tbuckley/cabot-search huggingface dataset:
B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors
Authors: William Damsky, Lucia Jilaveanu, Noel Turner, Curtis Perry, Christopher Zito, Mary Tomayko, Jonathan Leventhal, Kevan Herold, Eric Meffre, Marcus Bosenberg, Harriet M. Kluger
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> PD-1 inhibitors are approved for multiple malignancies and function by stimulating T cells. However, the role of B cells in the anti-tumor activity of these drugs is unknown, as is their activity in patients who have received B cell depleting drugs or with immunoglobulin deficiencies. <h3>Methods</h3> We studied B cell content in 40 melanomas from patients treated with pembrolizumab or nivolumab and assessed the association with response to therapy. Murine MC38 colon cancer and YUMMER1.7 melanoma models were used to determine whether concomitant anti-CD20 antibody injections diminish the anti-tumor effects of anti-PD-1. Results were validated in <i>mu</i>MT mice, which lack B cells. <h3>Results</h3> B cells were sparse in most melanomas and B cell content was not associated with response to anti-PD-1 or overall survival. Employing MC38 and YUMMER1.7 models, we demonstrated that anti-CD20 antibodies reduce tumor-infiltrating B cells yet had no effect on tumor growth, response to PD-1 inhibition, or survival. In <i>mu</i>MT mice, T-cell dependent tumor rejection and anti-PD-1 responses were no different than in wildtype C57BL/6 J mice. <h3>Conclusions</h3> The degree of tumor infiltrating B cell content is not associated with response to anti-PD-1 inhibitors in melanoma. PD-1 inhibitors cause tumor shrinkage in murine cancer models even when B cells are absent or are depleted. PD-1 inhibitors are likely to be active in patients with impaired B cell function, such as patients undergoing B cell depletion with drugs including rituximab for conditions such as B cell malignancies or autoimmune disorders.
Abstract 17678: Prognostic Value of Angina Related Health Status in Women With Suspected Coronary Artery Disease
Authors: Mohamed Khayata, Nima Ghasemzadeh, Abdulwahab Hritani, Hatem Al Kassem, Hannah Nguyen, Danny Eapen, Bushra Alzaraneh, Raghda Alanbari, Meriem El-Khattabi, Alysha Nazmin Kaba, Pankaj Manocha, riyaz patel, Emir Veledar, Kreton Mavromatis, Laurence Sperling, Viola Vaccarino, Arshed A Quyyumi
Journal: Circulation (2013)

Background: Angina-related health status as measured by the Seattle Angina Questionnaire (SAQ) has been shown to predict outcomes in patients with coronary artery disease (CAD), but few data are av...
PS996 TCF4 IS IMPORTANT FOR MUTANT RUNX1‐MEDIATED CELL IMMORTALIZATION AND PREDICTS OUTCOME IN ACUTE MYELOID LEUKEMIA
Authors: F. In ’T Hout, M. Gerritsen, L. Bullinger, B. van der Reijden, G. Huls, E. Vellenga, J. Jansen
Journal: HemaSphere (2019)

Background: Aberrations of the RUNX1 transcription factor, either mutations ( RUNX1 mut ) or translocations t(8;21) creating a RUNX1‐RUNXT1 fusion gene, are frequently observed in AML. However, the pathomechanisms underlying RUNX1 mut AML and explaining its poor prognosis in contrast to t(8;21) cases are still poorly understood. Aims: As recent data suggested deregulation of the transcription factor 4 ( TCF4 ) gene to play a potential role, we studied the importance of TCF4 in the context of RUNX1 mut and t(8;21). Methods: Chip‐sequencing data was analyzed to identify binding of RUNX1 on the TCF4 promoter and Luciferarse reporter assays were used to assay impact of RUNX1 on TCF4 promoter activity. CD34 + UCB cells were transduced with a pRRL construct overexpressing the RUNX1 R201Q mutant (RUNX1 mut ) or an empty vector (EV). Simultaneously, TCF4‐RNAi (TCF4 kd ) or a non‐targeting control (NT) was co‐transduced. These double transduced CD34 + UCB cells were cultured on MS5 bone marrow stromal layer and proliferation assays, colony forming unit assays and long‐term culture‐initiating cells assays were performed. TCF4 expression values were derived from a previously reported cohort of 436 AML patients of which 330 had a known RUNX1 status. Survival curves were calculated by the Kaplan‐Meier method and compared using the logrank test. Multivariate survival analysis was carried out using the Cox proportional hazards model, and covariates included were RUNX1 mutation and white blood cell count (WBC &gt; 100 ∗ 10 9 /L) with and without TCF4 expression (lowest 75% vs highest 25%). Results: While TCF4 is found upregulated in RUNX1 mut in contrast to t(8;21) AML, Chip‐seq and transactivation assays revealed that RUNX1 binds and regulates the TCF4 promoter activity. RUNX1 wild type (RUNX1 wt ) and the RUNX1‐RUNX1T1 fusion protein repressed TCF4 promoter activity, which was lost in RUNX1 mut AML. In CD34 + cells RUNX1 mut enhanced colony‐formation and increased long‐term culture initiating cells, whereas RNA interference based TCF4 downregulation in RUNX1 mut cells abolished this effect. Being required for stem cell maintenance activity in RUNX1 mut AML, TCF4 upregulation accounted for the poor prognostic outcome of RUNX1 mut in AML patients, as RUNX1 mut lost its significance in multivariate analysis if TCF4 expression was included. Summary/Conclusion: In summary, TCF4 is an important downstream target of RUNX1 mut AML contributing to leukemogenesis and poor response to standard AML therapy.
Association of Communication Interventions to Discuss Code Status With Patient Decisions for Do-Not-Resuscitate Orders
Authors: Christoph Becker, Leopold Lecheler, Seraina Hochstrasser, Kerstin A. Metzger, Madlaina Widmer, Emanuel B. Thommen, Katharina Nienhaus, Hannah Ewald, Christoph A. Meier, Florian Rueter, Rainer Schaefert, Stefano Bassetti, Sabina Hunziker
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Whether specific communication interventions to discuss code status alter patient decisions regarding do-not-resuscitate code status and knowledge about cardiopulmonary resuscitation (CPR) remains unclear. <h3>Objective</h3> To conduct a systematic review and meta-analysis regarding the association of communication interventions with patient decisions and knowledge about CPR. <h3>Data Sources</h3> PubMed, Embase, PsycINFO, and CINAHL were systematically searched from the inception of each database to November 19, 2018. <h3>Study Selection</h3> Randomized clinical trials focusing on interventions to facilitate code status discussions. Two independent reviewers performed the data extraction and assessed risk of bias using the Cochrane Risk of Bias Tool. Data were pooled using a fixed-effects model, and risk ratios (RRs) with corresponding 95% CIs are reported. <h3>Data Extraction and Synthesis</h3> The study was performed according to the PRISMA guidelines. <h3>Main Outcomes and Measures</h3> The primary outcome was patient preference for CPR, and the key secondary outcome was patient knowledge regarding life-sustaining treatment. <h3>Results</h3> Fifteen randomized clinical trials (2405 patients) were included in the qualitative synthesis, 11 trials (1463 patients) were included for the quantitative synthesis of the primary end point, and 5 trials (652 patients) were included for the secondary end point. Communication interventions were significantly associated with a lower preference for CPR (390 of 727 [53.6%] vs 284 of 736 [38.6%]; RR, 0.70; 95% CI, 0.63-0.78). In a preplanned subgroup analysis, studies using resuscitation videos as decision aids compared with other interventions showed a stronger decrease in preference for life-sustaining treatment (RR, 0.56; 95% CI, 0.48-0.64 vs 1.03; 95% CI, 0.87-1.22; between-group heterogeneity<i>P</i> &lt; .001). Also, a significant association was found between communication interventions and better patient knowledge (standardized mean difference, 0.55; 95% CI, 0.39-0.71). <h3>Conclusions and Relevance</h3> Communication interventions are associated with patient decisions regarding do-not-resuscitate code status and better patient knowledge and may thus improve code status discussions.
Abstract P218: Carotid Intima-media Thickness and Incident End-stage Renal Disease: The Atherosclerosis Risk in Communities Study
Authors: Yuanjie Pang, Yingying Sang, Shoshana Ballew, Morgan Grams, Gerardo Heiss, Josef Coresh, Kunihiro Matsushita
Journal: Circulation (2016)

Introduction: Carotid intima-media thickness (IMT) has been reported to predict kidney function decline. However, whether carotid IMT is associated with a hard kidney endpoint, end-stage renal disease (ESRD), has not been investigated. Hypothesis: We assessed the hypothesis that increased carotid IMT is associated with ESRD risk. Methods: We studied 13,197 ARIC participants at visit 1 (1987-1989) without history of cardiovascular disease including coronary heart disease, stroke and heart failure and assessed whether carotid IMT measured by B-mode ultrasound is associated with ESRD risk using Cox proportional-hazards models. Regarding carotid IMT parameters, we investigated the mean and maximum values of overall and segment-specific (common, bifurcation and internal carotid arteries) measurements. Results: Mean age was 54.0 (SD 5.7) years, and there were 3,373 (25.6%) blacks and 7,370 (55.8%) women. During a median follow-up of 22.7 years, 433 participants developed ESRD (1.4/1,000 person-years). After adjusting for shared risk factors for atherosclerosis and kidney disease, including baseline kidney function, carotid IMT was significantly associated with ESRD risk (hazard ratios between quartiles 4 and 1, 1.43 [95%CI: 1.01-2.04] for overall mean IMT and 1.73 [95%CI: 1.22-2.44] for overall maximum IMT). The associations were largely consistent in demographic and clinical subgroups. When we explored segment-specific IMTs, the associations with ESRD were most robust for bifurcation carotid. The adjusted hazard ratios between quartiles 4 and 1 were 1.48 (95%CI: 1.04-2.11) for mean bifurcation IMT and 1.42 (95%CI: 0.99-2.03) for maximum bifurcation IMT. Conclusions: Carotid IMT was independently associated with incident ESRD in the general population. Our findings suggest the shared etiology between atherosclerosis and ESRD and highlight the importance of monitoring kidney function over time in individuals with subclinical atherosclerosis.
SAT0227 MYOCARDIAL FIBROSIS IS ASSOCIATED WITH ANCA STATUS, ORGAN INVOLVEMENT AND DISEASE SEVERITY IN PATIENTSWITH GRANULOMATOSIS WITH POLYANGIITIS
Authors: Alessandro Giollo, Raluca-Bianca Dumitru, Peter Swoboda, Sven Plein, John Greenwood, Maya Buch, Jacqueline Andrews
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Granulomatosis with polyangiitis (GPA) is a systemic vasculitis with an increased burden of cardiovascular (CV) events compared to the general population, but the prevalence of primary cardiac involvement in this disease is unknown. <h3>Objectives:</h3> The objective of this prospective study was to describe with cardiac magnetic resonance (CMR) the myocardial abnormalities associated with GPA and their correlations with disease characteristics. <h3>Methods:</h3> Twenty-six patients with GPA and no prior CV disease (CVD) or diabetes mellitus underwent contrast-enhanced CMR, including late gadolinium-enhancement (LGE), T1 mapping for native T1 and extra-cellular volume (ECV) quantification for assessment of myocardial fibrosis and tissue tagging for assessment of left ventricular (LV) function. Characteristics of disease, treatments and CV risk factors were collected; disease relapse was defined as reappearance or worsening of vasculitis symptoms requiring an increase of the current treatment or introduction of additional immunosuppressive medication. Twenty-five healthy volunteers (HV) with comparable age, sex, BMI and arterial blood pressure served as controls. <h3>Results:</h3> Patients with GPA (median age 58 years, disease duration 8 years, BVAS 2; females 46%, PR3 ANCA 58%) had similar cardiovascular risk profile to HV. A focal, non-ischemic LGE pattern of fibrosis was detected in 24% of patients and no controls (p=0.010; Table 1). Patients with myocardial LGE were more frequently PR3 ANCA negative (93% vs 7%, p=0.007), and they presented more frequently with involvement of the lower respiratory tract (75% vs 25%, p=0.097) and skin (63% vs 38%, p=0.087). Values of LGE-related fibrotic mass were higher in patients presenting with renal involvement (p=0.036). Native T1 and ECV were higher in patients with GPA than HV (Table 1); ECV was higher in those with relapsing disease, and native T1 was inversely associated with PR3 ANCA (β=-0.664, p=0.001). Peak systolic strain was slightly reduced in GPA than controls (Table 1); LV ejection function (LVEF) was inversely correlated with disease duration (β=-0.454, p=0.026). <h3>Conclusion:</h3> Patients with GPA had significant myocardial abnormalities on CMR compared to HV. ANCA status, systemic organ involvement and disease severity were associated with CMR markers of myocardial fibrosis. CMR could be a useful tool for identification and future risk stratification of myocardial involvement of GPA. <h3>Disclosure of Interests:</h3> Alessandro Giollo: None declared, Raluca-Bianca Dumitru: None declared, Peter Swoboda: None declared, Sven Plein : None declared, John Greenwood: None declared, Maya Buch Grant/research support from: Pfizer LTD, UCB, Consultant for: AbbVie, Eli Lilly, EMD Serono, Pfizer Ltd., Sanofi, Jacqueline Andrews: None declared
Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification
Authors: Tian Tian, Jiajun Li, Yizhuo Li, Yun-Xin Lu, Yan-Lai Tang, Hua Wang, Fufu Zheng, Dingbo Shi, Qian Long, Miao Chen, Guillermo Garcia-Manero, Yumin Hu, Lijun Qin, Wuguo Deng
Journal: Theranostics (2019)

Acute myeloid leukemia (AML) with an internal tandem duplication in Fms-related tyrosine kinase 3 (FLT3-ITD) is identified as a subgroup with poor outcome and intrinsic resistance to chemotherapy and therefore urgent need for development of novel therapeutic strategies. Methods: The antitumor effects of melatonin alone or combined with sorafenib were evaluated via flow cytometry and immunoblotting assays in FLT-ITD AML cells. Also, the ex vivo and in vivo models were used to test the synergistic effects of melatonin and sorafenib against leukemia with FLT3/ITD mutation. Results: Our study shows for the first time that melatonin inhibits proliferation and induces apoptosis in FLT3/ITD-positive leukemia cells. Mechanistically, melatonin preferentially causes overproduction of reactive oxygen species (ROS) and ultimately massive cell death in FLT3-ITD AML cells. Moreover, melatonin significantly enhances the cytotoxicity induced by the FLT3 tyrosine kinase inhibitor sorafenib in AML cells with FLT3/ITD through redox modification. Importantly, combination of melatonin and sorafenib exhibited highly synergistic therapeutic activity in MV4-11 xenografts and a murine model bearing FLT3/ITD leukemia. Conclusion: This study indicates that melatonin, alone or in combination with sorafenib, has potential to improve the therapeutic outcome of AML patients with FLT3-ITD mutation that merits further investigation.
PS1019 HIGH CYTOMEGALOVIRUS VIRUS LOAD INDUCES A POTENT TUMOR‐SPECIFIC CD8+ T CELL RESPONSE AND PROTECTS PATIENT IN ACUTE MYELOID LEUKEMIA FROM RELAPSE AFTER SINGLE CORD BLOOD TRANSPLANTATION
Authors: M. Dong, Z. Sun, H. Liu
Journal: HemaSphere (2019)

Background: Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Interestingly, in recent studies, CMV infections have been shown to have potential anti‐leukemia effects in acute myeloid leukemia (AML) patients after HSCT. However, studies of CMV infection on relapse after single cord blood transplantation (CBT) are limited, and the effect of the virus load on relapse has not been assessed. Aims: We hypothesize that the role of MCV on outcomes in CBT are related to virus load. In this study, we retrospectively analyzed the effect of CMV infection on two‐year outcomes in 151 patients with AML after CBT according to the virus load. Additionally, the mechanism of the possible interaction with lymphocyte subsets was also analyzed. Methods: We comparatively analyzed the outcomes of the high virus load group (CMV DNA copies ≥ 1 000/mL) and the low virus load group (CMV DNA copies &lt;1 000/mL or negative CMV DNA copy) of two years after CBT. Furthermore, in order to explore the mechanism of CMV on relapse, a smaller cohort of 26 patients with immune reconstruction data at 1, 3, 6, 9 and 12 months after transplantation were simultaneously studied, and nine healthy physical examination populations were recruited as healthy controls. Results: The results showed that the high CMV virus load group had a lower two‐year cumulative incidence of relapse (Figure A, 2.2% vs. 15.2%, p = 0.008) without an increase in non‐relapse mortality (Figure B, 20.9% vs. 22.4%, p = 0.970) than the low CMV virus load group. Furthermore, the two groups had similar overall survivals (76.8% vs. 72.4%, p = 0.746). Moreover, the proportion and absolute number of CD8+ T cells were increased in the high CMV virus load group in different months after transplantation (Figure C and D). Summary/Conclusion: In conclusion, a high CMV virus load in AML patients after CBT indicated a lower incidence of relapse, and this anti‐leukemic effect might be mediated by the CMV‐driven expansion of CD8+ T cells. image
Radiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system
Authors: Claire Lhuillier, Nils-Petter Rudqvist, Olivier Elemento, Silvia C. Formenti, Sandra Demaria
Journal: Genome Medicine (2019)

The expression of antigens that are recognized by self-reactive T cells is essential for immune-mediated tumor rejection by immune checkpoint blockade (ICB) therapy. Growing evidence suggests that mutation-associated neoantigens drive ICB responses in tumors with high mutational burden. In most patients, only a few of the mutations in the cancer exome that are predicted to be immunogenic are recognized by T cells. One factor that limits this recognition is the level of expression of the mutated gene product in cancer cells. Substantial preclinical data show that radiation can convert the irradiated tumor into a site for priming of tumor-specific T cells, that is, an in situ vaccine, and can induce responses in otherwise ICB-resistant tumors. Critical for radiation-elicited T-cell activation is the induction of viral mimicry, which is mediated by the accumulation of cytosolic DNA in the irradiated cells, with consequent activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon (IFN) genes (STING) pathway and downstream production of type I IFN and other pro-inflammatory cytokines. Recent data suggest that radiation can also enhance cancer cell antigenicity by upregulating the expression of a large number of genes that are involved in the response to DNA damage and cellular stress, thus potentially exposing immunogenic mutations to the immune system. Here, we discuss how the principles of antigen presentation favor the presentation of peptides that are derived from newly synthesized proteins in irradiated cells. These concepts support a model that incorporates the presence of immunogenic mutations in genes that are upregulated by radiation to predict which patients might benefit from treatment with combinations of radiotherapy and ICB.
AB0841 PROSPECTIVE STUDY OF BONE METABOLISM AND FRACTURE INCIDENCE IN SPINAL CORD INJURY PATIENTS DURING A PERIOD OF 24 MONTHS
Authors: Isabel Martínez Cordellat, Jose Ivorra Cortés, Fátima Torralba Collados, Carmen Grao Castellote, Cristina Alcañiz Escandell, Inmaculada Chalmeta Verdejo, Marta De la Rubia Navarro, Jorge Juan Fragio-Gil, Roxana Gonzalez Mazario, Luis Gonzalez Puig, Elena Grau García, Rosa Negueroles Albuixech, Jose Eloy Oller Rodríguez, Francisco Miguel Ortiz Sanjuan, Cristobal Pávez Perales, Elvira Vicens Bernabeu, Carmen Nájera Herranz, Inés Cánovas Olmos, Jose Andrés Román Ivorra
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Spinal Cord Injury (SCI) produces a wide variety of changes in systemic physiology that can lead to several complications, such as Osteopenia or even Osteoporosis. It has been reported in several studies, an incidence of fracture between 30-40% in this population. <h3>Objectives</h3> To evaluate the evolution of bone turnover biomarkers before and after treatment (according to 2015 NOF guidelines) and to describe the incidence of fracture after a SCI. <h3>Methods</h3> A prospective study was conducted, including 48 SCI patients followed during an observation period of 24 months, with visits every six months. Thirty two patients concluded the study. In each visit patients were enquired about fractures. A blood test was also performed. In addition a dual-energy x-ray absorptiometry (DEXA) and simple x-ray of hip and spine was requested annually. Patients were also educated in lifestyle measures, such as an adequate calcium and vitamin D dietary intake. Oral supplementation was initiated in cases of low intake or deficit, respectively. In patients with bone mineral density (BMD) measured by DEXA in range of Osteoporosis, pharmacological therapy was initiated (bisphosphonate or Denosumab). Statistics had been performed with mixed linear regression models. <h3>Results</h3> Our sample was 56.25% men with an average age of 56.08 ± 13.82 years old. In 32 patients (68.09%) low Vitamin D levels were detected. At baseline in 12 cases (25%) DEXA showed a BMD in osteoporosis range; in 12 (25%) osteopenia, plus 6 fractures (2.6 fractures per 100 years/patient). Afterwards, until the end of the study only a fracture of the tibia was observed (however, it was after a high impact accident), so the fracture rate was 1.2 fractures per 100 year/patient. The evolution of the variables can be seen on the next table. On multivariate analysis an inverse relationship between vitamin D and CTX levels was detected (p≤ 0.05). DEXA hip measures tend to become stabilized after Bisphosphonate treatment. <h3>Conclusion</h3> On our cohort, bone resorption biomarkers decrease after Vitamin D restoring. Antiresorptive therapy in high risk patients stopped bone loss, especially in hip. After two years follow up, with the treatment algorithm applied, fracture incidence was lower than other series published. <h3>Reference</h3> [1] *J Musculoskelet Neuronal Interact 2011: 11(3):257-265 <h3>Disclosure of Interests</h3> None declared