tbuckley/cabot-search huggingface dataset:
Cutaneous toxicity secondary to erlotinib therapy in patients with non-small cell lung cancer in the NCIC CTG BR.21 study: Time course and correlation with survival.
Authors: Roman Perez-Soler, Larry Leon, Slawomir Wojtowicz-Praga
Journal: Journal of Clinical Oncology (2012)

7573 Background: Cutaneous rash often develops in erlotinib-treated patients (pts) and is thought to be associated with improved response and survival. This analysis focuses on incidence, severity, and time course of skin rash secondary to erlotinib, as well as the correlation between rash development and overall survival (OS) in pts in the NCIC CTG BR.21 (NCT00036647) trial. Methods: Pts with stage IIIB or IV non–small cell lung cancer (NSCLC) who had failed first- or second-line chemotherapy were randomized 2:1 to erlotinib or placebo. Cutaneous toxicity was graded per NCI CTC v2.0 and managed at the discretion of the treating investigator. This retrospective analysis used a landmark approach, dividing pts into rash and no-rash groups, by the appearance of rash by week 10. Results: A total of 366 of 488 erlotinib-treated pts (75%) and 40 of 243 placebo-treated pts (16%) developed rash at any time point. Of the former, 75% of rash episodes occurred by week 2. The incidence of grades 1 and 2 rash peaked at week 3; grade 3 rash peaked at week 5. The erlotinib dose was reduced in 48 pts (10%) due to rash. In most erlotinib-treated pts with rash, severity decreased or plateaued over time (Table). Some 311 erlotinib-treated pts (rash group) developed rash by week 10. Median OS in the erlotinib-treated rash (n=311) and no-rash (n=65) groups were 37.4 and 11.1 weeks, respectively (hazard ratio=0.51 [95% confidence interval, 0.38–0.68]; P&lt;.0001). Baseline factors significantly associated with prolonged OS in the rash population included race (Asian vs white), number of affected organs (&lt;3 vs ≥3), and smoking status (never vs ever). Conclusions: For most pts, rash secondary to erlotinib presented within the first 2 weeks, peaked during weeks 3–5, decreased thereafter, and did not necessitate dose reduction, thus supporting SATURN results (Perez-Soler, ASCO 2011, abst. 7610). Development of rash by week 10 of erlotinib therapy was associated with significantly improved OS. [Table: see text]
Deciphering drug resistance in Mycobacterium tuberculosis using whole-genome sequencing: progress, promise, and challenges
Authors: Keira A. Cohen, Abigail L. Manson, Christopher A. Desjardins, Thomas Abeel, Ashlee M. Earl
Journal: Genome Medicine (2019)

Tuberculosis (TB) is a global infectious threat that is intensified by an increasing incidence of highly drug-resistant disease. Whole-genome sequencing (WGS) studies of Mycobacterium tuberculosis, the causative agent of TB, have greatly increased our understanding of this pathogen. Since the first M. tuberculosis genome was published in 1998, WGS has provided a more complete account of the genomic features that cause resistance in populations of M. tuberculosis, has helped to fill gaps in our knowledge of how both classical and new antitubercular drugs work, and has identified specific mutations that allow M. tuberculosis to escape the effects of these drugs. WGS studies have also revealed how resistance evolves both within an individual patient and within patient populations, including the important roles of de novo acquisition of resistance and clonal spread. These findings have informed decisions about which drug-resistance mutations should be included on extended diagnostic panels. From its origins as a basic science technique, WGS of M. tuberculosis is becoming part of the modern clinical microbiology laboratory, promising rapid and improved detection of drug resistance, and detailed and real-time epidemiology of TB outbreaks. We review the successes and highlight the challenges that remain in applying WGS to improve the control of drug-resistant TB through monitoring its evolution and spread, and to inform more rapid and effective diagnostic and therapeutic strategies.
Lenalidomide (L) induces high response rates with molecular remission in patients (pts) with relapsed (rel) or refractory (ref) chronic lymphocytic leukemia (CLL)
Authors: K. Miller, M. S. Czuczman, L. Dimiceli, S. Padmanabhan, D. Lawrence, Z. Bernstein, K. Takeshita, D. Spaner, C. Byrne, C. Crystal, A. A. Chanan-Khan
Journal: Journal of Clinical Oncology (2006)

6517 Background: Tumor microenvironment (ME) is critical in CLL pathogenesis. Targeting the ME is a novel approach in CLL therapeutics. Lenalidomide (Revlimid, L) is an immunomodulating agent (IMiD), approved for pts with transfusion-dependent low or intermediate-1 risk myelodysplastic syndrome with deletion 5q cytogenetic abnormality. Its antitumor activity is possibly mediated through (a) downregulation of cytokine(s) - TNF-α, VEGF, PDGF and IL-6 and/or (b) activation of immune effector cells (T &amp; NK cells). We investigated its antitumor activity in rel/ref CLL pts. Here we present the final results of the first cohort of pts treated with 25mg daily dose of L. Methods: Oral L was given at 25mg/day for 21 out of a 28 day cycle. Anti-leukemic effects were recorded after each cycle using NCI-WG 1996 criteria. Treatment was continued until molecular complete response (mCR) or progressive disease (PD). Those with PD were then treated with L in combination with rituximab (reported separately). Polymerase chain reaction (PCR) for immunoglobulin heavy chain gene was used to determine molecular remission (mCR). Results: Twenty-nine pts (median age 64 years; range: 47–75) have been enrolled. Toxicity is reported on all, while response on 19 evaluable pts. Nine pts are inevaluable (2 withdrew consent and 5 received &lt; 2 months of therapy due to toxicity). Major response was noted in 13 of 19 evaluable pts (68%) with 3 CR (2 mCR) and 10 PR. Toxicity: Most common grade 3/4 adverse effects (AE) were neutropenia (60%) and thrombocytopenia (55%). Another common AE was tumor flare (79%); characterized by tender swelling of lymph nodes and/or rash, noted in almost all pts. Conclusions: L at 25mg/day dose given on days 1–21 in a 28 day cycle yields high ORR including mCR in rel/ref CLL. Hematologic toxicity was the most common AE requiring dose reduction. Overall safety profile was predictable and manageable. A slow dose escalation schema, starting at 15mg is being investigated. [Table: see text]
Fast-progression (FP), hyper-progression (HPD) and early deaths (ED) in advanced non-small cell lung cancer (NSCLC) patients (pts) upon PD-(L)-1 blockade (IO).
Authors: Roberto Ferrara, Laura Mezquita, Matthieu Texier, Jihene Lahmar, Clarisse Audigier-Valette, Laurent Tessonnier, Julien Mazieres, Solenn Brosseau, Laura Leroy, Boris Duchemann, Corentin Lefebvre, Remi Veillon, Virginie Westeel, Stephane Champiat, David Planchard, Jordi Remon, Anas Gazzah, Jean-Charles Soria, Caroline Caramella, Benjamin Besse
Journal: Journal of Clinical Oncology (2019)

9107 Background: HPD was described in 13.8% of NSCLC pts upon single-agent IO and correlated with high metastatic burden and poor prognosis. Other progression (PD) patterns as FP and ED within 12 weeks have been reported respectively in 4.7% and 5.6% of atezolizumab treated NSCLC pts. Whether FP/ED and HPD are different or overlapping patterns is currently unknown. Methods: We analyzed FP, ED and HPD in a multicentric (8 centers) retrospective cohort of IO treated NSCLC pts (11/2012-04/2017). Eligibility criteria required 2 CT scans before and one after IO start. HPD was defined as RECIST v 1.1 PD at first CT scan and a variation per month of tumor growth rate (TGR upon IO – TGR before IO) &gt; 50%. ED was defined as deaths due to disease PD within 12 wks of IO start. FP was defined as ≥ 50% increase in the sum of long diameters within 6 weeks (wks) from baseline. The associations between PD patterns and pts’ characteristics were performed using Fisher or t-student tests. Median overall survival (mOS) was estimated by Kaplan-Meier method and compared by log-rank test. Results: Out of 406 NSCLC pts, 46% were ≥65 years, 72% had non-squamous NSCLC, &gt; 90% received single agent IO in ≥2 line. 56 (13.8%) were HPD by TGR analysis. Among 72 pts (18%) who performed a CT scan within 6 wks after IO start, 6 (8.3%) were FP. These 6 FP pts were also classified as HPD by TGR analysis, while the other 50 (89%) of 56 HPD pts were not FP. The rate of PD in ≥ 3 sites (54% vs 0%, p = 0.002), the rate of liver PD (62% vs 5%, p = 0.002), the baseline tumor burden (BTB) (mean 176± 26 mm vs 55 ± 6 mm, p &lt; 0.0001) and the TGR upon IO (mean 439± 119% vs 216 ± 41%, p = 0.03) were significantly higher in FP pts compared to HPD pts who were not FP. At 4.4 months of median follow-up, FP pts had significantly worse mOS compared to HPD pts not FP [0.7 months (95% CI 0.6,0.8) vs 1.6 months (95% CI 1.1, 2.1); p = 0.02]. Of 406 IO treated pts, 46 (11%) were ED within 12 wks, and 21 (46%) of ED pts had also HPD by TGR analysis. Conclusions: FP and ED are not a surrogate of HPD. FP occurs in a small subgroup (11%) of HPD and correlates with more aggressive features (PD in ≥3 sites, liver-PD, high BTB, high TGR upon IO) and worse OS. ED within 12 wks overlapped with HPD for only 46% of pts.
Abstract 15769: Does HRQOL Decline in Ambulatory Advanced Heart Failure Patients and Their Caregivers Over Time?
Authors: Kathleen L Grady, Maria M Mountis, Josef Stehlik, Gregory A Ewald, Salpy Pamboukian, Donald C Haas, Douglas A Horstmanshof, Ulrich Jorde, Rhondalyn Forde-McLean, J. Timothy Baldwin, Wendy C Taddei-Peters, Shokoufeh Khalatbari, Catherine A Spino, Blair Richards, Douglas L Mann, Keith D Aaronson, Garrick C Stewart
Journal: Circulation (2018)

Introduction: Patient (pt) health-related quality of life (HRQOL) typically declines as heart failure (HF) progresses. HRQOL of caregivers (cgs) for HF pts may be affected by disease management tas...
Screening for Hepatitis B Virus Infection in Pregnant Women
Authors: Douglas K. Owens, Karina W. Davidson, Alex H. Krist, Michael J. Barry, Michael Cabana, Aaron B. Caughey, Chyke A. Doubeni, John W. Epling, Alex R. Kemper, Martha Kubik, C. Seth Landefeld, Carol M. Mangione, Lori Pbert, Michael Silverstein, Melissa A. Simon, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2019)

<h3>Importance</h3> Screening for hepatitis B virus (HBV) infection during pregnancy identifies women whose infants are at risk of perinatal transmission. Data from a nationally representative sample showed a prevalence of maternal HBV infection of 85.8 cases per 100 000 deliveries from 1998 to 2011 (0.09% of live-born singleton deliveries in the United States). Although there are guidelines for universal infant HBV vaccination, rates of maternal HBV infection have increased annually by 5.5% since 1998. Children infected with HBV during infancy or childhood are more likely to develop chronic infection. Chronic HBV infection increases long-term morbidity and mortality by predisposing infected persons to cirrhosis of the liver and liver cancer. <h3>Objective</h3> To update the 2009 US Preventive Services Task Force (USPSTF) recommendation on screening for HBV infection in pregnant women. <h3>Evidence Review</h3> The USPSTF commissioned a reaffirmation evidence update to identify substantial new evidence sufficient enough to change the prior recommendation. The USPSTF targeted its evidence review on the effectiveness and potential harms of screening and the effectiveness and harms of case management to prevent perinatal transmission. <h3>Findings</h3> The USPSTF previously found adequate evidence that serologic testing for hepatitis B surface antigen accurately identifies HBV infection. Interventions are effective for preventing perinatal transmission, based on foundational evidence and observational studies of US case management programs. In addition, there is evidence that over time, perinatal transmission has decreased among women and infants enrolled in case management, providing an overall substantial health benefit. Therefore, the USPSTF reaffirms its previous conclusion that there is convincing evidence that screening for HBV infection in pregnant women provides substantial benefit. <h3>Conclusions and Recommendation</h3> The USPSTF recommends screening for HBV infection in pregnant women at their first prenatal visit. (A recommendation)
Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment
Authors: Claudio L. A. Bassetti, Antoine Adamantidis, Denis Burdakov, Fang Han, Steffen Gay, Ulf Kallweit, Ramin Khatami, Frits Koning, Brigitte R. Kornum, Gert Jan Lammers, Roland S. Liblau, Pierre H. Luppi, Geert Mayer, Thomas Pollmächer, Takeshi Sakurai, Federica Sallusto, Thomas E. Scammell, Mehdi Tafti, Yves Dauvilliers
Journal: Nature Reviews Neurology (2019)
Asthma: assess all patients for future attack risk and tailor care accordingly, new guideline advises
Authors: Elisabeth Mahase
Journal: BMJ (2019)

All patients with asthma should have their risk of having a future attack assessed and have their monitoring, treatment, and care tailored accordingly, new guidelines from the British Thoracic Society and Scottish Intercollegiate Guidelines Network have said.1

The guidance also recommend that patients whose asthma is not adequately managed through standard controller therapies should be referred for specialist care, as new treatments are becoming available that could be effective.

Clinicians and patients need to be aware of the effect of inhalers on global warming, and patients should be encouraged to ask their pharmacy about inhaler recycling, the guidance added.

More than five million people in the UK are currently being treated for asthma, and the …
Silk Hydrogels Crosslinked by the Fenton Reaction
Authors: Jaewon Choi, Meghan McGill, Nicole R. Raia, Onur Hasturk, David L. Kaplan
Journal: Advanced Healthcare Materials (2019)

Here, the Fenton reaction is used to prepare silk hydrogels through oxidation of tyrosine residues in silk fibroin, leading to dityrosine crosslinking. At pH 5.7, gelation occurs rapidly within 30 s, and the resultant opaque gels show soft properties with a storage modulus of ≈100 Pa. The addition of ascorbic acid to the Fenton reaction increases the dityrosine bonds in the hydrogels but has little effect on the rheological or mechanical properties. The results indicate that Fe(III) ions significantly interacted with silk fibroin during the Fenton reaction, most likely binding to sites such as tyrosine, glutamate, and aspartate residues, triggering the formation of β-sheet structures that may impede dityrosine bond formation due to steric hindrance. The use of an iron chelator or the operation of the Fenton reaction at pH 9.2 enables control over the interaction of Fe(III) ions with silk fibroin, achieving a hydrogel with improved optical properties and enhanced dityrosine bond formation. Hydrogels prepared by the Fenton reaction are cytocompatible as L929 mouse fibroblasts remain viable and are proliferative when seeded on the hydrogels. The results offer a useful approach to generate chemically crosslinked silk fibroin hydrogels without the use of enzyme-catalyzed reactions for biomedical applications.
Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease
Authors: Jun Sone, Satomi Mitsuhashi, Atsushi Fujita, Takeshi Mizuguchi, Kohei Hamanaka, Keiko Mori, Haruki Koike, Akihiro Hashiguchi, Hiroshi Takashima, Hiroshi Sugiyama, Yutaka Kohno, Yoshihisa Takiyama, Kengo Maeda, Hiroshi Doi, Shigeru Koyano, Hideyuki Takeuchi, Michi Kawamoto, Nobuo Kohara, Tetsuo Ando, Toshiaki Ieda, Yasushi Kita, Norito Kokubun, Yoshio Tsuboi, Kazutaka Katoh, Yoshihiro Kino, Masahisa Katsuno, Yasushi Iwasaki, Mari Yoshida, Fumiaki Tanaka, Ikuo K. Suzuki, Martin C. Frith, Naomichi Matsumoto, Gen Sobue
Journal: Nature Genetics (2019)
Abstract 24063: Heart Fields Are Induced by Coordinated Activity of Wnt and Bmp Signaling and Identified by CD184 and EphA2 in PSC-Derived Organoids
Authors: Peter Andersen, Dennisse Jimenez-Cyrus, Stephen P Chelko, Suraj Kannan, Emmanouil Tampakakis, Amir Saberi, Sean Murphy, Matthew Miyamoto, Chulan Kwon
Journal: Circulation (2017)

Over the past few decades, major advances have been made in identifying the origins of cardiac cells from developing embryos. In particular, the discovery of the first heart field (FHF) and the second heart field (SHF), led us to understand how diverse lineages and different anatomical structures of the heart arise during cardiogenesis. However, it remains unknown how the two heart fields are specified and segregated, a fundamental step toward understanding heart formation and developing pluripotent stem cell (PSC)-based therapeutic strategies. Here, we generated 3D organoids with mouse PSCs that harbor green and red fluorescent protein (GFP and RFP) reporters under the control of the FHF marker Hcn4 and the SHF marker Tbx1 , respectively. We demonstrate how GFP+ cells and RFP+ cells appear from two distinct areas of mesodermal cells and develop in a complementary fashion, similar to the in vivo process. Consistently, these populations exhibit a high degree of similarities with FHF/SHF cells isolated from early embryos, determined by RNA-sequencing analysis. Through a series of bioinformatics approaches, we found that Bmp and Wnt are among the most differentially regulated pathways in the two populations. Importantly, an increased activity of Bmp or Wnt signaling resulted in selective induction of GFP+ or RFP+ cells from mesodermal cells, enabling us to generate heart field-specific cells from PSCs. We further found that FHF/SHF cells can be distinguished and isolated by the surface proteins CD184 and EphA2. This study provides fundamental insights into understanding the specification of two cardiac origins that enable generation of chamber-specific populations for studying heart field/chamber-specific heart disease in cell culture.
Methods for Development of the European Commission Initiative on Breast Cancer Guidelines
Authors: Holger J. Schünemann, Donata Lerda, Nadya Dimitrova, Pablo Alonso-Coello, Axel Gräwingholt, Cecily Quinn, Markus Follmann, Robert Mansel, Francesco Sardanelli, Paolo Giorgi Rossi, Annette Lebeau, Lennarth Nyström, Mireille Broeders, Lydia Ioannidou-Mouzaka, Stephen W. Duffy, Bettina Borisch, Patricia Fitzpatrick, Solveig Hofvind, Xavier Castells, Livia Giordano, Sue Warman, Zuleika Saz-Parkinson
Journal: Annals of Internal Medicine (2019)

Neither breast cancer prevention and early-detection programs, nor their outcomes, are uniform across Europe. This article describes the rationale, methods, and process for development of the European Commission (EC) Initiative on Breast Cancer Screening and Diagnosis Guidelines. To be consistent with standards set by the Institute of Medicine and others, the EC followed 6 general principles. First, the EC selected, via an open call, a panel with broad representation of areas of expertise. Second, it ensured that all recommendations were supported by systematic reviews. Third, the EC separately considered important subgroups of women, included patient advocates in the guidelines development group, and focused on good communication to inform women's decisions. Fourth, EC rules on conflicts of interest were followed and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision frameworks were used to structure the process and minimize the influence of competing interests. Fifth, it focused its recommendations on outcomes that matter to women, and certainty of the evidence is rated for each. Sixth, the EC elicited stakeholder feedback to ensure that the recommendations remain up to date and relevant to practice. This article describes the approach and highlights ways of disseminating and adapting the recommendations both within and outside Europe, using innovative information technology tools.
Immunogenicity of NY-ESO-1 cancer testis antigen in triple-negative breast cancer.
Authors: Foluso Olabisi Ademuyiwa, Wiam Bshara, Kristopher Attwood, Stephen B Edge, Christine B. Ambrosone, Carl D Morrison, Gerd Ritter, Anthony Miliotto, Sacha Gnjatic, Kunle Odunsi
Journal: Journal of Clinical Oncology (2012)

e11563 Background: NY-ESO-1 cancer testis (CT) antigen is an attractive candidate for immunotherapy as a result of its high immunogenicity. The aim of this study was to explore the potential for NY-ESO-1 antigen directed immunotherapy in triple negative breast cancer (TNBC) by determining the frequency of expression by immunohistochemistry (IHC) and the degree of inherent immunogenicity to NY-ESO-1. Methods: 168 TNBC and 47 ER+/HER2- primary breast cancer specimens were used to determine NY-ESO-1 frequency by IHC. As previous studies have shown that patients with a robust innate humoral immune response to CT antigens are more likely to develop CD8 T-cell responses to NY-ESO-1 peptides, we evaluated the degree to which patients with NY-ESO-1 expression had inherent immunogenicity by measuring antibodies. The relationship between NY-ESO-1 expression and CD8+ T lymphocytes was also examined. Results: The frequency of NY-ESO-1 expression in the TNBC cohort was 16% versus 2% in ER+/HER2- patients. A higher NY-ESO-1 score was associated with a younger age at diagnosis in the TNBC patients with NY-ESO-1 expression (p= 0.026). No differences in OS (p=0.278) or PFS (p=0.238) by NY-ESO-1 expression status were detected. Antibody responses to NY-ESO-1 were found in 73% of TNBC patients whose tumors were NY-ESO-1 positive. NY-ESO-1 positive patients had higher CD8 counts than negative patients (p=0.018). Conclusions: NY-ESO-1 is expressed in a substantial subset of TNBC patients and leads to a high humoral immune response in a large proportion of these individuals. Given these observations, patients with TNBC may benefit from targeted therapies directed against NY-ESO-1.
Abstract 10989: Diagnostic Impact Of Electrocardiogram And Emergency Coronary Angiography In Patients With Out-of-hospital-cardiac-arrest
Authors: Kazuya Tateishi, Daisuke Abe, Toru Iwama, Tatsuro Sassa, Kouichi Oohashi, Kazuki Miyazaki, Masakazu Kaneko, Tomohiko Harunari, Yashiaki Yui, Norihiro Kuroki, Takao Yuba, Ko Suzuki, Yuuichi Hamabe
Journal: Circulation (2015)

Objective: The guideline suggests that coronary angiography (CAG) should be performed for the patients with out-of-hospital-cardiac-arrest (OHCA) and return of spontaneous cardiac arrest (ROSC). We investigated the association between initial ST-segment change after ROSC and incidence of acute coronary lesion in patients with OHCA. We also researched the number of patients with OHCA caused by vasospastic angina pectoris (VSA). Methods: From April 2011 to March 2015, there were 2,779 OHCA patients in our institution. We underwent CAG for all patients with ROSC, except for obvious extra-cardiac cause of OHCA. Initial ST-segment change after ROSC of serial 155 patients(61±14.5years old,83.9% male) was reviewed. Results: The 34% of patients had ST-segment elevation and the 66% had other electrocardiogram (ECG) pattern. Significant coronary lesion which needs percutaneous coronary intervention (PCI) was shown in the 81% of patients with ST-segment elevation and in 33% with other ECG (P&lt;0.001). ST-segment analysis had a good positive predictive value (81%) but a low negative value (68%) in diagnosing the presence of acute coronary lesions. The patients who were diagnosed vasospastic angina were found in the 10% of patients with ST-segment elevation and in the 12% with other ECG. Conclusion: Even in the absence of ST-segment elevation, acute culprit coronary lesion may be present, and there is significant value to perform emergency CAG for ROSC patients. Furthermore, vasospastic angina pectoris may be present and considered the trigger of cardiac arrest. Emergency CAG could remove the coronary artery spasm by directly NO injection.