tbuckley/cabot-search huggingface dataset:
ACTR-18. PHASE II TRIAL OF TEMOZOLOMIDE AND TRC 102, BASE EXCISION REPAIR INHIBITOR, IN BEVACIZUMAB NAÏVE GLIOBLASTOMA AT FIRST RECURRENCE
Authors: Manmeet Ahluwalia, Jan Drappatz, Xiaobu Ye, Tobias Walbert, Matthias Holdhoff, Glenn Lesser, Tim Cloughesy, David Peereboom, L Burt Nabors, Patrick Wen, Stuart Grossman, Lisa Rogers
Journal: Neuro-Oncology (2018)

Temozolomide forms O6-methylguanine (O6mG), 7-methylguanine (N7mG), and 3- methyladenine (N3mA) DNA adducts. The O6mG DNA adduct is repaired by MGMT. N7mG and N3mA DNA adducts are removed by the base excision repair (BER) pathway. TRC-102 is a BER inhibitor that binds to the apurinic site created through the action of the glycosylase. A phase II study of adult patients with bevacizumab-naïve first recurrence of glioblastoma after radiation and temozolomide was performed in the Adult Brain Tumor Consortium. Temozolomide was administered at 150 mg/ m2 and oral TRC-102 at 150 mg daily, days 1–5 every 4 weeks. Primary objective was efficacy measured by objective radiographic response rate (RR= CR+PR). Secondary objectives included safety and PFS-6. Exploratory objectives were to assess treatment efficacy with tumor expression of N-methylpurine DNA glycosylase (MPG), a BER protein, and MGMT status with RR, PFS, and OS. The study was designed to test the hypothesis that combination therapy would achieve a RR of 30%. Nineteen patients were enrolled in the first stage. Median age was 60 years (range: 48–76), 53% females, median KPS was 80 (range: 70–90). Median cycles of treatment was 2 (range: 1–12). No responses were observed. Median OS was 11.0 months (95% CI: 8–18 months), median PFS was 2.0 months (95%CI: 1.8–3.6 months). PFS-6 rate was 10.5 % (2/19). The combination was safe; two grade 3–4 toxicities included lymphopenia, thrombocytopenia. MGMT promoter was unmethylated in all patients. MPG staining was negative in six, 1+ in five and 2+ in three patients. PFS of 11 + months in two patients was associated with MPG expression. TRC 102 and temozolomide has acceptable safety but did not meet the primary endpoint of response. Tissue correlates will be presented. The study was terminated early and the combination will not be tested in bevacizumab refractory patients.
Abstract 18800: Feeding Modifies the Relationship Between Glucose Metabolism, Inflammation and Outcomes After Pediatric Heart Surgery
Authors: Alejandro A Floh, Masayuki Nakada, Gustavo La Rotta, Cedric Manlhiot, Brian W McCrindle, Glen S Van Arsdell, Steven M Schwartz
Journal: Circulation (2012)

Introduction: We have previously shown that a low post-operative glucose:insulin ratio (GIR), which suggests insulin resistance, coupled with inflammation is associated with poor clinical outcomes in children following cardiac surgery. The purpose of this study was to determine if glucose infusion rate and enteral feeding alters this relationship and the association of these factors with morbidity following cardiopulmonary bypass (CPB). Methods: Subjects included children, age 0-18y, undergoing cardiac surgery with CPB. Blood samples were collected at baseline and every 6 hours for up to 72 hours. Feeding regimens included NPO with glucose infusion, low volume feeds (&lt;20mL/kg/day) and liberal feeding. Clinical outcomes were measured with a composite morbidity-mortality endpoint reflecting organ failure. Regression models adjusted for repeated measures were used to determine associations between GIR, inflammation and outcomes in those subjects who were NPO or on low volume feeds and those being fed more liberally. Results: We studied 132 subjects with a median (IQR) age of 200 days (54, 1132) and weighing 6.79 kg (4.57, 14.7). The median (IQR) time of CPB and aortic cross clamp were 107 (71.5, 158) and 77 (54,112) minutes respectively. Median glucose infusion (IQR) rate was 1.44 (0.89-2.17) mg/kg/min. Most subjects (80%) had enteral feeds during the study, of which 29% were low volume feeds. Feeds were started on average at 30±16 hours post-surgery. A lower GIR was associated with increased TNF-alpha (EST: -0.066 (0.011)/0.1, p&lt;0.001) and IL-6 (EST:-0.456 (0.127)/0.1, p=0.001. In children who were NPO or on low volume feeds, a low GIR was associated with increased IL-6 (EST: +0.215 (0.575)/0.1, p&lt;0.001) and higher risk of reaching the composite morbidity outcome (OR: 1.24 (1.08-1.41), p=0.002). This relationship was not observed in subjects who were fed more liberally (EST: +0.198 (0.689), p=0.77). Conclusion: A low GIR is associated with increased inflammation and worse outcomes in children who are NPO or are receiving only low volume feeds after CPB, but not in children receiving more liberal enteral feeds. This study suggests early feeding might be a way to modify outcomes after pediatric heart surgery.
GENE-24. IMPACT OF THERAPY ON EVOLUTION OF GBM
Authors: Astrid Wendler, Juliane Perner, Sarah Field, Andy Lynch, Colin Watts, Simon Tavare
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is the most malignant and common primary brain cancer in adults, with a 2.5-year survival of only ~8%. In this single case study we have analysed the development of a primary GBM over four years. We performed WGS and RNAseq on three, spatially distinct samples of the treatment naïve primary tumour, the first recurrence and, the fatal second recurrence. The DNA analysis showed only one shared mutation in all of the 9 samples: a mutation in EGFR (G598V). We hypothesise that subsequent tumours developed from an original clone bearing this mutation. This mutated oncogene is located on an extrachromosomal circular DNA structure known as double minute (DM), which is found in an estimated 40% of GBM. We performed long-range sequencing using the 10X genomics technology to reconstruct the DM and shed light on its emergence. We observed a massive increase in mutations from the first to the second recurrence, showing predominantly C > T/ A > G transitions, which is a pattern typical of TMZ treatment. The fact that the hypermutation did not appear until the second recurrence raises questions about the mechanism of hypermutation. The therapeutic apoptotic action of TMZ relies on the function of the mismatch repair (MMR) pathway. In the third recurrence we observed disruptive mutations of MSH2, 5 and 6 all of which are crucial to the MMR pathway. The pattern of mutations of these genes varied between the samples taken from the second recurrence, however, all three samples showed hypermutation. This suggests that the hypermutation observed after TMZ treatment only occurs if the MMR is damaged, but that this damage does not need to be at a specific locus. Using the CRISPR-CAS9 technology we are currently exploring the impact of MMR mutations on patient derived GBM cell lines.
TMIC-23. CHEMOTHERAPY AND TAU INTERPLAY FACILITATES BREAST TO BRAIN METASTASIS
Authors: Josh Neman, Behnaz Saatian, Krutika Deshpande, Alex Julian
Journal: Neuro-Oncology (2018)

Improving the treatment of breast to brain metastases (BBM) for women with breast cancer represents a leading edge of treatment failure for Her2+and triple negative disease. Over the past several decades a wide range of tumor-centric studies have identified genes and their regulators within signaling pathways promoting breast cancer metastasis. The current prevailing view which has dominated research focus is that metastatic cancer cells enter the brain by crossing the blood-brain-barrier (BBB). However, other than the popular BBB, the central nervous system has another crucial, yet more permeable barrier: blood-cerebral spinal fluid barrier (BCSFB) made up of choroid plexus (CP). The current study exploits foundations of neuroscience to advance our understanding of the brain and metastatic breast cancer cells through the perspective of the CP/BCSFB --This bidirectional interplay of tumor cells and this native brain cells in metastases remains poorly understood and studied. Many breast cancer patients treated with chemotherapy complain of impaired memory and several basic cognitive dysfunctions before brain metastases diagnosis. Several studies have confirmed the detrimental effects of chemotherapy on cognitive performance, known as “chemo-brain.” Furthermore, recent evidence show chemotherapy promotes breast cancer metastasis. The abnormally phosphorylated and aggregated form of tau plays a critical role in neurodegenerative diseases as of such as Alzheimer’s Disease (AD). We hypothesize that chemotherapy induces tau expression in primary breast cancer cells leading to BCSFB permeability and BBM. Our results show: 1) an increase in abnormal tau expression in chemo-treated primary breast cancer cells and BBMs, 2) BBM-derived tau is abnormal and forms paired helical filaments (PHFs), similar to AD, and 3) there was a downregulation of the tight junction markers in chemo-treated BCSFB. Our results suggest a mechanism underlying the linkage between chemo-brain, breast to brain metastasis and its subsequent neurodegeneration.
EXTH-19. WIRELESS INTRACRANIAL FLUORESCENCE MONITOR FOR DRUG DETECTION IN BRAIN TUMOR PATIENTS
Authors: Herbert Engelhard, Alden Shoup, Jasim Naeem, Jodi Finlay, Justas Jakubonis, Sebastian Pernal, Alexander Willis, Hananeh Esmailbeigi, Terry Layton
Journal: Neuro-Oncology (2018)

Currently, the brain penetration of drugs cannot be adequately evaluated in real-time, making chemotherapy selection for glioblastoma patients an unpredictable and inefficient process. Given recent progress in the microminiaturization of medical devices, our objective was to design and build the prototype of an implantable device allowing immediate quantification of fluorescent agents in vivo. The Wireless Intracranial Fluorescence Monitor (WIFM) was assembled from commercially -purchased electrical and optical components, a custom-made printed circuit board (PCB), and 3D-printed couplers. Parts included a cyan LED, light-filtering lenses, optical fibers, a phototransistor, and a Bluetooth-enabled Arduino microcontroller. The filters prevented overlap of wavelengths from the LED and fluorophore emission spectra, ensuring isolated emission signals. Clinically, the WIFM would fit inside a standard Ommaya Reservoir, surgically implanted into brain parenchyma during craniotomy. The WIFM was tested in vitro in solutions of 0, 0.01, 0.05 and 0.10 mg/mL of fluorescein isothiocyanate (FITC), in PBS. FITC emission signals were converted into millivoltage readings, and transmitted to a laptop computer, allowing instantaneous wireless determinations. Voltage separations occurred 10–90 milliseconds after FITC excitation, were linearly related to FITC concentration, and allowed for FITC quantification by the device. Specifically, FITC concentrations of 0, 0.01, 0.05, and 0.10 mg/mL produced relative mV readings of 0, 30.6 ± 13.4, 99.9 ± 25.9 and 214.3 ± 21.0, respectively (n=15, p<0.05). While animal studies are needed in order to enable discrimination of interstitial fluorophore concentration, WIFM implantation offers the potential for real-time detection and quantification of the delivery of fluorescently-labeled drugs and/or nanoparticles to selected areas of the brain. Further iterations of the WIFM device should allow the administration of therapeutic agents (whether by systemic administration or convection-enhanced delvery) to be optimized, thus prolonging survival for patients with glioblastoma.
INNV-13. ALLELE: A CONSORTIUM FOR PROSPECTIVE GENOMICS AND FUNCTIONAL DIAGNOSTICS TO GUIDE PATIENT CARE AND TRIAL ANALYSIS IN NEWLY-DIAGNOSED GLIOBLASTOMA
Authors: Mehdi Touat, Adrian Dubuc, David Meredith, Junko Tsuji, Caitlin Mills, Sarah Gaffey, Jack Geduldig, Fiona Watkinson, Kristine Pelton, Seth Malinowski, Niall Lennon, Peter Sorger, Lorenzo Trippa, Shakti Ramkissoon, David Reardon, John de Groot, Evanthia Galanis, Mary Welch, L Burt Nabors, Isabel Arrillaga-Romany, E Antonio Chiocca, Sandro Santagata, David Schiff, Manmeet Ahluwalia, Howard Colman, Jan Drappatz, Brian Alexander, Patrick Wen, Keith Ligon
Journal: Neuro-Oncology (2018)

reporting of events, among other biases.We developed a glioblastoma specific app (OurBrainBank) using a platform designed by uMotif, which was previously used in other conditions but has been customized for glioblastoma.All data are sent to a HIPPA compliant database.The subject can view or export their own data as well.Inclusion criteria included age 18 years or older, diagnosis of glioblastoma, English-speaking subject, and availability of a smartphone or tablet.After electronic informed consent, patients completed baseline questionnaires about their treatment and validated surveys (EORTC-QLQ, EORTC-BN20).Certain parameters such as sleep quality, exercise, mood, and fatigue were captured for all patients.In addition, patients picked 6 additional symptoms most relevant to their clinical condition.Over a 2-month period, since the study was IRB-approved and the app made available free of charge on app stores, there have been 591 individual patients downloads (167 on Android and 424 on iOS).Recruitment has relied heavily on social media and patient run online support groups.We will present the data on compliance, patient characteristics and symptoms tracking at the meeting.At this initial stage, OurBrainBank's focus is on capturing patients' symptoms.In the next steps, we plan to collect passive data from smartphones and other device trackers.Additionally, OurBrainBank will enable patients to donate their medical records to the database.The goal over the next few years is to create an unprecedented database of high quality and granularity with tens of thousands of de-identified glioblastoma patients, with open-access to qualified academic researchers.In addition, this powerful 'real world experience' database will be useful for pharma/biotech companies, and may also facilitate FDA drug approvals for glioblastoma.
ALLO-715, an Allogeneic BCMA CAR T Therapy Possessing an Off-Switch for the Treatment of Multiple Myeloma
Authors: Cesar Sommer, Bijan Boldajipour, Julien Valton, Roman Galetto, Trevor Bentley, Janette Sutton, Yajin Ni, Mark Leonard, Thomas Van Blarcom, Julianne Smith, Javier Chaparro-Riggers, Barbra Sasu
Journal: Blood (2018)
Current Understanding and Gaps in Research of Carotid Webs in Ischemic Strokes
Authors: Song J. Kim, Raul G. Nogueira, Diogo C. Haussen
Journal: JAMA Neurology (2018)

<h3>Importance</h3> A succession of research has explored the linkage between carotid webs (CaWs) and ischemic strokes. Imaging and pathologic analysis have defined CaW as an intimal variant of fibromuscular dysplasia, which appears as a shelflike lesion on the posterior aspect of the carotid bulb, more specifically at the origin of internal carotid artery. Reported findings of carotid webs in young patients with recurrent ischemic strokes without an otherwise determined cause have raised questions about the mechanism, natural history, and need for intervention. This review addresses the current understanding of CaW and highlights findings that prompt further investigation into this unique vascular entity as a modifiable stroke risk factor. <h3>Observations</h3> Imaging analysis demonstrates hemodynamic disturbance in the presence of CaWs. The protuberant shelflike structure creates a pocket therein that may subsequently lead to local thrombosis and cerebral embolism. Computed tomographic angiography is an accurate and often used noninvasive diagnostic modality. Although treatment paradigms have not been systematically evaluated, antiplatelet monotherapy may not be sufficient to reduce recurrent ischemic events in the small series of patients with stroke and symptomatic CaWs. <h3>Conclusions and Relevance</h3> The limited clinical data on CaWs, although complicated by selection bias, suggest an increased prevalence of these vascular entities in cerebral ischemic events among patients younger than 60 years. Imaging suggests CaW to be a possible nidus for cerebral thromboembolism. Physicians should consider CaW as a cause of stroke in younger patients with anterior circulation ischemic strokes of an otherwise undetermined cause. Treatment options in CaWs with ischemic strokes have not been extensively investigated. Multicenter observational studies evaluating the natural history of CaW are warranted.
INNV-18. CAREGIVER SUPPORT IN THE NEURO-ONCOLOGY CLINIC; IDEAS TO ADDRESS THE NEEDS OF CAREGIVERS AS PART OF THE PATIENT CAREPLAN
Authors: Margaretta Page, Rosemary Rossi, Marielle Woodall, Jennie Taylor, Susan Chang
Journal: Neuro-Oncology (2018)

Support of the neuro-oncology caregiver is a critical element of patient care, and enhances the well-being of the caregiver and patient. At UCSF, the Gordon Murray Caregiver Program has a RN, social worker, and coordinator team dedicated to providing tailored services to caregivers across the disease trajectory. For programs where resources may be more limited, it is a challenge to address caregiver needs as well as the clinical care of the patient. We identified the areas of highest need and program utilization as a focus point for those looking to expand into caregiver support. METHOD: We reviewed the experience in our program in providing services to over 800 caregivers over the last 5 years. We noted domains of highest need, time points along the illness trajectory where caregivers utilized the most services and noted the specifics of the care delivered. High need areas for caregivers include the need for emotional support, health information and health navigation. Significant time points noted for most referrals for care were at diagnosis, disease progression, and/or transition to hospice. Emotional needs were addressed through consultations with Caregiver Program members and/or a caregiver specific support group. Health information was provided using disease specific and illness trajectory specific materials. Navigation was facilitated with nurse or social worker consultations. Addressing the needs of the caregiver starts by acknowledging the caregiver as part of the care team from the time of diagnosis. Neuro-oncology programs can leverage existing resources to provide caregivers support, such as health information appropriate to the clinical status of the patient, connections to caregiver specific community resources, support in developing positive coping strategies and host a caregiver specific support group. These are efficient and low cost methods to work on addressing caregiver needs.
EXTH-06. CD38-TARGETED THERAPY IN GLIOBLASTOMA
Authors: Sonikpreet Aulakh, Alak Manna, Paula Schiapparelli, Sikander Ailawadhi, Aneel Paulus, Steven Rosenfeld, Alfredo Quinones-Hinojosa, Asher Chanan-Khan
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) remains a malignancy with a dismal prognosis in spite of current optimal management, including maximal resection, radiation therapy, and alkylating chemotherapy. Relapse is inevitable with the paucity of further effective therapies. The development of novel targeted therapeutics is of prime importance. One such target is CD38, a transmembrane glycoprotein, partakes in receptor-mediated adhesion and cell signaling. It is expressed on GBM microglia/macrophages microenvironment. In vivo studies have shown decreased tumor growth and increased survival in CD38 genetic knockout mice, as well as with the use of K-rhein. Daratumumab (DARA) is an FDA-approved IgG1 kappa human monoclonal antibody, with the ability to penetrate blood brain barrier, that upon binding to CD38-bearing tumor cells lead to apoptosis, immune-mediated cell death and downregulation of the immunosuppressive environment. Hence, we wished to see if DARA could enhance efficacy of GBM directed therapies. We used flow cytometric analysis to identify CD38 expression on human GBM cells. MTS viability assay is used to detect IC50 of DARA. In addition, Annexin V/PI dual staining is used to detect apoptosis. Further, antibody-dependent cell mediated cytotoxicity (ADCC) and complement mediated cytotoxicity (CDC) assays are used. Additionally, evaluated the effect of DARA on cytotoxicT-cell proliferation. Our in vitro data shows that 9% of human GBM cells express CD38 with 250 MFI. IC50 of DARA+DMSO was 150µg/ml vs 75µg/ml with DARA+ temozolomide (TMZ). MTS assay revealed apoptosis after treatment with DARA+TMZ (44.25 ± 1.05%)> DARA (36.33 ± 0.87%) >TMZ (26.59 ± 0.93%, p<0.05) in comparison with control(C, 5.359%). % specific lysis via ADCC assay: TMZ+DARA (56.74 ± 2.84%) > DARA (35.30 ± 4.12%) > TMZ (20.57 ± 4.89%), vs C (4.30 ± 1.74%). % specific lysis via CDC with DARA (70.28 ± 9.28%) > TMZ (44.49 ± 0.72%, p<0.05), vs C (7.07 ± 0.72). Cytotoxic CD8+ T-cell proliferation was induced with DARA (59.29%) >TMZ (40.47%) > TMZ+DARA (45.82%), vs C (1.43%). Hence, CD38 is a potential target in GBM that if targeted with DARA +/- TMZ will generate direct anti-GBM effect as well as modulate the tumor microenvironment.
Abstract 14134: Factors that Contribute to Tissue Characteristics of Coronary Plaques Differ Depending on Renal Function in Type 2 Diabetes Mellitus
Authors: Kentaro Kakuta, Kaoru Dohi, Keisuke Okuyama, Miho Miyoshi, Takashi Yamanaka, Masaki Kawamura, Jun Masuda, Tairo Kurita, Norikazu Yamada, Yasuhiro Sumida, Masaaki Ito
Journal: Circulation (2017)

Introduction: Glycemic variability plays an important role in the coronary plaque formation mainly via inflammatory pathways in patients with type 2 diabetes mellitus (T2DM), but the pathogenesis of diabetic kidney disease is also closely linked to chronic inflammatory processes and subsequent progression of coronary atheromatous plaques. Hypothesis: We hypothesized that factors that contribute to tissue characteristics of coronary plaques differ depending on renal function in T2DM. Methods: We prospectively enrolled 71 consecutive T2DM patients (mean age: 68 ± 9, male: 79%) with 153 coronary artery lesions. Patients were divided into 2 groups according to eGFR level: the normal eGFR group (≥60 mL/min/1.73m2, n = 40) and the low eGFR group (<60 mL/min/1.73m2, n = 31). All patients underwent continuous glucose monitoring for 120 hours and the mean amplitude of glycemic excursions (MAGE) were calculated. Serum TNF-α was also measured. In addition, iMap-coronary intravascular ultrasound (IVUS) and gray-scale...
CADD-58. PRECLINICAL DEVELOPMENT OF miR-10b ANTAGONIST FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Danling Wang, Ken Liu, Giulio Cattatossi, Mike Nelson, Tim Wright
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most aggressive primary brain cancer with a median survival of 15 months after diagnosis. miR-10b is highly expressed in all GBM molecular subtypes, and its expression in normal brain cells is nearly undetectable. Herein, we report the status of the preclinical development of oligonucleotide antagonists of miR-10b for the treatment of GBM. A library of 218 anti-miR-10b oligonucleotides with various lengths and chemical modifications was prepared and screened using a luciferase-based cellular miR-10b activity assay and liver slice assay (to assess potential off-target inflammatory effects). Compounds were profiled in vitro using multiple functional assays including selective inhibition of cell viability and induction of apoptosis comparing GBM cell lines and other cell lines lacking miR-10b expression. Nineteen compounds were selected for further evaluation in a xenograft mouse GBM model using human LN229 GBM cells injected intracranially. An anti-miR-10b lead compound exhibited consistent in vitro and in vivo efficacy in all screening assays. A single intratumoral injection of anti-miR-10b lead compound significantly increased median survival of tumor-bearing animals by 18%, while combination treatment with temozolomide (TMZ) extended median survival time by >120% (TMZ alone increased median survival by 27%). This anti-miR-10b lead compound exhibits favorable physiochemical properties and in vivo safety profile, which support its further development toward clinical testing. Preliminary mechanistic studies indicate that inhibition of miR-10b in GBM cell lines increased apoptosis/cell death-related and decreased proliferation-related gene expression and had synergistic inhibitory effects with TMZ on tumor cell viability.