tbuckley/cabot-search huggingface dataset:
Evaluation of Prophylactic Corticosteroid Eye Drop Use in the Management of Corneal Abnormalities Induced by the Antibody–Drug Conjugate Mirvetuximab Soravtansine
Authors: Ursula A. Matulonis, Michael J. Birrer, David M. O'Malley, Kathleen N. Moore, Jason Konner, Lucy Gilbert, Lainie P. Martin, Todd M. Bauer, Amit M. Oza, Karim Malek, Jan Pinkas, Stella K. Kim
Journal: Clinical Cancer Research (2018)

Reversible, low-grade ocular adverse events (AE) are associated with administration of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeted antibody-drug conjugate undergoing phase III clinical evaluation in platinum-resistant ovarian cancer. This study investigated the underlying mechanisms of ocular toxicity and evaluated primary prophylactic use of corticosteroid eye drops in patients receiving mirvetuximab soravtansine.Target expression in the human eye was determined by IHC. The ocular toxicity profile of mirvetuximab soravtansine was assessed preclinically using Dutch-Belted rabbits. In a phase I clinical study, patients with ovarian cancer were treated with 6 mg/kg mirvetuximab soravtansine intravenously once every 3 weeks, including one expansion cohort with corticosteroid eye drops administered daily for the first 10 days of each treatment cycle.FRα expression was absent from human corneal tissues. Ocular abnormalities in the rabbit eye appeared phenotypically consistent with off-target effects on the cornea. Forty patients were enrolled in the expansion cohort. Reversible grade 1 or 2 blurred vision and keratopathy occurred in 16 (40%) and 12 (30%) patients, respectively; no grade 3/4 ocular events were observed. Compared with those patients who did not receive primary prophylaxis, corticosteroid eye drop use resulted in fewer dose reductions (5% vs. 15%) and none discontinued due to ocular AEs.Preclinical modeling was predictive of the corneal-related symptoms seen in some patients dosed with mirvetuximab soravtansine. Primary prophylactic use of topical corticosteroid eye drops resulted in a trend toward symptomatic improvement and a reduction in ocular AE-related dose modifications in patients treated with mirvetuximab soravtansine.
IMMU-45. DOSE MODULATION OF TEMOZOLOMIDE HAVE DISTINCT EFFECTS ON HOST RESPONSE TO PD-1 BLOCKADE
Authors: Aida Karachi, Farhad Dastmalchi, Changlin Yang, Jianping Huang, Elias Sayour, Duane Mitchell, Maryam Rahman
Journal: Neuro-Oncology (2018)

Temozolomide is known to affect efficacy of immunotherapy due to effects on the tumor microenvironment and host immune cell function. The effects of temozolomide dosing on efficacy of immune checkpoint inhibition is unknown. HYPOTHESIS: Dose modification of temozolomide modulates host immunity to increase efficacy of immune checkpoint blockade in a murine syngeneic glioblastoma model. Experiments were performed utilizing GL261 tumor bearing mice treated with standard dose (SD) temozolomide (50mg/kg x 5 days), metronomic dose (MD) temozolomide (25mg/kg x 10 days) and/or anti-PD1 antibody. SD temozolomide treatment resulted in greater lymphopenia and a more immunosuppressive profile compared to MD temozolomide in GL261 tumor bearing mice. SD temozolomide caused an upregulation of Tim-3, Lag-3 and PD-1 on peripheral and splenic CD4 and CD8 T cells. MD temozolomide increased PD-1 expression without concomitant Tim-3 or Lag-3 expression on CD4 and CD8 T cells. SD temozolomide also resulted in an increase in myeloid derived suppressor cells which was not observed with MD temozolomide. Moreover, antigen specific CD8 T cells were less functional as measured by IFN-gamma secretion when treated with SD temozolomide as compared with MD temozolomide. Analysis of tumor infiltrating lymphocytes also demonstrated increased exhaustion when treated with SD temozolomide compared to MD temozolomide. Combination treatment with PD-1 blockade and either MD or SD temozolomide demonstrated higher expression of checkpoints and immune exhaustion profiles in the SD temozolomide group measured by RNA sequencing. Survival analysis revealed that PD-1 blockade resulted in survival benefit in tumor bearing animals. However, SD temozolomide abrogated this survival benefit when combined with PD-1 blockade. MD temozolomide preserved the survival advantage of PD-1 blockade. Dose modification of temozolomide impacts efficacy of immune checkpoint blockade by modulating immune effector cells. Strategies to reverse T cell exhaustion induced by SD temozolomide are underway.
Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants
Authors: Elizabeth R C Millett, Sanne A E Peters, Mark Woodward
Journal: BMJ (2018)

Abstract Objectives To investigate sex differences in risk factors for incident myocardial infarction (MI) and whether they vary with age. Design Prospective population based study. Setting UK Biobank. Participants 471 998 participants (56% women; mean age 56.2) with no history of cardiovascular disease. Main outcome measure Incident (fatal and non-fatal) MI. Results 5081 participants (1463 (28.8%) of whom were women) had MI over seven years’ mean follow-up, resulting in an incidence per 10 000 person years of 7.76 (95% confidence interval 7.37 to 8.16) for women and 24.35 (23.57 to 25.16) for men. Higher blood pressure indices, smoking intensity, body mass index, and the presence of diabetes were associated with an increased risk of MI in men and women, but associations were attenuated with age. In women, systolic blood pressure and hypertension, smoking status and intensity, and diabetes were associated with higher hazard ratios for MI compared with men: ratio of hazard ratios 1.09 (95% confidence interval 1.02 to 1.16) for systolic blood pressure, 1.55 (1.32 to 1.83) for current smoking, 2.91 (1.56 to 5.45) for type 1 diabetes, and 1.47 (1.16 to 1.87) for type 2 diabetes. There was no evidence that any of these ratios of hazard ratios decreased with age (P&gt;0.2). With the exception of type 1 diabetes, the incidence of MI was higher in men than in women for all risk factors. Conclusions Although the incidence of MI was higher in men than in women, several risk factors were more strongly associated with MI in women compared with men. Sex specific associations between risk factors and MI declined with age, but, where it occurred, the higher relative risk in women remained. As the population ages and the prevalence of lifestyle associated risk factors increase, the incidence of MI in women will likely become more similar to that in men.
MNGI-06. MENINGIOMA METASTASES: INCIDENCE AND SCREENING IN 1203 PATIENTS
Authors: Cecilia Dalle Ore, Stephen Magill, Adam Yen, Maryam Shahin, David Lee, Calixto-Hope Lucas, Jennifer Viner, Manish Aghi, Philip Theodosopoulos, David Raleigh, Javier Villanueva-Meyer, Michael McDermott
Journal: Neuro-Oncology (2018)

Extracranial meningioma metastases are rare, and patients with meningiomas are not routinely screened for systemic metastases. We report our experience with meningioma metastases and screening for metastases in select patients with recurrent meningiomas. All patients undergoing surgical resection or stereotactic radiosurgery for primary or recurrent meningioma from 2009 to 2017 at a single center were retrospectively reviewed. Indications for metastasis screening were patients with recurrent meningioma after 2 prior resections and radiation therapy or symptoms concerning for metastasis. Screening was performed with CT chest/abdomen/pelvis, FDG PET-CT, or somatostatin receptor specific (DOTATATE) PET-CT. Of 1203 patients treated, 929 (77.2%) had WHO grade 1 meningioma by surgical pathology or imaging, 234 (19.5%) had grade 2 and 35 (2.9%) had grade 3 meningioma. A total of 298 meningiomas (24.8%) recurred, with a mean of 1.6 recurrences per patient. Screening for metastases was performed in 28 patients; one (3.6%) had a grade 1 tumor, 16 (57.1%) were grade 2, and 11 (39.3%) were grade 3. Five patients (17.9%) were screened because of systemic symptoms. Of the patients screened, 27 (96.4%) had recurrent meningioma, with a mean 3.2 recurrences. Ten patients (35.7%) had suspicious extracranial lesions by imaging. On biopsy, 8 were meningioma metastases, 1 was a non-meningioma malignancy, and 1 was lost to follow-up. Biopsy-confirmed metastases occurred in: liver (5), lung (3), mediastinum (1) and bone (1). The overall incidence of metastases was 0.67% (n=8). Incidence increased to 2% of WHO grade II tumors and 8.6% of grade 3. Using our indications, the number needed to screen to identify one patient with biopsy-confirmed malignancy was 3.1. Screening of patients with multiply recurrent meningioma or symptoms concerning for metastasis may identify extracranial metastases in a significant proportion of patients and can inform decision making for additional treatments.
Enhanced detection of circulating tumor DNA by fragment size analysis
Authors: Florent Mouliere, Dineika Chandrananda, Anna M. Piskorz, Elizabeth K. Moore, James Morris, Lise Barlebo Ahlborn, Richard Mair, Teodora Goranova, Francesco Marass, Katrin Heider, Jonathan C. M. Wan, Anna Supernat, Irena Hudecova, Ioannis Gounaris, Susana Ros, Mercedes Jimenez-Linan, Javier Garcia-Corbacho, Keval Patel, Olga Østrup, Suzanne Murphy, Matthew D. Eldridge, Davina Gale, Grant D. Stewart, Johanna Burge, Wendy N. Cooper, Michiel S. van der Heijden, Charles E. Massie, Colin Watts, Pippa Corrie, Simon Pacey, Kevin M. Brindle, Richard D. Baird, Morten Mau-Sørensen, Christine A. Parkinson, Christopher G. Smith, James D. Brenton, Nitzan Rosenfeld
Journal: Science Translational Medicine (2018)

Selective sequencing or in silico analysis for differences in DNA fragment size can improve the detection of circulating tumor DNA.
IMMU-05. LATE EFFECTS OF INTRACRANIAL RADIATION INDUCES RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE THERAPY THAT IS PARTIALLY REVERSIBLE WITH CSF-1R INHIBITION
Authors: Tanner Johanns, Liya Yuan, John Engelbach, Gavin Dunn, Dinesh Thotala, Scott Beeman, Christina Tsien, Joseph Ackerman, Joel Garbow
Journal: Neuro-Oncology (2018)

Primary and metastatic CNS malignancies remain incurable despite aggressive therapy with surgery and radiation. Immunotherapy has shown promise in many solid and hematologic malignancies, however, results have been disappointing in recurrent primary CNS tumors. Additionally, while upfront immune checkpoint blockade therapy (ICB) has shown equal efficacy intracranially and extracranially, these responses are abrogated in previously irradiated brain lesions. Together, we hypothesize that radiation modulates the brain microenvironment to permit tumor growth and suppress anti-tumor immunity. As such, we developed a mouse model whereby orthotopic transplantation of murine gliomas into previously irradiated normal brain results in a more aggressive tumor phenotype. Moreover, the ICB-sensitive glioma cell line, GL261, is resistant to ICB therapy when implanted into a previously irradiated brain microenvironment. Immunophenotyping revealed a decreased ratio of CD8:CD4 T cells within tumor-infiltrating lymphocytes isolated from previously irradiated mice though the relative frequency of neoantigen-specific CD8 T cells was slightly increased and no difference in PD-1 expression was observed. Alternatively, the frequency of microglia and tumor-infiltrating CD11b+ Gr-1+ myeloid-derived suppressor cells (MDSC) was increased following irradiation suggesting a potential role for these myeloid cells in the immunosuppressive effects noted. Consistently, the administration of a CSF-1R inhibitor, which has been shown to reduce the number of microglia and block MDSCs, partially resensitizes GL261 cells to ICB therapy. In summary, we have developed a model that recapitulates the late effects of radiation on immunotherapy-resistance in CNS tumors. Preliminary results suggest that these late radiation effects are mediated through an increased myeloid population, and that inhibition of these cell subsets via the CSF-1R pathway can partially restore efficacy of ICB therapy. Furthermore, this model may provide further insight into additional therapeutic strategies that can be used to overcome these mechanisms of resistance induced by radiation therapy in the CNS.
Immunogenicity, safety, and tolerability of the measles-vectored chikungunya virus vaccine MV-CHIK: a double-blind, randomised, placebo-controlled and active-controlled phase 2 trial
Authors: Emil C Reisinger, Roland Tschismarov, Eckhard Beubler, Ursula Wiedermann, Christa Firbas, Micha Loebermann, Andrea Pfeiffer, Matthias Muellner, Erich Tauber, Katrin Ramsauer
Journal: The Lancet (2018)
RBTT-02. ENHANCING VACCINE RESPONSES WITH DOSE-INTENSIFIED TEMOZOLOMIDE IN GLIOBLASTOMA: INITIATION OF THE I-ATTAC TRIAL
Authors: Kristen Batich, David Ashley, Gary Archer, Luis Sanchez-Perez, Pam Norberg, Kendra Congdon, James Herndon, Frances McSherry, Sarah Gemberling, Rachel Hesler, Denise Jaggers, Rachael Van, Jordan Parker, Katherine Peters, Annick Desjardins, Henry Friedman, John Sampson
Journal: Neuro-Oncology (2018)

Two of our previous clinical trials targeting Cytomegalovirus (CMV) protein pp65 in newly diagnosed glioblastoma (GBM) using pp65-specific dendritic cell (DC) vaccines have yielded long term survival rates greatly exceeding those predicted with standard of care. In the ATTAC trial (IND 12839), patients received sequential DC vaccination throughout monthly cycles of standard temozolomide (STD-TMZ) 200mg/m2/d for 5d and were randomized to one of two vaccine site preconditioning regimens. Significantly higher rates of DC migration (p=0.04) and survival (p=0.013) were observed in patients randomized to tetanus preconditioning, with half of the cohort living to nearly five years after diagnosis. In the ATTAC-GM trial, we treated a subsequent cohort with dose-intensified TMZ (DI-TMZ) 100mg/m2/d for 21d prior to and throughout vaccination with GM-CSF-containing DC vaccines and observed extraordinarily prolonged progression-free survival (PFS) and overall survival (OS) (median 25.3 and 41.1 months, respectively). In this trial, DI-TMZ-induced lymphopenia facilitated homeostatic expansion of pp65 responses after an initial DI-TMZ cycle but later ablated T cell responses when monthly cycles were reintroduced. The benefit of DI-TMZ thus warrants further study in a larger series of patients. Here we describe the initiation of a validation trial, “I-ATTAC: Improved Anti-Tumor Immunotherapy Targeted Against Cytomegalovirus in Patients with Newly-Diagnosed WHO Grade IV Unmethylated Glioma” (IND-16301). This prospective single arm Phase 2 trial of 48 patients will validate our findings that tetanus preconditioning and GM-CSF in conjunction with pp65-DCs extends OS in patients with newly diagnosed, unmethylated GBM. By withholding additional TMZ cycles in this patient population, we hypothesize that CMV immune responses will not be abrogated as previously observed, and that this greater expansion will translate into further prolonged survival (primary objective). A series of secondary objectives will be evaluated for the association between increased DC migration, systemic mediators of tetanus preconditioning, and T cell polyfunctionality with survival.
Abstract 11815: Effects of Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers and Beta-Blockers on the Prevention of Atrial Fibrillation in Patients With Heart Failure With Preserved Ejection Fraction: A Prospective Study of Four-Years Follow-Up
Authors: Masanori Kawasaki, Ryuhei Tanaka, Shingo Minatoguchi, Takatomo Watanabe, Maki Saeki, Maki Nagaya, Koji Ono, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Shinya Minatoguchi
Journal: Circulation (2014)

Background: The incidence of new-onset atrial fibrillation (AF) is increasing with the prevalence of diastolic dysfunction. Diastolic dysfunction is thought to be responsible for heart failure with preserved ejection fraction (HFPEF). Effective medication for the treatment of HFPEF has been controversial, although angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) and beta-blockers (BBs) have been proven to be effective in heart failure with reduced EF. We recently reported that pulmonary capillary wedge pressure (ePCWP) estimated by the combination of left atrial (LA) volume (V) and emptying function (EF) evaluated by speckle tracking echocardiography (STE) had a strong correlation with PCWP measured by cardiac catheterization (r=0.86-0.92). Methods: We screened 663 elderly (&gt;65 years old) patients and identified 228 who had no AF history and met the criteria for diastolic dysfunction according to the Echocardiography Association of the European Society of Cardiology. These patients were prospectively followed for 4 years to identify new-onset AF. We measured echocardiographic parameters such as left ventricular (LV) mass index, LV ejection fraction, E/A, E/e’ and ePCWP at baseline. Concomitant medication was left to the discretion of the physicians in charge. Results: During a mean follow-up of 43 months, 63 elderly patients (age 73±6, 39 men) developed electrocardiographically-confirmed AF. There was no significant difference in the development of new-onset AF between the groups treated with and without BBs (hazard ratio (HR): 0.615, p=0.15). There was also no significant difference in new-onset AF between the groups with and without ACEIs or ARBs (HR: 0.796, p=0.46). However, in multivariate analysis that included ePCWP, LVM index, E/e’ and E/A, ePCWP at baseline independently predicted the risk of new-onset AF (HR: 1.42, 95% confidence interval: 1.29-1.57, p&lt;0.001). Conclusions: ACEIs, ARBs or BBs had no beneficial effects on the prevention of new-onset AF as a marker of diastolic dysfunction in the patients with HFPEF. Estimation of ePCWP by STE had incremental value for the risk stratification of new-onset AF.
CSIG-42. HIGH THROUGHPUT KINOME AND TRANSCRIPTOME ANALYSES REVEAL NOVEL THERAPEUTIC TARGETS IN NF2-DEFICIENT MENINGIOMA
Authors: Roberta Beauchamp, Serkan Erdin, Steven Angus, Timothy Stuhlmiller, Janet Oblinger, Justin Jordan, Stephen J Haggarty, Scott R. Plotkin, Long-Sheng Chang, Gary L. Johnson, James F. Gusella, Vijaya Ramesh
Journal: Neuro-Oncology (2018)

Meningiomas (MN), the most common adult primary intracranial tumor, arise from the arachnoid/meninges and are non-responsive to chemotherapies with a high recurrence rate despite surgery, necessitating effective non-invasive therapies. Our previous work showed that NF2 loss activates mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 signaling, which led to past NF2 clinical trials using rapalogs (RAD001/everolimus), and current meningioma clinical trials with dual mTORC1/mTORC2 inhibitor (mTORi) AZD2014. To understand additional dysregulated, potentially druggable pathways, we undertook an ‘omics approach of large-scale kinomics and RNA-sequencing employing CRISPR-modified human arachnoidal cells (ACs), NF2-expressing vs NF2-null. In NF2-null ACs, several kinases were elevated including erythropoietin-producing hepatocellular (EPH)-receptor tyrosine kinase (RTK) family members, Src family kinase (SFK) members, and c-KIT, all targets of dasatinib. In vitro treatment of MN cells using mTORi (AZD2014 or INK128) and dasatinib enhanced growth inhibition upon combination mTORi+dasatinib. In vivo treatment of an orthotopic mouse MN model showed moderate response to dasatinib with stronger response using INK128 or INK128+dasatinib (e-published in Neuro-Oncology). Our transcriptomic data also revealed increased expression of several ligands/growth factors, particularly NRG1/neuregulin. Expanding these results, we have confirmed increased expression of NRG1 in human NF2-null ACs. We also find NF2-null ACs secrete NRG1, and in conditioned-media experiments we observe stimulation of ErbB3, EPHA2 and mTOR pathways, suggesting an autocrine signaling mechanism. NF2-null AC or MN cells, when stimulated with exogenous NRG1, show enhanced activation of mTOR and EPH pathways besides ErbB3 signaling. Further, lapatinib (multi-ErbB inhibitor) but not erlotinib (EGFR inhibitor) attenuates the NRG1-stimulated activation of ErbB3, EPHA2 and mTOR, suggesting that NRG1-induced activation is EGFR-independent. Taken together, our results support a mechanistic link where NF2 loss increases NRG1/ErbB signaling to EPH/SFK and mTOR pathways, which may be a critical driver of tumorigenesis, thus providing a therapeutic opportunity to co-target these pathways in NF2-deficient meningiomas.
Abstract P389: Cardiovascular Disease Mortality Risk Prediction in Educational Classes across European Regions, in the MORGAM Project Populations
Authors: Marco M Ferrario, Giovanni Veronesi, Lloyd E Chambless, Hugh Tunstall-Pedoe, Kari Kuulasmaa, Veikko Salomaa, Anders Borglykke, Nigel Hart, Giancarlo Cesana
Journal: Circulation (2012)

Aims: Although socioeconomic status is a recognized independent risk factor for CVD mortality, the recommended European risk prediction equation for primary prevention does not consider it; an approach criticized by previous results in the UK and US. We aim to assess whether the SCORE project equation adequately estimates the risk in different educational classes, across several European populations. Methods: We considered 47 prospective population-based surveys from Nordic Countries (Finland, Denmark, Sweden), UK (Belfast and Scotland), Central Europe (France, Germany and Italy) and East Europe (Lithuania, Poland) and Russia. Baseline data collection and mortality follow-up (median time 10 years) adhered to standardized MONICA-like procedures. Three educational classes were derived from population-, sex- and birth year-specific tertiles of years of schooling. The individual SCORE risk was computed from age, total cholesterol, systolic blood pressure and smoking; the risk was recalibrated to the average observed risk in each population. We estimated age- and traditional risk factors-adjusted hazard ratios (HR) for 10 year CVD mortality (highest education as the reference), from Cox models. Moreover, the observed number of fatal CVD events by educational class was compared to the expected number, as estimated by the recalibrated SCORE function. Results: The cohorts summed-up 39,215 men and 29,240 women 40 to 64 years old and free from CVD event at baseline. Education was associated with CVD mortality in men (pooled age-adjusted HR for low vs high education: 1.6, 95% CI 1.4–1.9); the hazard ratios ranged from 1.3 (95%CI: 0.9–1.8) in Central Europe to 2.1 (1.6–2.7) in East Europe and Russia. The association attenuated after adjustment for SCORE risk factors and HDL-cholesterol. Among women, the association was significant in Nordic Countries only (age-adjusted HR for low vas high education: 1.7, 95% CI 1.1–2.6), but it was no more significant after adjustment for multiple risk factors. The original SCORE equation overestimated the risk at a population level, both in men and in women, except in East Europe and Russia. After recalibration, the SCORE equation overestimated the risk among the more educated men by 20% to 50% (in Central Europe, East Europe and Russia, respectively), but underestimated it in the less educated men by 7% to 23% (in Central Europe, East Europe and Russia, respectively). Conclusions: Our results, based on a well-harmonized study comprising several European populations, suggest the need to include country-specific socioeconomic status in the risk estimation equations.