tbuckley/cabot-search huggingface dataset:
Small cell lung cancer: The immune microenvironment and prognostic impact of checkpoint expression.
Authors: Gareth Rivalland, Marzena Walkiewicz, Gavin Michael Wright, Thomas John
Journal: Journal of Clinical Oncology (2017)

8569 Background: To date, immunotherapy has had limited success in small cell lung cancer (SCLC), despite the tumor’s high mutation load. Little is understood of the immune tumor microenvironment in SCLC due to a paucity of resected tumor. We present a SCLC cohort and describe the prognostic impact of checkpoint expression. Methods: SCLC tissue microarrays with triplicate cores from 105 SCLC specimens underwent IHC assessment for PD-L1, PD-L2, LAG3, TIM3, FoxP3, CD4 and CD8 on tumor and/or tumor infiltrating lymphocytes (TILs). Checkpoint positivity was defined &gt; 5% tumor expression or TIL expression in &gt; 5% of the total core area. Associations with clinicopathologic characteristics and survival were assessed. A Cox model was used for univariate and multivariate survival analysis. Results: Tumor expression of PD-L1 was positive (+) in 17/95 (18%), PD-L2+ in 2/96 (2%), and TIM3+ or LAG3+ in no cases. TILs expressed PD-L1+ in 64/95 (67%), PD-L2+ in 22/96 (22%), TIM3+ in 57/96 (59%) and LAG3+ in 43/96 (45%). FoxP3+ lymphocytes were found in all samples (range 0.02 – 2.98% of total core). TIL expression of PD-L1, PD-L2, TIM3 and LAG3 were all significantly correlated (p value ≤0.001 for all comparisons), and were associated with high FoxP3+ expression. All four checkpoints were expressed on TILs in 20/105 (19%) patients. PD-L1+ and PD-L2+, but not TIM3 or LAG3, on TILs were significantly higher in limited stage compared with extensive stage SCLC (76% v 52%, p 0.045 and 28% v 7%, p 0.02 respectively). There was no association between stage and tumor expression. TIL expression of PD-L1, PD-L2, TIM3 and LAG3 were all associated with improved prognosis. PD-L1+ median OS: 17.2 v 7.9 months (HR 0.36; 95%CI 0.22 – 0.6; p &lt; 0.001). Univariate analysis showed stage and TIL expression of PD-L1, PD-L2, TIM3 and LAG3 were associated with improved survival, but only stage and PD-L1+ TILs remained significant on multivariate analysis (p &lt; 0.01). Conclusions: Immune checkpoint molecules are frequently expressed in SCLC-associated TILs, but not the tumor itself. TIL expression of checkpoint molecules is associated with improved survival. Limited tumor expression of PD-L1 and an exhausted immune cell phenotype may contribute to immunotherapy failure.
Incidence and risk of pneumonitis associated with nivolumab and pembrolizumab in patients with cancer: A meta-analysis of clinical trials.
Authors: Ling Peng, Qiong Zhao, Xianghua Ye, Yina Wang, Haibo Mou
Journal: Journal of Clinical Oncology (2016)

e21651 Background: Anti PD-1 antibodies, nivolumab or pembrolizumab, have been approved for the treatment of a variety of malignant tumors including melanoma and non-small cell lung cancer (NSCLC). Pneumonitis has been described as a major adverse effect related with these agents, although the overall incidence and risk remain unclear. We performed a meta-analysis to characterize the overall incidence and risk of pneumonitis in cancer patients treated with these agents and to describe the relative risk compared with control. Methods: The electronic databases PubMed, Embase, Web of Science, Cochrane databases, and ASCO (American Society of Clinical Oncology) abstracts were searched for studies to include in the meta-analysis. Eligible studies were prospective phase II and III clinical trials of nivolumab or pembrolizumab with adequate safety data. Summary incidences, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed or random effect models depending on the heterogeneity of the included studies. Results: A total of 5005 patients with a variety of malignant tumors from 15 prospective clinical trials were included for the meta-analysis. The overall incidence of all-grade and high-grade pneumonitis due to anti PD-1 antibodies was 2.9% (95% CI: 2.4 – 3.6%) and 1.8% (95% CI: 1.6 – 2.1%), respectively. Compared with control, the RR of pneumonitis of anti PD-1 antibodies was increased for all-grade (RR = 3.42, 95% CI: 1.83 – 6.43, P < 0.001) but not high-grade (RR = 2.21, 95% CI: 0.87 – 5.62, P= 0.10) pneumonitis, respectively. The incidence of all-grade and high-grade pneumonitis in the nivolumab group was comparable to the pembrolizumab group. Subgroup analysis showed the incidence of all-grade and high-grade pneumotitis in non-melanoma patients was higher than melanoma patients. Conclusions: Treatment with anti PD-1 antibodies, nivolumab and pembrolizumab is associated with a significant increase in the all-grade risk of pneumonitis in patients with malignant tumors. Close monitoring for pneumonitis is critical for patients during their treatment with anti PD-1 antibodies.
Improved Survival for MDS/CMML Patients Treated with the Combination of Decitabine (DAC) and Arsenic Trioxide (ATO) in a Phase II Adaptive Three Arm Randomization Study: DAC Alone Vs. DAC +/- Carboplatin or ATO
Authors: Patricia L. Kropf, Raji Shameem, Philip A. Pancari, Henry Fung, Lianchun Xiao, Xuelin Huang, Woonbok Chung, Hagop M. Kantarjian, Jean-Pierre J. Issa
Journal: Blood (2016)
MAN-MADE JUMPS IN TERRAIN-PARKS AND THE RISK OF SEVERE SKI-PATROL REPORTED INJURIES IN ALPINE SKIERS AND SNOWBOARDERS
Authors: Claude Goulet, Denis Hamel, Benoit Tremblay, Olivier Audet, Brent E. Hagel
Journal: British Journal of Sports Medicine (2017)

Background Two ski areas in Québec, Canada, removed man-made jumps from their terrain parks (TPs) from seasons 2007–08 to 2009–10. Jumps were reintroduced starting in season 2010–11. Objective To determine if man-made jumps in TPs are associated with severe alpine ski and snowboard injuries. Design Retrospective study using ski-patrol Injury Report Forms (IRFs). Setting All ski areas with a TP in Québec. Patients (or Participants) Skiers and snowboarders who reported to the ski patrol with a TP injury during seasons 2000–01 to 2014–15, at all Québec ski areas with TP (two where jumps were removed, and others without jump removal). Interventions (or Assessment of Risk Factors) Risk factor data and injury outcomes were collected through IRFs. Main Outcome Measurements Severe injuries were defined based on type of injury or ambulance evacuation. The proportions of severe injuries before jump removal (2000–01 to 2006–07) and during jump reintroduction (2010–11 to 2014–15) were compared with proportions during jump removal (2007–08 to 2009–10). Logistic regression analysis was used to adjust the comparisons for age, sex, skill level, helmet use, and type of activity. Generalized Estimating Equations were used to account for potential ski area clustering of outcomes. Results At the hills that removed jumps (4,006 IRFs analysed), the crude proportion of severe TP injuries was 19.3% before removal, 14.5% during removal, and 24.3% at reintroduction. The odds of severe injury were higher before removal (adjusted odds ratio [AOR]: 1.39; 95% CI: 1.03–1.87) and during reintroduction (AOR: 1.90; 95% CI: 1.52–2.37). At other hills over the same time period (21,449 IRFs), there was no change before (23.7%) and during (22.0%) jump removal (AOR: 1.07; 95% CI: 0.94–1.21), but the proportion of severe injuries increased after reintroduction (26.4%; AOR: 1.26; 95% CI: 1.10–1.43). Conclusions Results suggest that removing man-made jumps from TPs may prevent severe injuries.
Role of Stromelysin 2 (Matrix Metalloproteinase 10) as a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated With Systemic Sclerosis
Authors: Jérôme Avouac, Christophe Guignabert, Anna Maria Hoffmann‐Vold, Barbara Ruiz, Peter Dorfmuller, Sonia Pezet, Olivia Amar, Ly Tu, Jérôme Van Wassenhove, Jérémy Sadoine, David Launay, Muriel Elhai, Anne Cauvet, Arun Subramaniam, Robert Resnick, Eric Hachulla, Øyvind Molberg, André Kahan, Marc Humbert, Yannick Allanore
Journal: Arthritis & Rheumatology (2017)

Objective To elucidate the role of gene candidates involved in pulmonary hypertension ( PH ) associated with systemic sclerosis ( SS c). Methods Gene candidates were identified through microarray experiments performed on Affymetrix GeneChip Human Exon 1.0 ST arrays in endothelial progenitor cell ( EPC )–derived endothelial cells ( EC s) obtained from patients with SS c‐associated PH , patients with SS c without PH , and healthy control subjects. Expression of identified gene candidates was assessed by quantitative sandwich enzyme‐linked immunosorbent assay in the serum, and by immunohistochemistry in lesional lung tissue. The functional importance of the identified gene candidates was then evaluated in fos ‐related antigen 2–transgenic (Fra‐2–Tg) mice that spontaneously develop SS c‐like features associated with an intense pulmonary vascular remodeling. Results Microarray experiments revealed that the matrix metalloproteinase 10 ( MMP ‐10) gene was the top up‐regulated gene in SS c‐associated PH EPC ‐derived EC s. Circulating serum pro MMP 10 concentrations were markedly increased in patients with SS c‐associated PH compared to SS c patients without PH and healthy controls. Consistent with these observations, a strong MMP 10 staining of the thickened wall of distal pulmonary arteries was found both in the lungs of patients with SS c‐associated PH and in the lungs of Fra‐2–Tg mice. Daily treatment of Fra‐2–Tg mice with neutralizing anti‐ MMP 10 antibodies did not significantly affect the development and severity of pulmonary fibrosis, but did reverse established PH and markedly reduced pulmonary vascular remodeling by reducing cell proliferation, cell survival, and the platelet‐derived growth factor signaling axis. Conclusion Gene expression profiling of EPC ‐derived EC s identified MMP 10 as a novel candidate gene in SS c‐associated PH . MMP 10 is overexpressed in the serum and pulmonary arteries of patients with SS c‐associated PH , and its blockade alleviates PH in the Fra‐2–Tg mouse model. MMP 10 appears to be a prospective treatment target for this devastating disorder.
Traceable PEO-poly(ester) micelles for breast cancer targeting: The effect of core structure and targeting peptide on micellar tumor accumulation
Authors: Shyam M. Garg, Igor M. Paiva, Mohammad R. Vakili, Rania Soudy, Kate Agopsowicz, Amir H. Soleimani, Mary Hitt, Kamaljit Kaur, Afsaneh Lavasanifar
Journal: Biomaterials (2017)
Abstract 444: Probiotic Administration Mitigates the Detrimental Effects of Myocardial Infarction in Mice
Authors: John Konhilas
Journal: Circulation Research (2016)

Advances in sequencing and bioinformatics technologies have allowed unprecedented characterization of the gut microbiome. As a result, there is a growing appreciation that our microbial environment plays a critical role in the maintenance of health and the pathogenesis of disease. Accordingly, recent evidence suggests a role for gut microbiota in modulating cardiovascular disease and cardiac injury. We hypothesized that administration of the probiotic, Bifidobacterium animalis subsp. lactis 420 (B420), to mice will mitigate the pathological impact of ischemic heart disease (IHD), and that anti-inflammatory T regulatory (T reg ) immune cells are necessary to impart protection against IHD as a result of B420 administration. Pretreatment with B420 for 14 or 35 days attenuated cardiac injury from ischemia/reperfusion or permanent coronary ligation. Infarcted hearts from B420 treated animals displayed a significant reduction in pro-inflammatory markers and an increase in anti-inflammatory regulatory T cells (T reg ). We further show that T reg immune cells are necessary players to communicate this protection by B420 administration. This protection is due, at least in part, to an increase in anti-inflammatory M2 type macrophages in B420 treated animals. These results suggest that administration of the probiotic B420 protects against cardiac injury and that regulatory T cells mediate this effect. Modulation of the inflammatory response by administration of a specific strain of probiotic may offer a rational, safe, and cost effective way to prevent inflammatory damage after cardiac injury.
Electroenhanced Antimicrobial Coating Based on Conjugated Polymers with Covalently Coupled Silver Nanoparticles Prevents <i>Staphylococcus aureus</i> Biofilm Formation
Authors: Salvador Gomez‐Carretero, Rolf Nybom, Agneta Richter‐Dahlfors
Journal: Advanced Healthcare Materials (2017)

The incidence of hospital-acquired infections is to a large extent due to device-associated infections. Bacterial attachment and biofilm formation on surfaces of medical devices often act as seeding points of infection. To prevent such infections, coatings based on silver nanoparticles (AgNPs) are often applied, however with varying clinical success. Here, the traditional AgNP-based antibacterial technology is reimagined, now forming the base for an electroenhanced antimicrobial coating. To integrate AgNPs in an electrically conducting polymer layer, a simple, yet effective chemical strategy based on poly(hydroxymethyl 3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT-MeOH:PSS) and (3-aminopropyl)triethoxysilane is designed. The resultant PEDOT-MeOH:PSS-AgNP composite presents a consistent coating of covalently linked AgNPs, as shown by scanning electron microscopy and surface plasmon resonance analysis. The efficacy of the coatings, with and without electrical addressing, is then tested against Staphylococcus aureus, a major colonizer of medical implants. Using custom-designed culturing devices, a nearly complete prevention of biofilm growth is obtained in AgNP composite devices addressed with a square wave voltage input. It is concluded that this electroenhancement of the bactericidal effect of the coupled AgNPs offers a novel, efficient solution against biofilm colonization of medical implants.
Private GP who ran autism clinic is banned from seeing patients pending investigation
Authors: Clare Dyer
Journal: BMJ (2017)

A London GP with a private practice has been banned from carrying out consultations or treatment for disorders relating to autism, and from offering online advice or information on matters related to autism.

The Medical Practitioners Tribunal Service has imposed the condition on David O’Connell on an interim basis, while the General Medical Council carries out a full investigation into …
SAT0652 Clinical and immunological significance of radiographic thymic alterations in patients with rheumatoid arthritis
Authors: O Murata, K Suzuki, H Sugiura, Y Kondo, M Takeshita, H Yasuoka, K Yamaoka, K Koga, R Morita, A Yoshimura, T Takeuchi
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The thymus, a primary lymphoid organ, plays a crucial role in immune system homeostasis [1,2]. Although several small-scale studies of the association between radiographic thymus alterations and serological features have been reported in systemic autoimmune diseases, information in patients with rheumatoid arthritis (RA) is limited. <h3>Objectives</h3> We conducted a large-scale cross-sectional analysis of radiographic thymus alterations and their association with clinical and immunological features in patients with RA. <h3>Methods</h3> RA patients were randomly selected from all patients who visited our department and underwent chest CT scan between January 2013 and December 2015. Patients with thymoma or thymic cyst and those aged less than 30 years were excluded. Thymic enlargement and thymus attenuation score in axial images of CT scans were quantitatively interpreted. We defined thymic enlargement as a thickness of more than 13 mm and graded the score by a four-point scale (score 0–3) according to previous studies [3,4]. Associations with immunophenotyping data of peripheral blood by flow cytometry and clinical and serological information were statistically analyzed in some available patients. <h3>Results</h3> 387 RA patients were enrolled. 78% were women and mean age was 65.2±12.3 years. Thymic enlargement was found in 76 (19.6%) patients. Thymus attenuation (score ≥2) was found in 154 (39.8%) patients. These findings were more frequent than in undiagnosed controls (11.3% (<i>P</i>=0.078) and 22.5% (<i>P</i>=0.017)). Importantly, radiographic thymus alterations in these RA patients, especially thymus attenuation score, were significantly associated with serological features such as serum level of CRP, ESR, IgG, RF-positivity or ACPA-positivity (<i>P</i>=0.0003, 0.001, 0.0009, 0.005, and 0.0009 respectively). When we investigated the association with the proportion of 68 peripheral blood subpopulations in 83 RA patients, thymic enlargement was significantly associated with the proportions of CD45RA+CCR7+ naïve CD4+T cell or CD45RO+CCR7-effector memory CD4+T cell (<i>P</i>=0.04 and 0.009). Furthermore, thymus attenuation score was also significantly associated with the proportions of CD4+ naïve T cell, CD4+effector memory T cell, CXCR5-CXCR3+CXCR6+CD4+Th1/Th17 cell, CD45RO-CCR7+CD95+CD4+ stem cell memory T cell, and CD19+ B cell (<i>P</i>=0.03, 0.02, 0.04, 0.04, and 0.037 respectively). <h3>Conclusions</h3> Radiographic thymus alterations are frequent in RA patients and may reflect immunological features of autoantibody production or T cell differentiation and function. <h3>References</h3> Gorozny JJ, et al. Trends Immunol 2001;22:251–255. Seddon B, et al. Immunol Today 2000;21:94–99. Naidich P, et al. Lippincott-Raven 1999:57–73. Ackman JB, et al. Radiology 2013;268(1):245–253. <h3>Disclosure of Interest</h3> None declared
Flow cytometry minimal residual disease assessment in peripheral blood of adult acute lymphoblastic leukemia patients.
Authors: Alissa Minkovsky, Karry Charest, Ryan Schmidt, Debra Briggs, Daniel J. DeAngelo, Betty Li, Elizabeth Morgan, Olga Pozdnyakova
Journal: Journal of Clinical Oncology (2017)

e18517 Background: Multiparametric flow cytometry (FC) of bone marrow aspirate (BM) is a widely used method of minimal residual disease (MRD) assessment in acute lymphoblastic leukemia (ALL). In practice, ALL with hematogone-like phenotype and patients with recurrence of isolated extramedullary disease present challenges in accurate determination of MRD status. We hypothesized that addition of FC MRD of peripheral blood would aid in the interpretation of MRD status. Methods: 76 matched BM and PB specimens were analyzed independently for presence of ALL MRD by 6-color FC. Results: The overall rate of BM MRD-positivity was 24% (18/76) and PB was also MRD-positive in 22% (4/18) of BM-positive cases. PB MRD sensitivity and specificity relative to BM MRD was 13% [95% confident interval (CI) 2%-42%] and 98% [88-100%] for B-ALL samples (n = 65) and 67% [13%-98%] and 75% [36%-95%] for T-ALL samples (n = 11), respectively. We identified 2 cases with evidence of leukemic cells in PB at the time of the extramedullary relapse that were interpreted as MRD-negative in BM. Conclusions: PB MRD demonstrates high specificity with relatively low sensitivity, especially in B-ALL when compared to T-ALL. The use of combined PB and BM samples in MRD assessment by current FC methods may have added clinical and diagnostic value in patients with high risk of extramedullary relapse, including PB MRD as a non-invasive method for monitoring of systemic relapse.
Angiogenesis in stage in Non-Small-Cell Lung cancer (NSCLC) expression of Human protesa - activated receptors (PARS)
Authors: P Ghio, G Selvaggi, S Novello, S Cappia, M Papotti, S Giorio, D Caggese, P Borasio, P Lausi, Gv Scagliotti
Journal: Annals of Oncology (2004)
Venetoclax Resistant Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Cells Are Also Resistant to ABL Inhibitors, Which Can be Overcome By Targeting the PI3K/AKT/ mTOR Pathway
Authors: Jessica T Leonard, Jeffrey W. Tyner, Joelle Rowley, Marc M. Loriaux, Brian J. Druker, Bill H. Chang
Journal: Blood (2016)
Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling
Authors: E I Andersson, S Pützer, B Yadav, O Dufva, S Khan, L He, L Sellner, A Schrader, G Crispatzu, M Oleś, H Zhang, S Adnan-Awad, S Lagström, D Bellanger, J P Mpindi, S Eldfors, T Pemovska, P Pietarinen, A Lauhio, K Tomska, C Cuesta-Mateos, E Faber, S Koschmieder, T H Brümmendorf, S Kytölä, E-R Savolainen, T Siitonen, P Ellonen, O Kallioniemi, K Wennerberg, W Ding, M-H Stern, W Huber, S Anders, J Tang, T Aittokallio, T Zenz, M Herling, S Mustjoki
Journal: Leukemia (2017)
PTU-038 Predictors of adenoma detection at colonoscopy after bowel scope surveillance
Authors: K Siau, AC Yew, S Shetty, S Ishaq, S Jewes, MJ Brookes, BC McKaig, A Veitch, A Murugananthan
Journal: Gut (2017)

Introduction  Flexible sigmoidoscopy (bowel scope) reduced colorectal cancer incidence and mortality in a population aged 55–64.[1]Patients progressed to colonoscopy based on ‘high risk’ features (Table 1).[1] Based on these pivotal findings, the UK bowel scope (BS) surveillance programme was introduced in 2013 to individuals aged 55. The Wolverhampton bowel cancer screening centre was the first UK site to fully roll out the programme. The correlation between BS findings and subsequent colonoscopy has not previously been evaluated in this specific cohort.  Method  We prospectively collated data from all BS patients at our centre and identified those undergoing colonoscopy between August 2013–2016. We assessed conversion rates, compliance with BS protocol and correlated endoscopic and histological findings to identify predictors for detection of pathology at colonoscopy. Univariate analysis was performed using Pearson’s chi2.  Results  11 711 bowel scopes were performed, with an adenoma detection rate (ADR) of 8.5%, and conversion to colonoscopy in 421 patients (3.6%). 386 were included for analysis after excluding incomplete colonoscopy/histology. All patients were aged 55 (64.8% male). Additional ADR at colonoscopy was 35.2%, with malignant diagnoses in 1.5% (all detected at BS). The adenoma miss rate at BS was 5.2%. On univariate analysis (Table 1), polyp ≥10 mm was the only indication associated with increased ADR at colonoscopy (OR 2.13, p  Conclusion  At BS, male gender, ≥10 mm polyps, and villous histology are predictors of proximal colonic pathology. Further analyses are required to clarify the benefits of converting low-risk tubulovillous adenomas at BS to colonoscopy.  Reference  . WS Atkin, Lancet2010;375:1624–33  Disclosure of Interest  None Declared
CD207+CD1a+ cells circulate in pediatric patients with active Langerhans cell histiocytosis
Authors: Eugenio Antonio Carrera Silva, Wanda Nowak, Licina Tessone, Cinthia Mariel Olexen, Juan Manuel Ortiz Wilczyñski, Ivana Gisele Estecho, Graciela Elena, Andrea Emilse Errasti, Diego Alfredo Rosso
Journal: Blood (2017)