, G Vanbiervliet, M Barthet
Journal: Endoscopy (2018)

EUS-guided gastro-jejunal anastomoses (GJA) are feasible in humans with Axios® stent (Boston Scientific, USA). Several cases have been performed under EUS, directly or using simple or double balloon. We present three cases of direct EUS guided GJA in post-operative anastomotic obstructions.
Subungual atypical lentiginous melanocytic proliferations in children and adolescents: A clinicopathologic study
Authors: Sameer S. Khatri, Min Wang, Kelly L. Harms, Alison B. Durham, Timothy M. Johnson, Rosalynn M. Nazarian, Paul W. Harms, Douglas R. Fullen, Aleodor A. Andea, May P. Chan
Journal: Journal of the American Academy of Dermatology (2018)
Extended adjuvant tamoxifen for early breast cancer: A meta-analysis.
Authors: Eitan Amir, Mustafa Al-Mubarak, Ariadna Tibau, Arnoud J. Templeton, Alberto Ocana, Bostjan Seruga
Journal: Journal of Clinical Oncology (2013)

539 Background: Hormone receptor positive breast cancer is characterized by the potential for disease recurrence many years after initial diagnosis. Endocrine therapy has been shown to reduce the risk of such recurrence, but the optimal duration of endocrine therapy remains unclear. Methods: We conducted a systematic review and meta-analysis to quantify the relative and absolute benefits and harms of extended adjuvant tamoxifen (&gt;5 years of therapy) compared with adjuvant tamoxifen (≤5 years of therapy). Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to treat (NNT) were computed for pre-specified events including disease recurrence, distant recurrence, all-cause death, endometrial carcinoma, cardiovascular death and treatment discontinuation. Subgroup analyses by timing of recurrence and baseline lymph node and menopause status were carried out. Results: Six trials comprising 25,326 patients were included. Extended adjuvant tamoxifen was associated with a non-significant reduction in the risk of recurrence (OR 0.89, 95% CI 0.77-1.04, p=0.14, NNT 74). Similar results were seen for distant recurrence (OR 0.88, 95% CI 0.75-1.04, p=0.14, NNT 70). There was no association between extended adjuvant tamoxifen and all-cause death (OR 1.06, 95% CI 0.86-1.31, p=0.58). There was no reduction in risk during extended adjuvant therapy (i.e. between years 5 and 9), but a potential reduction in the risk of recurrence after completion of extended adjuvant tamoxifen (i.e. beyond 10 years after diagnosis). Subgroup analysis suggested benefit in lymph node positive patients. Endometrial carcinoma was substantially more frequent with extended adjuvant tamoxifen (OR 1.81, 95% CI 1.45-2.25, p&lt;0.001, NNT 102), but among those with endometrial carcinoma, the odds of death were lower among the extended tamoxifen group (OR 0.50, 95% CI 0.28-0.90, p=0.02). Conclusions: Extended adjuvant tamoxifen is not associated with a significant reduction in recurrence or death in unselected patients. Patients with lymph node positive breast cancer may derive more benefit. Reduction in the risk of recurrence only appears after completion of extended adjuvant therapy.
Safety of lumen-apposing stent with or without coaxial plastic stent for endoscopic ultrasound-guided drainage of pancreatic fluid collections: a retrospective study
Authors: Manuel Puga, Claudia Consiglieri, Juli Busquets, Natàlia Pallarès, Lluis Secanella, Nuria Peláez, Joan Fabregat, José Castellote, Joan Gornals
Journal: Endoscopy (2018)

Abstract Background The aim of this study was to evaluate whether the placement of a coaxial double-pigtail plastic stent (DPS) within a lumen-apposing metal stent (LAMS) may improve the safety of endoscopic ultrasound (EUS)-guided drainage of pancreatic fluid collections (PFCs). Methods This was a retrospective cohort study including patients with PFCs and an indication for transmural drainage. Two strategies (LAMS alone or LAMS plus DPS) were used at the endoscopist’s discretion. Results A total of 41 patients were treated (21 LAMS alone; 20 LAMS plus DPS). The characteristics of the PFCs, and the technical and clinical success rates did not differ between groups. The LAMS alone group had a significantly higher rate of adverse events than the LAMS plus DPS group (42.9 % vs. 10.0 %; P = 0.04). Bleeding was the most frequent adverse event observed. Conclusions The addition of a coaxial DPS to LAMS was associated with a lower rate of adverse events in EUS-guided drainage of PFCs.
ENDOSCOPIC ULTRASOUND-GUIDED FINE-NEEDLE ASPIRATION IN SOLID PANCREATIC MASS IN PARAGUAY
Authors: G Aguero Garcete, JC Sosa, C Caballero, J Ferreira
Journal: Endoscopy (2018)

To present the evolution of endoscopic ultrasound (EUS) and the results of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in the study of solid tumors of the pancreas in Paraguay.
LONG TERM FOLLOW-UP AFTER EUS-GUIDED GALLBLADDER DRAINAGE FOR ACUTE CHOLECYSTITIS, USING USING HOT AXIOS SYSTEM
Authors: M Manno, C Barbera, VG Mirante, L Miglioli, T Gabbani, P Soriani
Journal: Endoscopy (2018)

Acute cholecystitis (AC) is a serious condition, especially in elderly patients, requiring urgent treatment. Surgery is the standard option, while EUS-guided gallbladder drainage is an emerging alternative strategy as definitive treatment, in poor surgical candidates. To overcome some limitations of past techniques, a novel endoscopic device containing a lumen-apposing metal stent with an electrocautery (ECE-LAMS) has been developed (Hot Axios System, Boston Scientific, USA).
The E3 ubiquitin ligase NEDD4 mediates cell migration signaling of EGFR in lung cancer cells
Authors: Genbao Shao, Ranran Wang, Aiqin Sun, Jing Wei, Ke Peng, Qian Dai, Wannian Yang, Qiong Lin
Journal: Molecular Cancer (2018)

EGFR-dependent cell migration plays an important role in lung cancer progression. Our previous study observed that the HECT E3 ubiquitin ligase NEDD4 is significantly correlated with tumor metastasis and required for migration and invasion signaling of EGFR in gastric cancer cells. However, how NEDD4 promotes the EGFR-dependent lung cancer cell migration is unknown. This study is to elucidate the mechanism by which NEDD4 mediates the EGFR lung cancer migration signaling. Lentiviral vector-loaded NEDD4 shRNA was used to deplete endogenous NEDD4 in lung cancer cell lines. Effects of the NEDD4 knockdown on the EGFR-dependent or independent lung cancer cell migration were determined using the wound-healing and transwell assays. Association of NEDD4 with activated EGFR was assayed by co-immunoprecipitation. Co-expression of NEDD4 with EGFR or PTEN was determined by immunohistochemical (IHC) staining in 63 lung adenocarcinoma tissue samples. Effects of NEDD4 ectopic expression or knockdown on PTEN ubiquitination and down-regulation, AKT activation and lysosomal secretion were examined using the GST-Uba pulldown assay, immunoblotting, immunofluorescent staining and a human cathepsin B ELISA assay respectively. The specific cathepsin B inhibitor CA-074Me was used for assessing the role of cathepsin B in lung cancer cell migration. Knockdown of NEDD4 significantly reduced EGF-stimulated cell migration in non-small cell lung carcinoma (NSCLC) cells. Co-immunoprecipitation assay found that NEDD4 is associated with EGFR complex upon EGF stimulation, and IHC staining indicates that NEDD4 is co-expressed with EGFR in lung adenocarcinoma tumor tissues, suggesting that NEDD4 might mediate lung cancer cell migration by interaction with the EGFR signaling complex. Interestingly, NEDD4 promotes the EGF-induced cathepsin B secretion, possibly through lysosomal exocytosis, as overexpression of the ligase-dead mutant of NEDD4 impedes lysosomal secretion, and knockdown of NEDD4 significantly reduced extracellular amount of cathepsin B induced by EGF. Consistent with the role of NEDD4, cathepsin B is pivotal for both basal and the EGF-stimulated lung cancer cell migration. Our studies propose a novel mechanism underlying the EGFR-promoted lung cancer cell migration that is mediated by NEDD4 through regulation of cathepsin B secretion. NEDD4 mediates the EGFR lung cancer cell migration signaling through promoting lysosomal secretion of cathepsin B.
Clinical Utility of Cell-Free DNA for the Detection of <i>ALK</i> Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non–Small Cell Lung Cancer
Authors: Caroline E. McCoach, Collin M. Blakely, Kimberly C. Banks, Benjamin Levy, Ben M. Chue, Victoria M. Raymond, Anh T. Le, Christine E. Lee, Joseph Diaz, Saiama N. Waqar, William T. Purcell, Dara L. Aisner, Kurtis D. Davies, Richard B. Lanman, Alice T. Shaw, Robert C. Doebele
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Patients with advanced non–small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a noninvasive way to identify ALK fusions and actionable resistance mechanisms without an invasive biopsy. Patients and Methods: The Guardant360 (G360; Guardant Health) deidentified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected ALK fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma. Results: Identified fusion partners included EML4 (85.4%), STRN (6%), and KCNQ, KLC1, KIF5B, PPM1B, and TGF (totaling 8.3%). Forty-two ALK-positive patients had no history of targeted therapy (cohort 1), with tissue ALK molecular testing attempted in 21 (5 negative, 5 positive, and 11 tissue insufficient). Follow-up of 3 of the 5 tissue-negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 to 3 ALK resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known EGFR-activating mutations, an ALK fusion was identified on progression (cohort 4; 4 STRN, 1 EML4; one both STRN and EML4); five harbored EGFR T790M. Conclusions: In this cohort of cfDNA-detected ALK fusions, we demonstrate that comprehensive cfDNA NGS provides a noninvasive means of detecting targetable alterations and characterizing resistance mechanisms on progression. Clin Cancer Res; 24(12); 2758–70. ©2018 AACR.
Tumor-Derived GM-CSF Promotes Granulocyte Immunosuppression in Mesothelioma Patients
Authors: Swati Khanna, Suzanne Graef, Francis Mussai, Anish Thomas, Neha Wali, Bahar Guliz Yenidunya, Constance Yuan, Betsy Morrow, Jingli Zhang, Firouzeh Korangy, Tim F. Greten, Seth M. Steinberg, Maryalice Stetler-Stevenson, Gary Middleton, Carmela De Santo, Raffit Hassan
Journal: Clinical Cancer Research (2018)

The cross-talk between tumor cells, myeloid cells, and T cells can play a critical role in tumor pathogenesis and response to immunotherapies. Although the etiology of mesothelioma is well understood, the impact of mesothelioma tumor cells on the surrounding immune microenvironment is less well studied. In this study, the effect of the mesothelioma tumor microenvironment on circulating and infiltrating granulocytes and T cells is investigated.
Risk assessment in pulmonary arterial hypertension
Authors: Athénaïs Boucly, Jason Weatherald, Marc Humbert, Olivier Sitbon
Journal: European Respiratory Journal (2018)

<b>Risk stratification of pulmonary arterial hypertension based on the number of noninvasive low-risk criteria achieved at first follow-up provides an accurate identification of patients with an excellent prognosis</b>http://ow.ly/IyNI30irqpK
Safety and efficacy of fosaprepitant in pediatric patients for prevention of chemotherapy induced nausea and vomiting.
Authors: Karissa N Kusick, Madeline Waldron, Anthony Zembillas, Maya Wai, Rabi Hanna, Peter Meade Anderson
Journal: Journal of Clinical Oncology (2017)

e22023 Background: Aprepitant is an antiemetic that antagonizes the substance P neurokinin-1 receptor. Fosaprepitant is an intravenous prodrug of aprepitant and is FDA-approved for the prevention of chemotherapy-induced nausea and vomiting (CINV) in adults. Although the FDA extended approval of oral aprepitant to children and adolescents for CINV, pediatric patients have challenges obtaining aprepitant due to insurance or have difficulty taking oral medications during chemotherapy. Fosaprepitant is a logical alternative but data are lacking for safe and effective dosing in children. In 2015, fosaprepitant was added to our hospital formulary for pediatric patients receiving moderate to highly emetogenic chemotherapy. The fosaprepitant dose established was 150mg for weight ≥30kg or 3mg/kg/dose for &lt; 30kg. There is also potential for overall cost savings to our institution. Fosaprepitant is about half the cost of aprepitant using equivalent adult doses. Methods: This retrospective chart review was considered exempt from IRB.All pediatric patients who received fosaprepitant between April 2015 and October 2016 while inpatient were included.Patients undergoing bone marrow transplant were excluded from the study.The primary objective was to determine safety of fosaprepitant. To evaluate safety, incidence of infusion related reactions related to fosaprepitant administration were assessed. Secondary objectives include efficacy of fosaprepitant in pediatric patients and evaluation of cost savings. To evaluate efficacy, the use of breakthrough antiemetics, documented emesis, and Adapted Rhodes Index for Nausea and Vomiting score were collected. Descriptive statistics were used for all data analyses on a per cycle basis. Results: A preliminary safety evaluation of 20 patients ages 9 months through 16 years received 87 doses of fosaprepitant for CINV prophylaxis.Six patients &lt; 30kg received weight-based dosing; the other 14 patients received a dose of 150mg.One patient experienced an infusion related reaction from fosaprepitant but symptoms resolved after the infusion was stopped. Conclusions: Fosaprepitant appears to be safe and cost-effective to prevent CINV in children.
Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway
Authors: Yoshiyasu Fukusumi, Ying Zhang, Ryohei Yamagishi, Kanako Oda, Toru Watanabe, Katsuyuki Matsui, Hiroshi Kawachi
Journal: Journal of the American Society of Nephrology (2018)

Background B-type ephrins are membrane-bound proteins that maintain tissue function in several organs. We previously reported that ephrin-B1 is localized at the slit diaphragm of glomerular podocytes. However, the function of ephrin-B1 at this location is unclear. Methods We analyzed the phenotype of podocyte-specific ephrin-B1 knockout mice and assessed the molecular association of ephrin-B1 and nephrin, a key molecule of the slit diaphragm, in HEK293 cells and rats with anti-nephrin antibody-induced nephropathy. Results Compared with controls, ephrin-B1 conditional knockout mice displayed altered podocyte morphology, disarrangement of the slit diaphragm molecules, and proteinuria. Ephrin-B1 expressed in HEK293 cells immunoprecipitated with nephrin, which required the basal regions of the extracellular domains of both proteins. Treatment of cells with an anti-nephrin antibody promoted the phosphorylation of nephrin and ephrin-B1. However, phosphorylation of ephrin-B1 did not occur in cells expressing a mutant nephrin lacking the ephrin-B1 binding site or in cells treated with an Src kinase inhibitor. The phosphorylation of ephrin-B1 enhanced the phosphorylation of nephrin and promoted the phosphorylation of c-Jun N-terminal kinase (JNK), which was required for ephrin-B1–promoted cell motility in wound-healing assays. Notably, phosphorylated JNK was detected in the glomeruli of control mice but not ephrin-B1 conditional knockout mice. In rats, the phosphorylation of ephrin-B1, JNK, and nephrin occurred in the early phase (24 hours) of anti-nephrin antibody-induced nephropathy. Conclusions Through interactions with nephrin, ephrin-B1 maintains the structure and barrier function of the slit diaphragm. Moreover, phosphorylation of ephrin-B1 and, consequently, JNK are involved in the development of podocyte injury.
A related proposal: An interactionist perspective on reason
Authors: Hugo Mercier
Journal: Behavioral and Brain Sciences (2018)

This comment introduces the interactionist perspective on reason that Dan Sperber and I developed. In this perspective, reason is a specific cognitive mechanism that evolved so that humans can exchange justifications and arguments with each other. The interactionist perspective significantly aligns with Doris's views in rejecting reflectivism and individualism. Indeed, I suggest that it offers different, and maybe stronger arguments to reject these views.
DIAGNOSIS AND PREDICTIVE FACTORS OF MALIGNANCIES ASSOCIATED PSEUDOACHALASIA: STILL A CLINICAL CHALLENGE
Authors: N Elleuch, S Jardak, A Sabbek, A Ben Slama, H Jaziri, A Hammami, A Braham, M Ksiaa, A Jmaa, M Medhioub
Journal: Endoscopy (2018)

A coherent distinction between primary and secondary achalasia is considerably important to physicians. This is because the treatment is entirely different. While pneumatic dilation is the gold standard for primary achalasia, it exposes to potential risk of complication and cause a diagnosis delay.
Complete ?medical mediastinoscopy? under conscious sedation: A prospective blinded comparison of endoscopic and endobronchial ultrasound to bronchoscopic fine needle aspiration for malignant mediastinal lymph nodes
Authors: M Wallace, J Pascual, M Raimondo, T Woodward, B McComb, M Johnson, M Al-Haddad, K Noh, S Pungpapong, J Hardee, O Pajaro, J Odell
Journal: Endoscopy (2006)

Background: We have previously reported a retrospective study suggesting endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) are superior to blind bronchoscopic (“Wang“) FNA for detection of malignant mediastinal lymph nodes (Wallace et al. DDW 2005). We now report a prospective, blinded trial comparing the accuracy and feasibility of each modality.