tbuckley/cabot-search huggingface dataset:
A phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with nab-paclitaxel for patients with previously treated advanced pancreatic cancer.
Authors: Christine Campo Alewine, Raffit Hassan, M. Iqra Ahmad, Jane B Trepel, Cody Peer, William Douglas Figg, Ira Pastan
Journal: Journal of Clinical Oncology (2019)

307 Background: LMB-100 is a Pseudomonas exotoxin A-based immunotoxin that targets mesothelin (MSLN). MSLN is expressed by &gt;75% of pancreatic adenocarcinomas (PDAC). LMB-100 kills MSLN-expressing cells by irreversibly modifying elongation factor-2 to halt protein synthesis. Phase I studies of LMB-100 defined the maximum tolerated dose (MTD) of 140 mcg/kg IV given on D1, 3 and 5 of a 21-day cycle. Development of anti-drug antibodies (ADAs) limited patient drug exposure beyond cycle 2. Our pre-clinical data showed that combination of LMB-100 with a taxane resulted in synergistic anti-tumor activity. Methods: We conducted a phase I single center study (standard 3+3 design) to determine the MTD of LMB-100 given with nab-paclitaxel in patients with previously treated advanced PDAC. LMB-100 was given on D1, 3 and 5 of a 21-day cycle, and nab-paclitaxel (125 mg/m 2 ) on D1 and D8. Initial patients could receive a maximum of 4 cycles, but subsequently a 2-cycle maximum was employed. Results: Fourteen patients (median age 58) were enrolled. Two of 6 patients experienced DLTs at the 100 mcg/kg dose of LMB-100 (myalgia- 2 pts, fatigue- 1 pt, hypotension- 1 pt; all grade 3). One of 8 patients had DLT at the 65 mcg/kg dose (edema, urine output decrease- both grade 3). Other toxicities related to LMB-100 included hypoalbuminemia, edema-associated weight gain, hyponatremia, fatigue, drug fever, infusion-related reaction, hypophosphatemia, nausea and anorexia. One patient died on treatment from complications of bowel perforation attributed to cancer. All patients achieved detectable serum levels of LMB-100 during the first cycle, even those with pre-existing ADAs, and 5 of 8 did so during cycle 2. One patient receiving the 65 mcg/kg dose had a confirmed partial response, and CA 19-9 dropped by &gt; 50% in 5 of 8 evaluable patients. Conclusions: MTD of LMB-100 is 65 mcg/kg given with nab-paclitaxel on this schedule. Anti-tumor activity was observed. A phase II cohort is currently being accrued. Clinical trial information: NCT02810418.
Irradiated Almond Flour Meets Established Criteria for use in Oral Immunotherapy
Authors: Anusha Penumarti, Nicole Szczepanski, Janelle Kesselring, Elizabeth Gabel, Rohini Sheth, Jelena Petrovic Berglund, Edwin Kim, A. Wesley Burks, Michael D. Kulis
Journal: Journal of Allergy and Clinical Immunology (2019)
Sirolimus therapy for children with problematic kaposiform haemangioendothelioma and tufted angioma
Authors: M. Tasani, P. Ancliff, M. Glover
Journal: British Journal of Dermatology (2017)

Kaposiform haemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumours that typically present during infancy or childhood. Originally regarded as distinct lesions, they are now considered as part of a spectrum. Presentation is usually as an enlarging, tender, blue or red mass. Both KHE and TA may be associated with Kasabach-Merritt Phenomenon (KMP), a severe haemorrhagic state arising from intralesional platelet trapping, microangiopathic haemolytic anaemia, and consumptive coagulopathy.

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Royal college stops taking funding from formula milk firms
Authors: Susan Mayor
Journal: BMJ (2019)

The Royal College of Paediatrics and Child Health has announced that it has stopped accepting funding from companies that make formula milk.1

The college said that it received in the region of £40 000 (€46 000; $52 000) a year from formula milk companies in event sponsorship and advertising, but after a review by the RCPCH council,2 which advises on policy issues, it ended this practice on 31 January.

“The college, which has 19 000 members worldwide, wishes to reiterate the importance of promoting breastfeeding as the best possible …
Aligning Guideline Criteria for Asthma Control with Digitally Collected Data
Authors: Linda Zhu, Yesenia Ramirez, Daniel Villalobos-Terrazas, Karen Reyes, Naomi BenIsrael-Olive, Rahul Gondalia, Leanne Kaye, David A. Stempel, Giselle Mosnaim
Journal: Journal of Allergy and Clinical Immunology (2019)
Pre-Treatment with Bendamustine Does Not Affect Stem Cell Mobilization in Patients with Indolent Non-Hodgkin Lymphomas: A Multicenter Study on Behalf of the Fondazione Italiana Linfomi
Authors: Michele Merli, Stefano Luminari, Lucia Farina, Federica Cocito, Irene Defrancesco, Guido Gini, Annalisa Arcari, Greta Scapinello, Massimo Gentile, Maria Goldaniga, Giacomo Loseto, Emanuele Cencini, Antonino Greco, Andrea Ferrario, Benedetta Bianchi, Francesca Gaia Rossi, Silvia Bolis, Francesco Passamonti, Luca Arcaini
Journal: Blood (2018)
Postnatal probiotics and allergic disease in very preterm infants: sub-study to the ProPrems randomized trial
Authors: Adriana Chebar Lozinsky, Erica Plummer, Jacinta Tobin, Jessica Uebergang, Christine Axerald, Suzanne Garland, Suzan E. Jacobs, Mimi L.K. Tang
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 12422: Influence of Polypharmacy on the Efficacy And Safety Of Dabigatran Versus Warfarin for the Treatment of Acute Venous Thromboembolism: A Pooled Analysis of RE-COVER® and RE-COVER II™
Authors: Samuel Z Goldhaber, Henry Eriksson, Ajay Kakkar, Sebastian M Schellong, Martin Feuring, Mandy Fraessdorf, Joerg Kreuzer, Sam Schulman
Journal: Circulation (2015)

Background: Polypharmacy in patients treated for acute venous thromboembolism (VTE) has been associated with increased bleeding risk during warfarin (W) treatment. Polypharmacy is common in patient...
Cocirculation of Hajj and non-Hajj strains among serogroup W meningococci in Italy, 2000 to 2016
Authors: Cecilia Fazio, Arianna Neri, Paola Vacca, Andrea Ciammaruconi, Milena Arghittu, Anna Maria Barbui, Caterina Vocale, Paola Bernaschi, Patrizia Isola, Irene Alessandra Galanti, Antonella Mencacci, Rosella De Nittis, Maria Chironna, Anna Giammanco, Elisabetta Pagani, Alessandro Bisbano, Paola Stefanelli
Journal: Eurosurveillance (2019)

In Italy, B and C are the predominant serogroups among meningococci causing invasive diseases. Nevertheless, in the period from 2013 to 2016, an increase in serogroup W Neisseria meningitidis (MenW) was observed. This study intends to define the main characteristics of 63 MenW isolates responsible of invasive meningococcal disease (IMD) in Italy from 2000 to 2016. We performed whole genome sequencing on bacterial isolates or single gene sequencing on culture-negative samples to evaluate molecular heterogeneity. Our main finding was the cocirculation of the Hajj and the South American sublineages belonging to MenW/clonal complex (cc)11, which gradually surpassed the MenW/cc22 in Italy. All MenW/cc11 isolates were fully susceptible to cefotaxime, ceftriaxone, ciprofloxacin, penicillin G and rifampicin. We identified the full-length NadA protein variant 2/3, present in all the MenW/cc11. We also identified the fHbp variant 1, which we found exclusively in the MenW/cc11/Hajj sublineage. Concern about the epidemic potential of MenW/cc11 has increased worldwide since the year 2000. Continued surveillance, supported by genomic characterisation, allows high-resolution tracking of pathogen dissemination and the detection of epidemic-associated strains.
A Novel Fully Human Bispecific CD19 x CD3 Antibody That Kills Lymphoma Cells with Minimal Cytokine Secretion
Authors: Harbani Malik, Ben Buelow, Brian Avanzino, Aarti Balasubramani, Andrew Boudreau, Starlynn Clarke, Kevin Dang, Laura Davison, Shelley Force Aldred, Katherine Harris, Brett Jorgensen, Yuping Li, Harish Medlari, Keshav Narayan, Heather Ogana, Duy Pham, Kirthana Prabhakar, Udaya Rangaswamy, Preethi Sankaran, Ute Schellenberger, Harshad Ugamraj, Nathan Trinklein, Wim Van Schooten
Journal: Blood (2018)
DHODH Inhibitors in the Treatment of Acute Myeloid Leukemia: Defining the Mechanism of Action and the Basis of the Metabolic Therapeutic Window
Authors: Peggy P. Hsu, Youmna Kfoury, Najihah Aziz, Jenna Elkhoury, Brittany Hallgren, David T. Scadden, Matthew Vander Heiden, David B Sykes
Journal: Blood (2018)
Outcomes after cessation of therapy with alkylating agents (AA) for pancreatic neuroendocrine tumors (panNETs).
Authors: Linda Wu, Diane Lauren Reidy, Agata Bielska, Virginia Kelly, Nitya Prabhakar Raj
Journal: Journal of Clinical Oncology (2019)

394 Background: There are several therapies now available for panNETs, raising concern that treatment-related toxicity, namely myelosuppression, may preclude use of all treatments. AA are an effective therapy in panNETs, but can cause irreversible bone marrow suppression. For this reason, our institutional approach is to treat patients (pts) with AA for a defined time period of up to 12 months prior to a treatment holiday; anecdotally, we observed continued disease shrinkage or stability after drug cessation. We aimed to identify and characterize these exceptional responders (ER). Methods: We retrospectively identified pts with well differentiated panNETs treated at MSKCC with AA from 2007 to present, and identified those that were placed on a treatment holiday after response to therapy. Pts with continued disease response by radiographic report (tumor shrinkage or stable disease) for greater than 9 months while on a treatment holiday were considered exceptional responders (ER). Results: 124 patients were evaluable, with 104 pts (84%) receiving temozolomide and 18 pts (15%) receiving dacarbazine. 40 (32%), 57 (46%), and 22 (18%) pts had low, intermediate and high-grade tumors, respectively. 80 pts (65%) achieved a response to AA and 21 pts (17%) responded to therapy initially with subsequent disease progression. In total, 58 pts (47%) entered a treatment holiday; 39/58 pts (67%) were ER and 16/58 pts (28%) had disease growth in &lt; 9 months. No significant differences in tumor grade ( P = 0.85) were seen between ER and those who had disease growth in &lt; 9 months. Next generation sequencing results were available in 17 tumors of pts classified as ER; 14/17 (82%) with alterations in chromatin remodeling genes ( MEN1/DAXX/ATRX). Upon disease progression, 11 ER were reintroduced to alkylating agents; 9/11 (82%) had progressive disease or death after reintroduction of drug, and 2/11 (18%) responded and went on a second treatment holiday. Conclusions: We observed durable responses to AA after cessation of therapy. Many of the ER tumors harbored alterations in chromatin remodeling genes. Reintroduction of alkylating agents upon disease progression was generally ineffective.
Major duodenal papilla prolapse in Cronkhite–Canada syndrome
Authors: Beatrice Marinoni, Gian Tontini, Luca Elli, Barbara Bruni, Marco Maggioni, Luca Pastorelli, Maurizio Vecchi
Journal: Endoscopy (2019)

We describe the case of a 59-year-old Japanese woman presenting with recurrent proctorrhagia. Her clinical history was unremarkable except for recently presenting alopecia, dysgeusia, and onychodystrophy.
F‐box/WD Repeat‐Containing Protein 5 Mediates the Ubiquitination of Apoptosis Signal‐Regulating Kinase 1 and Exacerbates Nonalcoholic Steatohepatitis in Mice
Authors: Lan Bai, Ming‐Ming Chen, Ze‐Dong Chen, Peng Zhang, Song Tian, Yan Zhang, Xue‐Yong Zhu, Ye Liu, Zhi‐Gang She, Yan‐Xiao Ji, Hongliang Li
Journal: Hepatology (2019)

Inhibition of apoptosis signal‐regulating kinase 1 (ASK1) activation has emerged as a promising target for the treatment of nonalcoholic steatohepatitis (NASH). Multiple forms of posttranslational modifications determine the activity of ASK1. In addition to phosphorylation, recent studies revealed that ubiquitination is essential for ASK1 activation. However, the endogenous factor that regulates ASK1 ubiquitination and activation remains poorly defined. In this study, we identified the E3 ligase Skp1‐Cul1‐F‐box (SCF) protein F‐box/WD repeat‐containing protein 5 (FBXW5) as a key endogenous activator of ASK1 ubiquitination. FBXW5 is the central component of the SCF complex (SCF Fbxw5 ) that directly interacts with and ubiquitinates ASK1 in hepatocytes during NASH development. An in vivo study showed that hepatocyte‐specific overexpression of FBXW5 exacerbated diet‐induced systemic and hepatic metabolic disorders, as well as the activation of ASK1‐related mitogen‐activated protein kinase (MAPK) signaling in the liver. Conversely, hepatocyte‐specific deletion of FBXW5 significantly prevented the progression of these abnormalities. Mechanically, FBXW5 facilitated the addition of Lys63‐linked ubiquitin to ASK1 and thus exacerbated ASK1‐c‐Jun N‐terminal kinase/p38 MAPK signaling, inflammation, and lipid accumulation. Furthermore, we demonstrated that the N‐terminus (S1) and C‐terminus (S3) of FBXW5 respectively and competitively ablate the function of FBXW5 on ASK1 activation and served as effective inhibitors of NASH progression. Conclusion: This evidence strongly suggests that SCF Fbxw5 is an important activator of ASK1 ubiquitination in the context of NASH. The development of FBXW5(S1) or FBXW5(S3)‐mimicking drugs and screening of small‐molecular inhibitors specifically abrogating ASK1 ubiquitination‐dependent activation are viable approaches for NASH treatment.
<i>Porphyromonas gingivalis</i> experimentally induces periodontis and an anti-CCP2-associated arthritis in the rat
Authors: Guillaume Courbon, Mélanie Rinaudo-Gaujous, Vincent Blasco-Baque, Isabelle Auger, Robin Caire, Lambert Mijola, Laurence Vico, Stéphane Paul, Hubert Marotte
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Objectives</h3> Association between periodontal disease (PD) and rheumatoid arthritis (RA) has been extensively described, but direct evidence of causal involvement of PD in RA is missing. We investigated the priming role of oral <i>Porphyromonas gingivalis</i> (<i>P. gingivalis</i>) in PD and subsequent RA and we assessed biomarkers of bone resorption and arthritis development in rats. <h3>Methods</h3> Lewis rats were orally exposed to either <i>P. gingivalis</i>, <i>Prevotella intermedia</i> or control gel for 1 month and then followed for 8 months. The onset and development of PD was assessed by serology, gingivitis severity and micro-CT (µCT). We investigated arthritis development using circulating proinflammatory markers, anticyclic citrullinated peptide (CCP), anticitrullinated protein antibody (ACPA), ankle histology and µCT. <h3>Results</h3> PD was only observed in the <i>P. gingivalis</i> treated rats, as early as 1 month postexposure. Joint and systemic inflammation were detected only in the <i>P. gingivalis</i> group after 4 and 8 months. At 8 months, inflammatory cell infiltrate was observed in ankle joints and paralleled cortical erosions and overall cortical bone reduction. Furthermore, anti-CCP2 correlated with local and systemic bone loss. <h3>Conclusions</h3> In our long-term study, PD induced by oral exposure to <i>P. gingivalis</i> triggered seropositive arthritis, with systemic inflammation and bone erosions. This is the first in vivo demonstration of arthritis induced by oral priming with <i>P. gingivalis</i>.
Abstract 15714: Elamipretide Normalizes Nicotinic-Acetyl-Choline-Receptor-Alpha-7 Protein Levels in Mitochondria of Left Ventricular Myocardium of Dogs With Advanced Heart Failure
Authors: Ramesh C Gupta, Vinita Singh-Gupta, Hani N Sabbah
Journal: Circulation (2017)

Introduction: Alpha-7 nicotinic acetylcholine receptors (α7-nAChRs) are ligand-gated ion channels that are expressed in non-excitable cells and regulate cell survival and proliferation. Recent studies have shown that α7-nAChRs are also expressed on the outer membrane of mitochondria (MITO) and function as regulators of cytochrome c release, calcium loading and MITO production of reactive oxygen species (ROS). Elamipretide (ELAM), a novel MITO-targeting peptide, has been shown to improve MITO function, prevent/attenuate the release of cytochrome c into the cytosol and reduce the formation of MITO ROS in myocardium of dogs with chronic heart failure (HF). Hypothesis: This study tested the hypothesis that protein levels of α7-nAChRs are reduced in MITO of dogs with HF and that long-term therapy with ELAM reverses the dysregulation of MITO α7-nAChRs. Methods: LV tissue from 14 coronary microembolization-induced HF dogs (LV ejection fraction ~30%) randomized to 3 months monotherapy with subcutaneous daily inje...
Watch and wait approach following neoadjuvant chemoradiotherapy for rectal cancer patients: A single-centre experience.
Authors: Ji Zhu, Jingwen Wang
Journal: Journal of Clinical Oncology (2019)

681 Background: A watch-and-wait approach for patients with clinical complete response to neoadjuvant chemoradiation could avoid the morbidity of conventional surgery for rectal cancer. Here, we report the survival outcome of patients with this strategy in our center. Methods: We retrospectively analyzed the rectal cancer patients who received neoadjuvant chemoradiotherapy since 2015 in our center. Preoperative regimen included long-course radiotherapy (50 Gy / 25 Fx) combined fluoropyrimidin–based chemotherapy concurrently. MRI and endoscopic evaluation were performed after preoperative treatment. Patients with complete tumor response were referred to the “watch-and-wait” approach and omitted the surgery. Four to six cycles of consolidation chemotherapy were performed. Patients were followed up clinically, endoscopically, and radiologically to assess for local recurrence or disease progression. Results: From January 2015 to March 2018, a total of 47 patients with rectal cancer in our center received conservative treatment following neoadjuvant therapy. The median age of the patients is 58 (53-66). The proportions of stages I to IV are 4.3%, 12.8%, 70.2%, 8.5%, respectively. After a median follow-up of 20 month, tumor regrowth occurred in five out of 47 (10.6%) patients. All local regrowth was diagnosed in the first two years, and four out of five (80%) of local regrowth was located in the bowel wall. All patients underwent salvage surgery. Distant metastasis was diagnosed in four of 47 patients (8.5%). two-year overall survival was 89.9%, and two-year disease-free survival was 76.5%. Conclusions: Organ preservation for locally advanced rectal cancer is feasible for selected patients who achieve a complete response to individualized neoadjuvant CRT. The survival of patients is not impaired with “watch-and-wait” strategy.
Abstract 012: Capture-Recapture Using Multiple Data Sources: Estimating the Prevalence of Congenital Heart Disease
Authors: Lindsey M Duca, Amber D Khanna, Christopher M Rausch, David Kao, Tessa Crume
Journal: Circulation (2018)

Introduction: Improvements in the treatment of congenital heart disease (CHD) have resulted in the majority of infants born with CHD surviving into adulthood; completely modifying the epidemiologic profile of patients with CHD. Although the prevalence of CHD at birth has been robustly estimated, the prevalence of CHD in adolescents and adults in the U.S. is uncertain due to a lack of systematically collected population-based data. The unique disjointed healthcare system in the U.S. makes population-based surveillance of conditions like CHD difficult. Hypothesis: Use of capture-recapture methodology in a state-wide CHD surveillance system will result in a higher estimated prevalence of CHD in adolescents and adults by adjusting for incomplete case ascertainment. Methods: Adolescents and adults age 11 to 64 years with a CHD lesion listed as a diagnostic code on an encounter occurring between January 1, 2011 to December 31, 2013 were captured by the Colorado CHD surveillance system. Five primary data sources, representing electronic medical records (EMR) from participating healthcare systems and claims data from the All Payer Claims database, were used for case ascertainment. These sources provide inpatient, outpatient and emergency care across the state of Colorado. Once CHD cases were identified in one of the above data sources, a probabilistic record linkage algorithm was used for de-duplication of cases within and across data sources. Crude prevalence estimates were generated and then capture-recapture methods were employed to estimate the number of adolescents and adults with CHD in Colorado that were not captured in the surveillance system. Data were analyzed using a log-linear model incorporating severity of CHD as a variable of potential heterogeneous catchability. Results: The five primary data sources identified 24,907 CHD cases that met our case definition corresponding to 19,849 unique individuals during our 3-year surveillance period. The observed overall crude prevalence rate of CHD in adolescents and adults was 5.19 per 1000 population (95% CI 5.07 - 5.31 per 1000 population). Using capture-recapture methodology, the estimated prevalence of CHD in adolescents and adults corrected for incomplete case ascertainment was 5.68 per 1000 population (95% CI 5.59 - 5.77 per 1000 population), so an estimated 3,641 CHD cases were not identified in the five primary case finding data sources. Conclusion: Our study provides novel insight into strategies for EMR-based surveillance at the population-level by demonstrating the utility of capture-recapture methodology to estimate, and then correct for, cases missed in standard surveillance techniques.
A guide to systematic review and meta-analysis of prognostic factor studies
Authors: Richard D Riley, Karel G M Moons, Kym I E Snell, Joie Ensor, Lotty Hooft, Douglas G Altman, Jill Hayden, Gary S Collins, Thomas P A Debray
Journal: BMJ (2019)

Prognostic factors are associated with the risk of future health outcomes in individuals with a particular health condition or some clinical start point (eg, a particular diagnosis). Research to identify genuine prognostic factors is important because these factors can help improve risk stratification, treatment, and lifestyle decisions, and the design of randomised trials. Although thousands of prognostic factor studies are published each year, often they are of variable quality and the findings are inconsistent. Systematic reviews and meta-analyses are therefore needed that summarise the evidence about the prognostic value of particular factors. In this article, the key steps involved in this review process are described.
Second Primary Malignancies and Disease Transformation in Newly Diagnosed Symptomatic Patients with Waldenstrom's Macroglobulinemia: An Analysis from the Greek Myeloma Study Group
Authors: Maria Gavriatopoulou, Efstathios Kastritis, Ioannis Ntanasis-Stathopoulos, Marie-Christine Kyrtsonis, Argiris Symeonidis, Evdoxia Hatjiharissi, Panagiotis Repousis, Nikolaos Giannakoulas, Emmanouil G Spanoudakis, Sossana Delibasi, Evridiki Michali, Michalis D Michael, Amalia Vassou, Stavroula Giannouli, Michail Iskas, Georgia Kaiafa, Panagiotis Tsirigotis, Anastasia Pouli, Elina Vervessou, Dimitrios Christoulas, Eirini Katodritou, Evangelos Terpos, Meletios A Dimopoulos
Journal: Blood (2018)