tbuckley/cabot-search huggingface dataset:
Checkpoint immunotherapy: good for cancer therapy, bad for rheumatic diseases
Authors: Leonard Calabrese, Vamsidhar Velcheti
Journal: Annals of the Rheumatic Diseases (2016)

The goal of harnessing the immune system to fight cancer is not new; it dates back 125 years to when William Coley advocated that the body's response to infection could have anti-tumoural effects.1 However, decades of efforts using vaccines and immune stimulant therapies to harness the immune system to fight tumours have had limited success and at times have been fraught with serious adverse outcomes. Recently, drugs blocking negative immune checkpoint pathways have shown remarkable clinical activity in various solid tumours.2 Several agents targeting two such negative checkpoints, the programmed death-1 (PD-1) pathway (pembrolizumab, nivolumab and atezolizumab) and the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) (ipilimumab) are currently Food and Drug Administration and European Medicines Agency approved. These negative checkpoint pathways play a role in immune tolerance in normal tissues and the activation of these pathways is largely contextual. While these therapies have added immeasurably to the longevity of many patients with malignancies, they have come at a cost with the development of numerous untoward autoimmune inflammatory conditions.

The anti-tumour mechanism for checkpoint inhibitor therapies is incompletely understood but clearly relates to the manipulation of T-cell pathways involved in cellular activation and deactivation.2 T-cell homeostasis is a tightly choreographed process whereby naive T cells rapidly proliferate in a logarithmic fashion when effectively activated and then contract following successful defeat of the challenge. CD4 T-cell activation canonically requires two signals: a primary signal ( signal 1 ), mediated by recognition of cognate antigen by the T-cell receptor via presentation by self-major histocompatibility complex class II molecules on the antigen-presenting cell, and a secondary signal ( signal 2 ), mediated by CD28 on the T-cell, binding its ligand partner of the B7 family on the antigen-presenting cell.3 Of vital importance to the host is the integration of deactivating pathways or checkpoints leading to contraction …
Clinical Outcomes of Patients Who Received the Subcutaneous Implantable Cardioverter Defibrillator
Authors: N. A. Mark Estes
Journal: JAMA Cardiology (2016)

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P29 Bristol interstitial lung disease (BILD) service experience: BILDing on the MDT: Abstract P29 Table 1
Authors: C Sharp, A Edwards, L Mayers, H Lamb, S Barrett, N Bhatt, L Chandratreya, M Darby, A Edey, AB Millar, H Adamali
Journal: Thorax (2015)

<h3>Introduction</h3> The weekly Bristol Interstitial Lung Disease (BILD) multidisciplinary team (MDT) meeting decides consensus diagnoses for patients from around the South West. A database records cases at the time of discussion. Referrals have increased since the advent of novel agents for Idiopathic Pulmonary Fibrosis, prompting this retrospective review of the MDT experience. <h3>Aims</h3> Establish the range of cases referred, determining the proportion for whom MDT discussion leads to changes in diagnosis and which variables influence this. Examine IPF patients, identifying differences between those prescribed Pirfenidone or otherwise. <h3>Methods</h3> For all cases recorded in the MDT database between 1/1/2013 and 1/1/2015, the pre-MDT differential diagnosis and consensus diagnosis, dates of referral/discussion, referral source, demographics, investigation results, the number of discussions and dispensing of Pirfenidone were reviewed. For patients with multiple entries, initial differential diagnoses were compared to final consensus. Outcome measures of interest were change in diagnosis and decision to use Pirfenidone in IPF patients. <h3>Results</h3> 846 discussions occurred (651 individual patients) over this period. Pre/post MDT diagnoses are shown in the Table 1. 78% of cases were discussed within 2 weeks of referral. 25% were discussed more than once (range 1–5). 54.7% of IPF cases were external referrals vs 32.3% overall. Diagnosis changed following discussion for 44.1% of patients. Pre-MDT diagnosis of IPF changed for 36.7%. Logistic regression suggests pre-MDT differential diagnosis and age at referral are main influences on change in diagnosis. Overall mean age was 65.5 years (17–91), 58.1% male. For IPF cases, mean age was 74.4 years, 76.9% male. Pirfenidone was prescribed to 46.2% of IPF cases; median time to dispensing 61 days. 6MWD was greater where Pirfenidone was given (284 m vs 249 m, p = 0.03); however lung function and HRCT pattern did not differ. 12-month mortality was 6.7% in the Pirfenidone group, 27.1% where not given (p = 0.002). <h3>Conclusion</h3> Specialist MDT discussion influenced changes in diagnosis in 44.2% of patients. The majority of IPF cases discussed are external referrals. This has implications for design and delivery of specialist ILD services. Case selection for Pirfenidone does not appear based on lung function differences. This has implications for guidelines for its use.
Rheumatoid arthritis-associated autoantibodies and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis
Authors: Elana J Bernstein, R Graham Barr, John H M Austin, Steven M Kawut, Ganesh Raghu, Jessica L Sell, Eric A Hoffman, John D Newell, Jubal R Watts, P Hrudaya Nath, Sushil K Sonavane, Joan M Bathon, Darcy S Majka, David J Lederer
Journal: Thorax (2016)

<h3>Background</h3> Adults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of uncertain significance without overt autoimmune disease. We examined associations of rheumatoid arthritis (RA)-associated antibodies with subclinical ILD in community-dwelling adults. <h3>Methods</h3> We measured serum rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) and high attenuation areas (HAAs; CT attenuation values between −600 and −250 Hounsfield units) on cardiac CT in 6736 community-dwelling US adults enrolled in the Multi-Ethnic Study of Atherosclerosis. We measured interstitial lung abnormalities (ILAs) in 2907 full-lung CTs at 9.5-year median follow-up. We used generalised linear and additive models to examine associations between autoantibodies and both HAA and ILA, and tested for effect modification by smoking. <h3>Results</h3> In adjusted models, HAA increased by 0.49% (95% CI 0.11% to 0.86%) per doubling of RF IgM and by 0.95% (95% CI 0.50% to 1.40%) per RF IgA doubling. ILA prevalence increased by 11% (95% CI 3% to 20%) per RF IgA doubling. Smoking modified the associations of both RF IgM and anti-CCP with both HAA and ILA (interaction p values varied from 0.01 to 0.09). Among ever smokers, HAA increased by 0.81% (95% CI 0.33% to 1.30%) and ILA prevalence increased by 14% (95% CI 5% to 24%,) per RF IgM doubling; and HAA increased by 1.31% (95% CI 0.45% to 2.18%) and ILA prevalence increased by 13% (95% CI 2% to 24%) per anti-CCP doubling. Among never smokers, no meaningful associations were detected. <h3>Conclusions</h3> RA-related autoimmunity is associated with both quantitative and qualitative subclinical ILD phenotypes on CT, particularly among ever smokers.
Inverse Relationship Between Organ-Specific Autoantibodies and Systemic Immune Mediators in Type 1 Diabetes and Type 2 Diabetes: Action LADA 11
Authors: Nanette C. Schloot, Minh N. Pham, Mohammed I. Hawa, Paolo Pozzilli, Werner A. Scherbaum, Matthias Schott, Hubert Kolb, Steven Hunter, Guntram Schernthaner, Charles Thivolet, Jochen Seissler, Richard David Leslie
Journal: Diabetes Care (2016)

OBJECTIVE We related organ-specific autoantibodies, including diabetes-associated autoantibodies (DAAs) and non-DAAs to systemic cytokines/chemokines in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS From the European Action LADA (latent autoimmune diabetes in adults) cohort, patients with adult-onset type 1 diabetes (n = 80, of whom 50 had LADA and 30 had classic type 1 diabetes) and type 2 diabetes (n = 626) were analyzed for DAAs (GAD antibody [GADA], IA-2 antigen, islet cell antibody, and zinc transporter T8), non-DAAs (transglutaminase, thyroid peroxide autoantibodies, parietal cell antibodies), and 10 immune mediator concentrations (measured by LUMINEX). RESULTS Type 1 diabetes patients (whether having classic type 1 diabetes or LADA), apart from their clinical phenotype, could not be distinguished by either autoantibodies (both DAAs and non-DAAs) or immune mediators. In type 1 diabetes, most immune mediators (9 of 10) were negatively correlated with DAA titers. Type 2 diabetes patients, who by definition were without DAAs, had fewer non-DAAs (P &amp;lt; 0.0005), but had higher levels of proinflammatory immune mediators, especially compared with patients with type 1 diabetes who had high GADA titers (interleukin [IL]-6 [P &amp;lt; 0.001], soluble E-selectin [P &amp;lt; 0.01], and IL-1 receptor antagonist [P = 0.052], for trend). CONCLUSIONS Patients with type 1 diabetes had more DAAs and non-DAAs than did those with type 2 diabetes, whereas the frequency and nature of these autoantibodies was broadly similar in classic type 1 diabetes and LADA. Systemic immune mediator levels, in the main, were negatively correlated with DAA titers, and, for some, were higher in patients with type 2 diabetes, especially when compared with patients who had high GADA titers. Differences in the clinical classification of diabetes are associated with graded differences in adaptive and innate immune reactivity.
Efficacy and safety of gemcitabine containing regimen for refractory and relapsed non-Hodgkin lymphoma
Authors: Chisato Mizutani, Katsuyuki Nishi, Satoshi Takahashi, Sachiko Mitani, Kohei Tada, Hitomi Kaneko, Kazuo Hatanaka, Naoya Ukyo, Hirokazu Hirata, Mituru Tsudo
Journal: Annals of Oncology (2015)
Tenascin-C Is a Major Component of the Fibrogenic Niche in Kidney Fibrosis
Authors: Haiyan Fu, Yuan Tian, Lili Zhou, Dong Zhou, Roderick J. Tan, Donna B. Stolz, Youhua Liu
Journal: Journal of the American Society of Nephrology (2016)

Kidney fibrosis initiates at certain focal sites in which the fibrogenic niche provides a specialized microenvironment that facilitates fibroblast activation and proliferation. However, the molecular identity of these fibrogenic niches is poorly characterized. Here, we determined whether tenascin-C (TNC), an extracellular matrix glycoprotein, is a component of the fibrogenic niche in kidney fibrosis. In vivo, TNC expression increased rapidly in kidneys subjected to unilateral ureteral obstruction or ischemia/reperfusion injury and predominantly localized at the foci rich in fibroblasts in renal interstitium. In vitro, TNC selectively promoted renal interstitial fibroblast proliferation, bromodeoxyuridine incorporation, and the expression of proliferation-related genes. The mitogenic activity of TNC required the integrin/focal adhesion kinase/mitogen-activated protein kinase signaling cascade. Using decellularized extracellular matrix scaffolds, we found that TNC-enriched scaffolds facilitated fibroblast proliferation, whereas TNC-deprived scaffolds inhibited proliferation. Matrix scaffold prepared from fibrotic kidney also promoted greater ex vivo fibroblast proliferation than did scaffolds prepared from healthy kidney. Conversely, small interfering RNA-mediated knockdown of TNC in vivo repressed injury-induced fibroblast expansion and renal fibrosis. These studies identify TNC as a major constituent of the fibrogenic niche that promotes fibroblast proliferation, and illustrate a pivotal role for the TNC-enriched microenvironment in kidney fibrogenesis.
IgA Levels Can Predict Survival in CLL Patients: A Retrospective Analysis of 183 Cases in a Brazilian Cohort
Authors: Sérgio Costa Fortier, Natália Zing, Fabio Lima da Silva, Viviane Mayumi Endo, Talita Silveira Da Rocha, Bárbara Tannus, Maeva Pinto, Carlos Chiattone
Journal: Blood (2015)
A phase I study of IPI-926, a novel hedgehog pathway inhibitor, in patients (pts) with advanced or metastatic solid tumors.
Authors: C. M. Rudin, A. Jimeno, W. H. Miller, B. J. Eigl, S. N. Gettinger, A. L. S. Chang, K. Faia, J. Sweeney, G. Loewen, R. W. Ross, G. J. Weiss
Journal: Journal of Clinical Oncology (2011)

3014 Background: IPI-926 is a novel, selective, oral, natural- product derived small molecule that targets the Hedgehog (Hh) pathway by inhibiting Smoothened (Smo). Inhibition of Smo can repress malignant activation of the Hh pathway, making Smo a target for treatment of a broad range of cancers. We conducted a phase I dose-escalation study to evaluate the safety, maximum tolerated dose and anti-tumor activity of IPI-926. Methods: Eligible pts had advanced or metastatic solid tumors and adequate bone marrow, hepatic and renal function. IPI-926 was administered orally, daily (QD), in 1 to 6 pt cohorts. A cycle was 28 days in length. An expanded cohort in basal cell carcinoma (BCC) was implemented. All pts were evaluated for safety, pharmacokinetics, pharmacodynamics (PD) and tumor response. Dose-limiting toxicities (DLTs) were evaluated during Cycle 1. Results: As of December 2010, 79 pts had been enrolled at dose levels of IPI-926 ranging from 20-210 mg QD. 31 pts had locally-advanced (LA) or metastatic (M) BCC. The median age for all patients was 60 years (range 40-87) and median number of cycles received was 3 (range 1-22), with 3 (1 LA-BCC and 2 M-BCC) pts receiving IPI-926 for > 12 months. No grade 4/5 related adverse events (AEs) have been observed. The most common IPI-926–related AEs to date include fatigue (29% total, 2.5% grade 3), ALT increased (20%, 7.6% grade 3), AST increased (19%, 3.8% grade 3) and nausea (19%, 0% grade 3). DLTs noted to date were asymptomatic grade 2/3 increased transaminases and/or bilirubin (1 pt at 160 mg, 4 pts at > 160 mg), all of which resolved when drug was held. IPI-926 exposure generally increased with increasing dose. 41 (72%) pts demonstrated a PD effect in normal skin. 6 (27%) clinical or radiologic partial responses have been observed in the 22 pts with Hh-inhibitor naive BCC treated at doses ≥ 130 mg, with 18 of these patients still on study, with a median of 7 cycles received (1-10). 27 pts in total are currently on study. Conclusions: IPI-926, a potent and selective Smo inhibitor, was well tolerated up to 160 mg in pts with advanced or metastatic solid tumor malignancies. Evidence of clinical activity has been observed in BCC pts. The recommended dose for phase II studies will be presented.
Prognostic Impact Of Body Mass Index (BMI) In Acute Myeloid Leukemia (AML)
Authors: Emmanuelle Kempf, Pierre Hirsch, Myriam Labopin, Christophe Marzac, Jean-Yves Perrot, Françoise Isnard, Jean-Pierre Marie, Mohamad Mohty, Ollivier Legrand
Journal: Blood (2013)
Clinical impact of dose modification and dose intensity on response to ponatinib (PON) in patients (pts) with Philadelphia chromosome-positive (Ph+) leukemias.
Authors: Andreas Hochhaus, Javier Pinilla-Ibarz, Dong-Wook Kim, Philipp D. Le Coutre, Ronald Paquette, Charles Chuah, Franck E. Nicolini, Jane Apperley, Hanna Jean Khoury, Michele Baccarani, Stephanie Lustgarten, Victor M. Rivera, Frank G. Haluska, Francois Guilhot, Michael W.N. Deininger, Timothy P. Hughes, Neil P. Shah, Hagop M. Kantarjian, Moshe Talpaz, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2014)

7084 Background: PON is a potent oral pan–BCR-ABL tyrosine kinase inhibitor with clinical activity in pretreated pts with Ph+ leukemias. Dose modification of PON may be used to avoid or manage adverse events (AEs). This post hoc analysis assessed the clinical impact of dose modification and dose intensity on outcomes of pts in the phase 2 PACE trial. Methods: PON starting dose was 45 mg QD. Dose reduction: any reduction below 45 mg/d; dose interruption: treatment held for ≥3 consecutive days. Efficacy analyses were performed on CP-CML pts (N=267). Analysis of arterial thrombotic events (ATEs) included all pts (CP/BP/AP-CML, Ph+ ALL; N=449). Data are as of 3 Sept 2013; median follow-up was 24 (0.1-35) mo for all pts. Results: 78% of CP-CML pts had dose modification within the first 12 mo (82% at any time). Responses in pts with/without modification were comparable (Table). Of 149 responders, 87 (58%) achieved MCyR at 45 mg/d, 46 (31%) at 30 mg/d, 16 (11%) at 15 mg/d. Most pts who had a dose reduction after achieving a response maintained that response: MCyR (97%), complete cytogenetic response (CCyR; 96%), major molecular response (MMR; 92%). Among pts with a dose reduction lasting ≥6 mo after achieving response at a higher dose, 100% maintained MCyR (96%, CCyR; 93%, MMR). While dose intensity was the most significant predictor of MCyR by 12 mo (multivariate analysis [MVA]), substantial responses occurred at lower doses; estimated response rates were ~75% at 45 mg, ~60% at 30 mg, and ~30% at 15 mg. ATEs occurred in 17% of pts; each 15 mg/d reduction in avg daily dose is predicted to lead to ~40% reduction in risk of ATE (MVA). 2 yr overall survival was similar for CP-CML pts who had dose modifications (86%) v those who did not (86%) and for pts who had ATE (85%) v those who did not (87%). Of pts with ATEs, 46% had dose modifications. Conclusions: Pts on PON who undergo dose modification may still respond to treatment and dose modification may be an effective management tool. Careful consideration of the potential benefits and risks of PON should guide treatment decisions. Clinical trial information: NCT01207440. CP-CML n MCyRb % CCyRb % MMRa % Dose modificationa 218 58 47 38 No dose modification 49 47 45 35 a, anytime; b, by 12 mo.
Malignant Mesothelioma Effusions Are Infiltrated by CD3+ T Cells Highly Expressing PD-L1 and the PD-L1+ Tumor Cells within These Effusions Are Susceptible to ADCC by the Anti–PD-L1 Antibody Avelumab
Authors: Swati Khanna, Anish Thomas, Daniel Abate-Daga, Jingli Zhang, Betsy Morrow, Seth M. Steinberg, Augusto Orlandi, Patrizia Ferroni, Jeffrey Schlom, Fiorella Guadagni, Raffit Hassan
Journal: Journal of Thoracic Oncology (2016)
Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial
Authors: Howard L Kaufman, Jeffery Russell, Omid Hamid, Shailender Bhatia, Patrick Terheyden, Sandra P D'Angelo, Kent C Shih, Céleste Lebbé, Gerald P Linette, Michele Milella, Isaac Brownell, Karl D Lewis, Jochen H Lorch, Kevin Chin, Lisa Mahnke, Anja von Heydebreck, Jean-Marie Cuillerot, Paul Nghiem
Journal: The Lancet Oncology (2016)
Abstract 252: Antibody-mediated phosphatidylserine blockade significantly enhances the efficacy of immune checkpoint blockades in K1735 and B16 mouse melanoma models
Authors: Bruce Freimark, Jian Gong, Dan Ye, Rolf Brekken, Shen Yin, Jeff Hutchins, Van Nguyen, Chris Hughes, Xianming Huang
Journal: Cancer Research (2015)

Abstract Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane and becomes exposed abundantly on tumor endothelial cells, tumor-secreted microvesicles, and tumor cells in response to chemo- and radiotherapy. Extensive studies have shown that PS is a global immune checkpoint and major contributor to tumor immunosuppression, which promotes the expansion of immunosuppressive cells, such MDSC and M2 macrophages, inhibits DCs maturation, while stimulates them to secrete immunosuppressive mediators. We have shown that PS targeting can override PS-mediated immunosuppression, reactivate innate tumor immunity, and evoke adaptive antitumor immunity. In the present study, we assessed the antitumor effect of the combination of PS blockade and anti-CTLA-4 or anti-PD-1 antibodies in B16 and K1735 melanoma models. Both combinations showed significantly superior tumor growth inhibition over single treatment, with many mice achieving complete tumor regression. Flow cytometry analysis showed that the combination treatment had significantly greater total and functional tumor-infiltrating CD8+ T, more IL-2- and IFNγ-producing splenic T cells, and lower number of splenic MDSCs than did single treatment. In addition, the ratio of M2 to M1 in the tumor was significantly lower in the combination treatment than that in single treatment. Finally, no toxicity was observed in any of the treatment groups following multiple treatment doses. These data suggest that combination of PS blockade with immune checkpoint blockade promotes strong, localized, enhanced therapeutic efficacy without the side-effects of systemic immune activation and represents a promising combinatorial strategy for cancer immunotherapy. A chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in multiple late-stage clinical trials. These data support our Phase I IST evaluation of our PS-targeting antibody bavituximab in combination with ipilimumab in advanced melanoma patients. Citation Format: Bruce Freimark, Jian Gong, Dan Ye, Rolf Brekken, Shen Yin, Jeff Hutchins, Van Nguyen, Chris Hughes, Xianming Huang. Antibody-mediated phosphatidylserine blockade significantly enhances the efficacy of immune checkpoint blockades in K1735 and B16 mouse melanoma models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 252. doi:10.1158/1538-7445.AM2015-252