tbuckley/cabot-search huggingface dataset:
CSIG-24. miR-575 IS ASSOCIATED WITH WORSE SURVIVAL OF GBM PATIENTS AND ACTS AS A NOVEL ONCOGENE THROUGH TARGETING p27/CDKN1B AND BLID/BRCC2
Authors: Tiantian Cui, Ashley Gray, Erica Hlavin Bell, Joseph McElroy, Marjolein Geurts, Wei Meng, Jahar Haque, Pierre Robe, Arnab Chakravarti
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) patients currently face poor survival outcomes with an average survival period of less than 15 months, while only 3–5% of patients survive longer than 36 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. Here, we determined the correlation between miR-575 expression in GBM tumors and overall survival (OS) of patients and undertook functional studies to unfold the contribution of this miR to GBM tumorigenesis. Total RNAs were isolated from 268 FFPE GBM tumor samples and miR expression was assayed (simultaneously) using NanoString Technologies, and univariable and multivariable cox regression analyses were performed. Cell proliferation, colony formation, migration assay, qPCR, immunoblotting, and luciferase assay were conducted to define the function of miR-575 in GBM. Our survival analysis (n=268) show that miR-575 is associated with worse OS of GBM patients (HR=1.5, p-value=5.77E-05) by continuous UVA. miR-575 was also found to be significantly associated with OS, independent of age, gender, treatment, and KPS in a MVA (HR=1.208, p=0.012). Since miR-575 was found to be negatively associated with OS, we hypothesized that miR-575 overexpression would increase tumor progression. Our functional studies indicate that overexpression of miR-575 significantly increased the proliferation and motility of LN229 and U251 GBM cells in vitro. Consistent with the result found in LN229 and U251 cells, inhibition of miR-575 in U87 cells significantly decreased their proliferation and motility. Subsequent in silico and mechanistic studies identified p27/CDKN1B and BLID/BRCC2 aspotential target genes of miR-575 in GBM. Overexpression of miR-575 in GBM cells reduced the expression of both BLID and p27 at both mRNA and protein levels. miR-575 has prognostic value in GBM, with higher expression correlating with worse OS of patients, and contributes to GBM tumorigenesis by inhibiting expression of p27 and BLID.
Suppression of Murine Lupus by <scp>CD</scp>4+ and <scp>CD</scp>8+ Treg Cells Induced by T Cell–Targeted Nanoparticles Loaded With Interleukin‐2 and Transforming Growth Factor β
Authors: David A. Horwitz, Sean Bickerton, Michael Koss, Tarek M. Fahmy, Antonio La Cava
Journal: Arthritis & Rheumatology (2018)

Objective To develop a nanoparticle ( NP ) platform that can expand both CD 4+ and CD 8+ Treg cells in vivo for the suppression of autoimmune responses in systemic lupus erythematosus ( SLE ). Methods Poly(lactic‐co‐glycolic acid) ( PLGA ) NP s encapsulating interleukin‐2 ( IL ‐2) and transforming growth factor β ( TGF β) were coated with anti‐ CD 2/ CD 4 antibodies and administered to mice with lupus‐like disease induced by the transfer of DBA /2 T cells into (C57 BL /6 × DBA /2)F 1 ( BDF 1) mice. The peripheral frequency of Treg cells was monitored ex vivo by flow cytometry. Disease progression was assessed by measuring serum anti–double‐stranded DNA antibody levels by enzyme‐linked immunosorbent assay. Kidney disease was defined as the presence of proteinuria or renal histopathologic features. Results Anti‐ CD 2/ CD 4 antibody–coated, but not noncoated, NP s encapsulating IL ‐2 and TGF β induced CD 4+ and CD 8+ FoxP3+ Treg cells in vitro. The optimal dosing regimen of NP s for expansion of CD 4+ and CD 8+ Treg cells was determined in in vivo studies in mice without lupus and then tested in BDF 1 mice with lupus. The administration of anti‐ CD 2/ CD 4 antibody–coated NP s encapsulating IL ‐2 and TGF β resulted in the expansion of CD 4+ and CD 8+ Treg cells, a marked suppression of anti‐ DNA antibody production, and reduced renal disease. Conclusion This study shows for the first time that T cell–targeted PLGA NP s encapsulating IL ‐2 and TGF β can expand both CD 4+ and CD 8+ Treg cells in vivo and suppress murine lupus. This approach, which enables the expansion of Treg cells in vivo and inhibits pathogenic immune responses in SLE , could represent a potential new therapeutic modality in autoimmune conditions characterized by impaired Treg cell function associated with IL ‐2 deficiency.
INNV-07. BRACHYTHERAPY IN GLIOBLASTOMA: A SURVEILLANCE, EPIDEMIOLOGY, AND END RESULTS (SEER) ANALYSIS
Authors: Ali Alattar, Jiri Bartek, Sanjay Dhawan, Jun Ma, Clark Chen
Journal: Neuro-Oncology (2018)

There are several justifications for brachytherapy as treatment for glioblastoma, including continuous dose rate, high cumulative dose, and rapid radiation delivery. However, two landmark randomized clinical trials (RCT) have failed to demonstrate clinical efficacy. With the development of novel radiation sources and an improved technology, there has been a resurgence in interest in brachytherapy. Here, we used a large national cancer registry to assess the survival benefit of adjuvant brachytherapy in glioblastoma. We identified patients diagnosed with glioblastoma in the Surveillance, Epidemiology, and End Results (SEER) database between 1975–2015. We grouped patients based on receipt of brachytherapy. We collected information on clinical and demographic variables associated with survival. We analyzed group differences using Student’s t-test and Pearson’s chi-squared test and studied survival using Kaplan-Meier curves and Cox proportional hazards models. Of 54,589 glioblastoma patients, 325 were treated with adjuvant brachytherapy. Brachytherapy patients were younger, had smaller tumors, and were more likely to receive extensive surgery and chemotherapy. Median survival was 16 months for patients who received brachytherapy compared to 9 months for patients who did not (log-rank p<0.001). In univariable analysis, variables associated with improved survival include: younger age, tumors <4 cm, no midline extension, extensive surgery, and treatment with chemotherapy. In a multivariable analysis that controlled for these variables, the association between improved survival and brachytherapy remain robust. In this analysis, the hazard of death was reduced in patients receiving brachytherapy (HR 0.758, p<0.001) relative to patients who did not receive brachytherapy. Given the effect size observed, we estimate that previous RCTs did not have sufficient sample size. Our SEER analysis suggests potential efficacy of brachytherapy as a glioblastoma therapy. Interpretation of our analysis need to be framed in the context of the inherent limitations of the SEER database, the two previously published randomized controlled studies, and the available literature.
QOLP-12. A NOVEL MULTIDISCIPLINARY CARE CLINIC MODEL FOR FRAIL PATIENTS WITH CENTRAL NERVOUS SYSTEM MALIGNANCIES
Authors: Kathryn Nevel, Mary Elizabeth Davis, Anna Skakodub, Jessica Ali, Anne Sullivan-Henry, Jodi Gilman, Mabel Harrison, Melody Huang, Lauren Bailey, Kyle Mack, Gayle Rawlins-Peters, Dominique Jean-Charles, Dawn Kilkenny, Anne Martin, Brian Kelly, Lindsay Cohen, Abiola Saliu, Michael Trapani, Stephanie Zavolas, Jesuel Padro Guzman, Eli Diamond, Alan Carver, Lisa DeAngelis, Kara Barnett, Lisa Ruppert, Elena Pentsova
Journal: Neuro-Oncology (2018)

Physical, cognitive, and existential needs are common in patients with central nervous system (CNS) malignancies, however not all needs can be addressed in routine clinic visits. To identify and address complex patient and caregiver needs, we implemented a novel multidisciplinary care clinic (MDCC) for patients with CNS malignancies at our institution. Monthly between 8/2017-4/2018, a team comprising a neurologist, physiatrist, nurse, physical therapist, case manager, social worker, dietitian and chaplain assessed patients with CNS malignancies, neurological deficits and KPS ≤80. Within a 3 hour-visit, providers rotated in to see patient/caregiver. Starting in 11/2017, participants completed validated surveys on unmet needs, financial strain, and home equipment prior to MDCC and on satisfaction after clinic. Descriptive statistics were used to analyze results. Forty-two patients were seen: twenty-two (50%) were female; median age=64. Diagnoses included gliomas (n=30), brain metastases (n=8), other primary brain tumors (n=4); median KPS=70 (range 50–80). Thirty-one (74%) patients were on cancer-directed therapy and eleven (26%) on surveillance. Twenty-five patients completed pre-MDCC surveys, the predominant unmet need (96%) was: “not being able to do the things you used to do”; 15 (60%) expressed worry about their ability to pay for cancer care. Twenty-four caregivers completed the pre-MDCC survey, the predominant unmet need (83%) was: “I need my partner to have an ongoing case manager.” At MDCC, 38 (90%) patients received recommendations for symptom management, 34 (81%) discussed prognosis and/or coping with cancer, and 33 (78%) established or updated their physical therapy and/or home services. Twenty-four patients (57%) completed a post-MDCC satisfaction survey: 100% felt the clinic was helpful, and 96% would recommend the clinic to others. This study identifies a new shared-appointment model of care to identify and address unmet needs. Additional prospective study is needed to determine the role of this clinic in neuro-oncologic care.
Abstract 18452: Importance of “Dynamic” Rather Than “Static” Central Venous Pressure and Venous Capacitance in Fontan Circulation During Exercise
Authors: Clara Kurishima, Seiko Kuwata, Yoichi Iwamoto, Hirotaka Ishido, Satoshi Masutani, Hideaki Senzaki
Journal: Circulation (2015)

Background: High central venous pressure (CVP) is a key driver of developing late complications in patients after Fontan operation. However, we often realize diversity of clinical outcome among patients with similar levels of CVP measured at resting condition during catheterization. We hypothesized that CVP variably increases with exercise and that degree of the increase is associated with clinical outcomes. We also hypothesized that venous capacitance (VC) is an important determinant of the CVP elevation. Methods: Dynamic changes in CVP estimated from continuous monitoring of peripheral venous pressure were measured during treadmill exercise (TM) in 21 Fontan patients and 10 age-matched control patients with biventricular (BV) circulation. The VC was calculated during temporal occlusion of inferior vena cava (IVC) at the time of catheterization. Results: Fontan patients exhibited significantly shorter duration of exercise with limited increases in heart rate and cardiac output. CVP significantly increased during exercise in both groups, but the degree of CVP elevation was much higher in Fontan patients than in controls (Fontan: from 10.8 to 18.4 mmHg vs. control: from 4.3 to 8.8 mmHg, P&lt;0.05). Importantly, maximum CVP during exercise in Fontan group varied considerably among patients with similar resting CVP, and is significantly and positively correlated with a liver fibrosis marker of type 4 collagen 7S (P &lt;0.01). Furthermore, maximum CVP during exercise in Fontan group negatively correlated with the VC, but not with pulmonary resistance. Conclusions: CVP of the Fontan circulation easily rises during exercise in proportion to the reduced VC, and the degree of CVP rise may be a contributor of hepatic complication. These results suggest the importance of assessing dynamic CVP in patients after Fontan operation. The results also suggest potential importance of daily life modification and/or medical treatment to minimize the dynamic changes in CVP to improve the prognosis of Fontan patients. VC may be a viable target for this purpose.
Abstract 13381: The Relationship Between PAD Symptomatology and Ischemia: a Mixed Method Evaluation
Authors: Erica Schorr, Diane Treat-Jacobson, Kay Savik, Ruth Lindquist
Journal: Circulation (2014)

Introduction: Classic claudication is only reported by 7.5% to 33% of patients with PAD. Atypical symptom reporting is common, but it is unknown if ischemic changes are occurring since the relationship between atypical symptoms and tissue oxygen saturation (StO 2 ) has not previously been reported. The purpose of this study was to measure calf StO 2 during treadmill exercise and recovery, and evaluate its relationship with self-reported symptoms. Methods: Adults diagnosed with PAD and experiencing exercise-limiting ischemic symptoms were asked to: (a) use a numeric rating scale (0 to 5) to rate symptoms during exercise and recovery; (b) provide symptom descriptors; and (c) wear a near-infrared spectroscopy device to obtain calf StO 2 during exercise and recovery. Data analysis included descriptive statistics, exploration of individual and grouped graphical trajectories, and multilevel modeling. Results: During three successive bouts of treadmill exercise, 40 participants (80% Caucasian males, mean age 68±9 years) provided 22 symptom descriptors in eight lower extremity locations. Only 69.2% of exercise tests were stopped due to discomfort in the calf and classic descriptors were used only half the time to describe maximum calf discomfort (55.4%). The most rapid decline in StO 2 during exercise occurred between the start of exercise and the onset of symptoms. The nadir StO 2 was often reached prior to the report of maximum discomfort. In the exercise model, changes in StO 2 were related to total exercise time ( p &lt;0.001), baseline StO 2 ( p &lt;0.001), exercise ratings ( p &lt;0.001) and ABI ( p &lt;0.05). During recovery, StO 2 increased steadily for most participants between maximum discomfort and full symptom recovery; changes in StO 2 were related to recovery ratings ( p &lt;0.001) and ABI ( p &lt;0.03). Conclusions: Ischemic symptoms extended beyond classic locations and descriptors. Interestingly, participant perception of maximum discomfort frequently occurred after the nadir StO 2 . Similarly, most reports of full symptom recovery occurred prior to complete resolution of ischemia. Further research is necessary to explore mechanisms that could explain this objective-subjective mismatch to better understand the full range of ischemic symptoms associated with PAD.
ACTR-55. TUMOR VOLUME AS A PREDICTOR OF RESPONSE TO ANTI-EGFR ADC ABT-414
Authors: Hui Gan, Aidan Seow, Eddie Lau, Lee Sze-Ting, Malaka Ameratunga, Yuliya Perchyonok, Diana Cao, Angela Rigopoulos, Ho-Jin Lee, Erica Gomez, David Maag, Andrew Scott
Journal: Neuro-Oncology (2018)

BACKGROUNDAdverse biophysical factors (abnormal vessels and increased interstitial pressure) are increased in larger brain tumors, which negatively impacts penetration of antibody drug conjugates (ADC). The tumour-specific anti-EGFR ADC, depatuxizumab mafadotin (depatux-m), demonstrated encouraging activity in a Phase 1 glioblastoma study (M12-356 study, NCT01800695). The impact of tumour size on depatux-m efficacy was investigated. PRECLINICAL STUDY: Forty mice were engrafted with patient derived xenografts from an M12-356 patient. Eight mice were imaged in a zirconium-labelled depatux-m (3mg/kg) biodistribution study at small (70mm3,n=2) or large (350mm3,n=2) tumour volumes; another 4 mice were imaged with a control ADC. In the controls, non-specific uptake due to blood pool activity was 5% ID/g. In the 89Zr-depatux-m treated groups, mice with larger tumours had significantly less uptake compared smaller tumours (11 vs 21 %ID/gram, p<0.0001). Similarly, tumour inhibition due to depatux-m (3mg/kg every 3 days for 3 weeks, n=16 mice) was significantly less when treatment commenced at larger volumes (27% vs 93%, p<0.001). CLINICAL STUDY: To confirm our preclinical data, two reviewers (EL, AS) retrospectively undertook a blinded volumetric analysis of baseline tumor volumes in M12-356. Inter-rater agreement was excellent. Response was compared by chi-square analysis and OS by log-rank. 110 patients with EGFR-amplified, recurrent glioblastoma were treated with depatux-m, alone or in combination with temozolomide. Patients with larger tumours had significant worse response rates (0% in > 25cm3 vs 17% in < 25cm3, p=0.009) and worse overall survival (0.52 vs 0.81 years, p=0.001). The results were similar in patients treated with depatux-m monotherapy for response (n=60, 0% vs 10%, p=0.287) and survival (n=62, 0.50 vs 0.89 years, p=0.001)
BIOL-01. PHOSPHORYLATION OF EZH2 PROMOTES GLIOBLASTOMA STEM-LIKE CELLS SELF-RENEWAL THROUGH NF-κB METHYLATION
Authors: Hailong Liu
Journal: Neuro-Oncology (2019)

Glioma stem-like cells (GSCs) comprise the critical subpopulation with the properties of self-renewal and tumorigenesis. Striking parallels between cancer stem-like cells (CSCs) and normal stem cells indicate that tumor cells may evolve from CSCs. Although the oncogenic roles of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homologue 2 (EZH2) have been reported in accumulated research, the specific mechanistic contribution of these two ones to the stemness of GSCs remains incompletely identifiable. Here, we report that EZH2 phosphorylated by MELK binding to NF-κB methylates it in GSCs, which promotes its ability to mediate the development of glioblastoma. Clinically, the proportion of MEKL/EZH2/NF-κB axis elevates progressively during the increasing glioma grades and can be considered as the potential indicator of survival. Conversely, loss of this signaling dramatically suppresses the proliferation of GSCs. In conclusion, our findings show that the MELK/EZH2/NF-κB pathway is required for the GSCs derived neoplastic proliferation, thereby uncovering in the signaling a therapeutic candidate to treat this malignancy.
DDIS-25. TARGETING GLIOBLASTOMA HETEROGENEITY WITH miR-34a
Authors: Muhammad Khan, Rosamaria Ruggieri, Nhan Tran, Jann Sarkaria, Jennifer MacDiarmid, Himanshu Brahmbhatt, John Boockvar, Marc Symons
Journal: Neuro-Oncology (2018)

microRNA-34a could serve as a novel therapeutic agent as it is under-expressed in Glioblastoma and modulates the expression of multiple genes in the deregulated p53, Rb and receptor tyrosine kinase networks which confer selective growth advantage and represent significant intra-tumoral heterogeneity, a major cause of therapeutic resistance. We studied the effects of microRNA-34a transfection in three primary patient-derived lines (GBM 6, GBM118 and GBM 126, respectively belonging to classical, mesenchymal and proneural subtypes), four established cell lines (T98G, U251, A172, LN229; where T98G and U251 show primary resistance to treatment while A172 and LN229 are sensitive) and two cell lines with acquired resistance to temozolomide (A172-TR, LN229-TR). Transfection with microRNA-34a mimics significantly reduced proliferation and sensitized to temozolomide (Combination Index< 0.2–0.6) and radiation (dose enhancement factor 1.7–2.2) treatment, regardless of baseline treatment resistance in all studied cell lines. We identified broadly conserved binding sites in the 3’UTR of multiple mRNAs in the Glioblastoma deregulated networks and genes known to confer therapeutic resistance and validated the direct downregulation of Bcl-2 protein as a major contributor to temozolomide sensitization. For in vivo delivery, nanocells (400 nm diameter), termed EDV, were derived from genetically modified bacteria, provided with a bispecific antibody targeting EGFR and loaded with microRNA-34a. EDVs were injected intravenously while temozolomide was administered by oral gavage in GBM6 orthotopic mouse model. We observed a significant reduction in tumor growth in mice treated with microRNA-34a EDV relative to control EDV-treated mice (p=0.021). Further, microRNA-34a EDV significantly improved survival and synergized with temozolomide therapy [p<0.001, median survival of control EDV, microRNA-34a EDV, control EDV with temozolomide and microRNA-34a EDV with temozolomide was 44, 48, 86 and 147+ days respectively]. In conclusion, microRNA-34a EDV is a promising novel therapeutic that inhibits Glioblastoma tumor growth and counteracts therapeutic resistance and intra-tumor heterogeneity.
Patients with type 1 diabetes are missing out on flash glucose devices, finds BMJ investigation
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Tens of thousands of UK patients with type 1 diabetes are being denied the potential benefits of “flash” glucose monitoring devices because they are not being recommended in some areas, an investigation by The BMJ has found. Flash glucose monitoring, which works from a sensor attached to the skin, has been available on prescription since 1 November 2017. Users get glucose readings by scanning the sensor with a portable reader or a smartphone app. The reading shows an arrow that indicates whether glucose concentrations are rising or falling. Abbott’s FreeStyle Libre is currently the only such device available in the UK. NHS England has advised clinical commissioning groups which patients should get prescriptions for the devices (box 1). It said that the flash device has the potential to improve patients’ quality of life, supports self management, and could save money in the long term by reducing complications and hospital admissions, although it has acknowledged gaps in the evidence base. But a year after the device became available, around a quarter of CCGs in England are not recommending it for patients even if they meet NHS England’s criteria, The BMJ ’s investigation shows. Box 1 ### Who should get a FreeStyle Libre prescription? The NHS’s Regional Medicines Optimisation Committee for the North of England says that, at present, FreeStyle Libre should be used only by people with type 1 diabetes aged 4 years or above who need to have multiple daily injections of insulin or insulin pump therapy and who meet one or more of the following criteria1:RETURN TO TEXT
Getting Rid of Stupid Stuff
Authors: Melinda Ashton
Journal: New England Journal of Medicine (2018)

Interview with Dr. Melinda Ashton on easing the burden of administrative tasks in medicine and helping clinicians find more meaning in their work. (10:18)Download In an effort to reduce unintended burdens for clinicians, leaders at a health system in Hawaii asked all employees to look at their daily documentation experience and report anything in the EHR that they thought was poorly designed, unnecessary, or just plain stupid.