tbuckley/cabot-search huggingface dataset:
The Effects of Public Access Defibrillation on Survival After Out-of-Hospital Cardiac Arrest
Authors: Josefine S. Bækgaard, Søren Viereck, Thea Palsgaard Møller, Annette Kjær Ersbøll, Freddy Lippert, Fredrik Folke
Journal: Circulation (2017)

Despite recent advances, the average survival after out-of-hospital cardiac arrest (OHCA) remains <10%. Early defibrillation by an automated external defibrillator is the most important intervention for patients with OHCA, showing survival proportions >50%. Accordingly, placement of automated external defibrillators in the community as part of a public access defibrillation program (PAD) is recommended by international guidelines. However, different strategies have been proposed on how exactly to increase and make use of publicly available automated external defibrillators. This systematic review aimed to evaluate the effect of PAD and the different PAD strategies on survival after OHCA.PubMed, Embase, and the Cochrane Library were systematically searched on August 31, 2015 for observational studies reporting survival to hospital discharge in OHCA patients where an automated external defibrillator had been used by nonemergency medical services. PAD was divided into 3 groups according to who applied the defibrillator: nondispatched lay first responders, professional first responders (firefighters/police) dispatched by the Emergency Medical Dispatch Center (EMDC), or lay first responders dispatched by the EMDC.A total of 41 studies were included; 18 reported PAD by nondispatched lay first responders, 20 reported PAD by EMDC-dispatched professional first responders (firefighters/police), and 3 reported both. We identified no qualified studies reporting survival after PAD by EMDC-dispatched lay first responders. The overall survival to hospital discharge after OHCA treated with PAD showed a median survival of 40.0% (range, 9.1-83.3). Defibrillation by nondispatched lay first responders was associated with the highest survival with a median survival of 53.0% (range, 26.0-72.0), whereas defibrillation by EMDC-dispatched professional first responders (firefighters/police) was associated with a median survival of 28.6% (range, 9.0-76.0). A meta-analysis of the different survival outcomes could not be performed because of the large heterogeneity of the included studies.This systematic review showed a median overall survival of 40% for patients with OHCA treated by PAD. Defibrillation by nondispatched lay first responders was found to correlate with the highest impact on survival in comparison with EMDC-dispatched professional first responders. PAD by EMDC-dispatched lay first responders could be a promising strategy, but evidence is lacking.
Results of the randomized Intergroup trial Inter-B-NHL Ritux 2010 for children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and mature acute leukemia (B-AL): Evaluation of rituximab (R) efficacy in addition to standard LMB chemotherapy (CT) regimen.
Authors: Veronique Minard-Colin, Anne Auperin, Marta Pillon, Amos Burke, James Robert Anderson, Donald A. Barkauskas, Keith Wheatley, Rafael Delgado, Sarah Alexander, Anne Uyttebroeck, Catherine Bollard, Jozsef Zsiros, Monika Csoka, Gisele Goma, Anne Tulard, Catherine Patte, Thomas G. Gross
Journal: Journal of Clinical Oncology (2016)

10507 Background: R with CT improves survival of adult B-cell malignancies. Beyond pilot studies, no randomized trial evaluated efficacy and safety of R added to CT in childhood B-NHL/AL. Methods: The international randomized phase III trial sponsored by Gustave Roussy and COG compared the standard LMB CT to the same CT+R in pts < 18 years with high risk B-NHL (stage III with LDH level > 2N, stage IV) and B-AL. R was given (375 mg/m²) on days -2 and 1 during the first 2 CT courses and on day 1 of the 2 following courses (total 6 infusions). The randomization was stratified on national group, histology and therapeutic group (B: Stage III or IV, central nervous system (CNS) neg; C1: Stage IV/B-AL cerebrospinal fluid (CSF) neg; C3: CSF pos). The primary endpoint was event free survival (EFS). To detect a hazard ratio (HR) of 0.50 (increase in 3-year EFS from 84% to 92%), 72 events were required to achieve 90% power at one-sided significance level of 0.05. 600 pts were planned to enroll. Interim analyses using Lan-DeMets alpha-spending function with O’Brien-Fleming boundary were planned after ~33% of events and yearly thereafter. Results: The first interim analysis was done in Aug 2015 and based on 27 events (37.5% information) occurring in 310 pts (155/arm) randomized since Dec 2011. 85% had Burkitt lymphoma. 51% were in group B, 39% in C1 and 10% in C3. With a median follow-up of 11.5 months, pts on the R arm achieved better EFS than those on the control arm: 1-year EFS (95%CI) was 94.2% (88.5-97.2) vs. 81.5% (73.0-87.8). The HR was 0.33 (90%CI: 0.16-0.69), one-sided p-value = 0.006. This p-value was higher than the nominal alpha (0.0014) of this first interim analysis. However, the conditional power analysis demonstrated high likelihood of getting a positive study in later interim/final analyses (from 100% to 87% for HR = 0.33 to 0.75). Thus, the randomization was stopped in Nov 2015 following the recommendations of the Independent Data Monitoring Committee. Conclusions: Rituximab in addition to standard LMB therapy improves EFS of children/adolescents with high risk B-NHL and B-AL. Clinical trial information: NCT01516580.
CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis
Authors: Ahmet Ozen, William A. Comrie, Rico C. Ardy, Cecilia Domínguez Conde, Buket Dalgic, Ömer F. Beser, Aaron R. Morawski, Elif Karakoc-Aydiner, Engin Tutar, Safa Baris, Figen Ozcay, Nina K. Serwas, Yu Zhang, Helen F. Matthews, Stefania Pittaluga, Les R. Folio, Aysel Unlusoy Aksu, Joshua J. McElwee, Ana Krolo, Ayca Kiykim, Zeren Baris, Meltem Gulsan, Ismail Ogulur, Scott B. Snapper, Roderick H.J. Houwen, Helen L. Leavis, Deniz Ertem, Renate Kain, Sinan Sari, Tülay Erkan, Helen C. Su, Kaan Boztug, Michael J. Lenardo
Journal: New England Journal of Medicine (2017)

Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies.
Detection of single nucleotide polymorphism in the PDCD5 gene in Japanese non-small cell lung cancer patients.
Authors: Shinichi Toyooka, Kei Nanba, Hiromasa Yamamoto, Naruyuki Kobayashi, Keitaro Matsuo, Kenji Shimizu, Hiroshi Date
Journal: Cancer Research (2008)

1904   The rs1862214 single nucleotide polymorphism (SNP) in  Programmed cell death 5 (PDCD5)  gene has been reported to be associated with lung cancer risk and prognosis in smokers in the study conducted in Europe (Spinola et al JCO 2006). According to Spinola et al, the patients with genotypes GG or CG for  PDCD5  showed an increased risk of lung cancer, a higher incidence of poor clinical stage disease and short term survivorship compared to those with the common genotype CC. We examined rs1862214 SNP in  PDCD5  in Japanese cases to examine the impact of SNP in PDCD5 in Japanese population. Genotyping was performed for 117 cases of volunteer with smoking history and 90 cases of lung cancer patients with smoking history. For this purpose, we developed a real time PCR based melting curve analysis for genotyping and determined rs1862214 SNP distribution in Japanese lung cancer patients. The frequencies of the CC, CG and GG genotype in 117 volunteer with smoking history from Japan were 24, 52 and 41, respectively. Those in 90 lung cancer patients were 12, 43, and 35, respectively. There was no significant difference between volunteer and lung cancer patients in this cohort. In addition, no difference in patient prognosis was found among the different genotype in rs1862214 in our small sample size of Japanese patients. Regarding the ethnic difference, based on the published data (Spinola et al JCO 2006), there was significant difference in distribution of the genotype of rs1862214 ( P  PDCD5  gene. Our result along with the previous report suggests the ethnic difference in rs1862214 SNP. Whereas no difference in patient prognosis was found among the different genotype in rs1862214 in our small sample size of Japanese patients, further investigation is warranted for East-Asian and various ethnic groups.
Response of breast cancer cell lines to aminoflavone (NSC 686288) is associated with histone H2AX phosphorylation and estrogen receptor expression
Authors: Melinda K. Wilson, Erica Stone, Michele Vitolo, Kurt Bachman, Brian Leyland-Jones, Angelika M. Burger, Edward A. Sausville
Journal: Cancer Research (2006)

555  Aminoflavone (AF; 5-amino-2,3-fluorophenyl)-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one; NSC 686288) is a novel anticancer agent which has entered early clinical trials sponsored by the US-National Cancer Institute. AF has shown exquisite sensitivity toward a limited number of human tumor cell lines including lung, ovarian, renal, and breast carcinomas. AF is a ligand of the aryl hydrocarbon receptor (AhR). Its activity has been linked to the presence of cytoplasmic AhR, translocation of the AhR:AF complex to the nucleus followed by induction of cytochrome P450 (CYP) 1A1 and DNA damage caused by metabolites. The latter is exemplified by the occurrence of gamma-histone 2AX (H2AX) phosphorylation consistent with induction of DNA single-strand breaks and DNA-protein cross-links. In this study, we examined determinants of AF response in a panel of molecularly well defined breast cell lines, they include: MCF-7 (estrogen receptor positive, ER+), T47D (ER+), MCF-7/HER2-18 (ER+), MDA-MB-231 (ER-), and MCF10A (ER-). Antiproliferative effects were measured by MTT assay, and concentrations that inhibit cell growth to 50 % of control (IC50) were established for each cell line. The response to AF was compared to ER status, AhR localization, and gamma-H2AX foci formation in a time and concentration dependent manner by dual immunofluorescence labeling. We found that AF potently inhibited the growth of ER+ breast cancer cell lines at nanomolar concentrations (mean IC50s: MCF-7 = 18 nM; MCF-7/HER2-18 = 20 nM; T47D = 14 nM), whereas the ER- breast cancer cell line MDA-MB-231 (IC50 = 25 μM) and the immortalized ER- breast cell line MCF10A (IC50 = 3 μM) were several log-fold less sensitive. In cell lines that were exquisitely sensitive to AF, AhR expression was found to be more cytoplasmic than nuclear. In contrast, the cell lines resistant to AF showed a predominantly nuclear AhR localization. Gamma-H2AX foci occurred between 6 to 24 hours only in AF responsive ER+ breast cancer cells treated at their respective IC50s, but not in the ER- cell lines. Interestingly, MCF-7/HER2-18 (IC50 = 20 nM, IC100 = 375 nM), which is a HER2/neu receptor overexpressing Herceptin and tamoxifen resistant subclone of MCF-7 (IC50 4-OH-tamoxifen >1μM), retained its sensitivity to AF if compared to the parental MCF-7 cells (IC50 = 18 nM, IC100 = 300 nM). These observations suggest that AF, unlike other antineoplastic agents, requires a specific activation to cause DNA damage and that AhR and its cross talk with ER are determinates of this specific response. AF activity in Herceptin and tamoxifen resistant MCF-7 cells indicates that AF might provide a new treatment strategy for hormone-refractory ER positive breast cancers and that this hypothesis should be tested in a larger sample cohort and in vivo models.
Long-term results on trastuzumab (T) in elderly patients (EP) with locally advanced or metastatic HER2-positive breast cancer (BC).
Authors: Christian Jackisch, Winfried Schoenegg, Dietmar Arno Reichert, Manfred Welslau, Johannes Selbach, Hanns-Detlev Harich, Hans Tesch, Tim Wohlfarth, Heidi Eustermann, Axel Hinke
Journal: Journal of Clinical Oncology (2014)

624 Background: In a prospective, non-interventional observation study, routine T treatment in advanced, HER2-positive BC was evaluated in a total of 1,843 patients (pts) enrolled between 2001 and 2010. With a follow-up duration of up to more than 11 years (y), this report focuses on the relatively large subgroup of EP (> 65 y). Methods: Pts were enrolled by 223 institutions in Germany. HER2-positivity was defined as 3+ staining in immunohistochemistry or a positive fluorescence in situ hybridization (FISH) test in case of 2+ staining. All types of pretreatments were acceptable. Detailed information on study treatment, its safety and the course of disease was collected for at least 1 y. Thereafter, long-term outcome data were additionally retrieved at specified follow-up time points. Results: The median age of the total observation group was 59.5 y (range: 21–95), with 505 pts being > 65 y (28%), 257 pts > 70 y (14%), and 58 pts even 80 y or older (3%). The percentage of EP constantly increased over the 10 y recruitment period. In EP, the proportion receiving T in combination with chemotherapy was 69% compared to 74% in younger pts (YP). Correspondingly, EP more often received T in combination with endocrine therapy only (19% vs 13%). With 11%, T monotherapy was not given more frequently in EP, but this proportion increased clearly in the cohorts > 70 y (14%) and ≥ 80 y (29%). Univariately, progression-free survival was almost identical for EP and YP (medians: 11.4 vs 10.7 months; p=0.99). Overall survival (OS) was shorter in EP with borderline significance (28.4 vs. 33.4 months; p=0.072). In multivariate analysis of OS, higher age retained its significance (HR=1.23; p= 0.022). Cardiac toxicity incidence was 2.3% overall (all grades; no grade 4 event), but distinctly higher in EP (4.2% vs 1.5%). Conclusions: To the best of our knowledge, our database comprises the largest population of EP with information on the longest follow-up period reported on T treatment in this disease setting. The antineoplastic efficacy of T seems to be independent of age, while the multivariately independent moderate impact of age on OS simply appears to reflect the higher background mortality of the older population.
CMV Viremia and African-American Ethnicity Are Risk Factors for Post-Engraftment Blood Stream Infections in Pediatric Allogeneic Blood and Marrow Transplantation
Authors: Hirozumi Sano, Joseph Hilinski, Kristy Applegate, Andres Camacho-Gonzalez, Shanmuganathan Chandrakasan, Kuang-Yueh Chiang, Ann Haight, Lakshmanan Krishnamurti, Elizabeth Stenger, Muna Qayed, John Horan
Journal: Blood (2016)
OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis): A prospective trial to validate the predictive utility and cost-effectiveness of gene expression test-directed chemotherapy decisions.
Authors: Andreas Makris, Luke Hughes-Davies, Iain R. MacPherson, Andrea Marshall, Amy F. Campbell, John Bartlett, Peter Hall, David A. Cameron, Leila Rooshenas, Daniel Rea, Helena Margaret Earl, Christopher John Poole, Adele Francis, Adrienne Morgan, Sarah Pinder, Claire Hulme, Victoria Harmer, Christopher McCabe, Janet Dunn, Robert C. Stein
Journal: Journal of Clinical Oncology (2016)

TPS623 Background: Multi-parameter gene expression assays (MPAs) are widely used to estimate individual patient residual risk and guide chemotherapy use in hormone sensitive HER2-ve early breast cancer, but prospective validation data are not available. OPTIMA aims to validate the use of MPA testing to predict chemotherapy sensitivity in a largely node-positive breast cancer population. Methods: OPTIMA is a partially blinded multi-center, phase 3 RCT with an adaptive two-stage design. The preliminary phase (OPTIMA prelim) evaluated the performance of MPAs to identify a suitable test to be used in the main efficacy trial, and demonstrated the feasibility and acceptability of a large UK trial. Eligible patients (pts) are men or women aged ≥ 40 years who have surgically resected early stage ER+ve and HER2-ve breast cancer, and have either 1-9 involved axillary lymph nodes or tumors of ≥ 30mm diameter. Randomization is to standard management (chemotherapy followed by endocrine therapy) or to MPA-directed therapy. Those with a tumor categorized as “high-risk” by the test will be assigned to standard management whilst those at “low-risk” will be treated with endocrine therapy alone. OPTIMA prelim used Oncotype DX as the primary discriminator; the main trial will use Prosigna (PAM50). The co-primary outcomes are Invasive Disease Free Survival (IDFS) and cost-effectiveness. Secondary outcomes include IDFS in “low-risk” pts, distant disease free survival, breast cancer specific survival, overall survival and quality of life. Tumor blocks from all consenting pts will be banked to allow the evaluation of alternative MPAs. Recruitment of 4500 pts over 4 years will permit demonstration of 3% non-inferiority of test-directed therapy, with 5% significance and 85% power, assuming 3 years follow-up and a control arm 5-year IDFS of ≥ 85%. The addition of the 412 pts from OPTIMA prelim will allow assessment of non-inferiority with 2.5% significance. Funding: Project funded by NIHR HTA Programme (10/34/501). Views expressed are those of the authors and not those of the HTA Programme, NIHR, NHS or the DoH. Clinical trial information: 42400492.
Lack of growth inhibitory synergism with combined MAPK/PI3K inhibition in preclinical models of pancreatic cancer
Authors: L. Ciuffreda, A. Del Curatolo, I. Falcone, F. Conciatori, C. Bazzichetto, F. Cognetti, V. Corbo, A. Scarpa, M. Milella
Journal: Annals of Oncology (2017)
Perspective of the FIRST Trial Investigators on Accreditation Council for Graduate Medical Education Changes in Resident Work Environment and Duty Hours
Authors: Karl Y. Bilimoria, David B. Hoyt, Frank Lewis
Journal: JAMA Surgery (2017)

This Viewpoint discusses the Accreditation Council for Graduate Medical Education changes in resident duty hour requirements from the perspective of the Flexibility In Duty Hour Requirements for Surgical Trainees trial investigators.
Impact of Human Leukocyte Antigen (HLA) Alleles on Outcomes of Allogeneic Transplantation (Allo-HCT) for B-Cell Non-Hodgkin Lymphomas (B-NHL); A CIBMTR Analysis
Authors: Basem M William, Tao Wang, Michael D Haagenson, Marcos J de Lima, Marcelo Anibal Fernandez-Vina, Spellman Stephen, Stephanie J. Lee, Brian T. Hill
Journal: Blood (2016)
Ovarian metastasectomy in colorectal cancer may improve the clinical outcomes of patients with metastatic colorectal cancer regardless of BRAF or KRAS mutational profiles
Authors: Yoshiko Mori, Takeshi Nagasaka, Hiroaki Tanioka, Akihiro Nyuya, Takashi Kawai, Toshiaki Toshima, Kazuya Yasui, Kunitoshi Shigeyasu, Hiroyuki Kishimoto, Yuzo Umeda, Toshiyoshi Fujiwara
Journal: Annals of Oncology (2017)
Modelling FVIII Levels for Prediction of Zero Spontaneous-Joint Bleeding in a Cohort of Severe Hemophilia a Subjects with Target Joints Initiated on Tertiary Prophylaxis
Authors: Kathelijn Fischer, Pratima Chowdary, Peter Collins, Amy Cotterill, Barbara Konkle, Victor S. Blanchette, Steven W. Pipe, Martin Wolfsegger, Werner Engl, Jimena V Goldstine, Leonard A. Valentino, Gerald Spotts
Journal: Blood (2016)
Abstract 104: Protein Kinase GIα Functions in the Cardiac Myocyte as a Tonic Inhibitor of Pathologic Cardiac Hypertrophy In Vivo
Authors: Robert M Blanton, James P Mendoza, Mark Aronovitz, David A Kass, Michael E Mendelsohn, Richard H Karas
Journal: Circulation Research (2012)

Objectives: We and others previously demonstrated that activation of the NO-cGMP-Protein Kinase G (PKG) pathway inhibits cardiac hypertrophy and remodeling in vivo. However, it remains untested whether PKG specifically in the cardiac myocyte (CM) mediates these effects. We therefore tested the hypothesis that PKGIα inhibits pathologic cardiac hypertrophy through a specific role in the CM. Methods and Results: We created and characterized mice with CM-restricted excision of PKGIα. Mice were generated in which the PKGI exon 1 (specific for the Iα isoform) was flanked by loxP sites. We crossed these PKGIα fl/fl mice with αMHC-Cre mice which constitutively express Cre recombinase selectively in the CM. The resultant PKGIα fl/fl / αMHC-Cre+/- mice were compared with PKGIα fl/fl / αMHC-Cre-/- littermate controls (termed PKG CMKO and Ctrl, respectively). By age 3 months (n=5 per genotype), male PKG CMKO mice developed atrial and LV hypertrophy compared with Ctrl littermates PKG CMKO atrial weight/tibia length 0.33 ± 0.03 mg/mm vs 0.22 ± .01 in Ctrl, P &lt;0.05; PKG CMKO LV/TL 5.0 ± 0.2 mg/mm vs 4.1 ± 0.4 in Ctrl, P &lt;0.05). LV CM cross sectional area also increased in the 3 month old PKG CMKO mice (9445 ± 282 pixels PKG CMKO vs 8273 ± 213 in Ctrl, n&gt;400 cells/genotype, 5 hearts per genotype; P &lt;0.001). The systolic index end systolic elastance was decreased in 3 month old PKG CMKO mice (PKG CMKO 3.1 ± 0.4 mmHg/μ l vs 6.1 ± 1.0 in Ctrl-; P &lt;0.05). Importantly, blood pressure did not differ between genotypes. By age 6 months, PKG CMKO mice developed early mortality (3 of 4 PKG CMKO males died at 6 months of age vs 0 of 4 Ctrl males). Total heart and atrial weights of male mice (n=3 PKG CMKO , 4 Ctrl) increased in PKG CMKO mice (heart weight/tibia length 10.8 ± 1.7 mg/mm in PKG CMKO vs 7.1 ± 0.6 in Ctrl; P &lt;0.05; atrial weight/tibia length 2.3 ± 1.1 mg/mm in PKG CMKO vs 0.30 ± 0.1 Ctrl, P &lt;0.05). LV fractional shortening percentage, recorded at 6 months age, trended lower in the PKG CMKO mice as well (35 ± 3% PKG CMKO vs 44 ± 4% Ctrl, P 0.09). Conclusions: These data provide the first evidence that PKGIα functions in the CM as a tonic inhibitor of age-dependent pathologic hypertrophy, supporting further study of PKGIα as a therapeutic target in the prevention and treatment of LV remodeling and congestive heart failure.
A new tool for rapid and reliable diagnosis of HLA loss relapses after HSCT
Authors: Müberra Ahci, Cristina Toffalori, Evelien Bouwmans, Pietro Crivello, Chiara Brambati, Cinzia Pultrone, Karin Stempelmann, Douglas Bost, Benedetta Mazzi, Dietrich W. Beelen, Fabio Ciceri, Wietse Mulder, Katharina Fleischhauer, Luca Vago
Journal: Blood (2017)
Use of Array Comparative Genomic Hybridisation to Differentiate between Metastatic and Non-Metastatic Colorectal Cancer
Authors: A Coss, E Fox, A Lloyd, S Sullivan, D O'Donoghue, J Hyland, K Sheahan, J O'Sullivan, H Mulcahy, D Leahy
Journal: Endoscopy (2006)

Background: Chromosomal instability is a key pathway involved in colorectal cancer (CRC) progression. However, little is known about how patterns of this instability may vary according to tumour stage and survival. Array comparative genomic hybridisation (array CGH) is a highly sensitive method of detecting changes in chromosomal DNA copy number across the human genome.
Successful endoscopic suturing of esophageal perforation after surgical suturing failure
Authors: Roberta Maselli, Edi Viale, Lorella Fanti, Pier Testoni
Journal: Endoscopy (2017)

Esophageal perforations still present a life-threatening situation. Although stent insertion and clips have a proven high success rate, some perforations are extremely challenging and persist despite several attempts using different closure techniques. Recently a new endoscopic suturing system (OverStitch; Apollo Endosurgery Inc., Austin, Texas, USA) has been introduced for full-thickness tissue approximation. We report two cases of successful suturing of an esophageal perforation using the OverStitch device, after the failure of surgical suturing.