tbuckley/cabot-search huggingface dataset:
ACTR-34. INTEGRATED CLINICAL EXPERIENCE WITH ONC201 IN PREVIOUSLY-TREATED H3 K27M-MUTANT GLIOMA PATIENTS
Authors: Andrew Chi, Isabel Arrillaga-Romany, Sharon Gardner, Patrick Wen, Tracy Batchelor, Matthew Hall, Yazmin Odia, Soumen Khatua, Wafik Zaky, Susan McGovern, Rebecca Harrison, John de Groot, Ashley Sumrall, Nicole Shonka, Zaid Khatib, Matthias Karajannis, Sabine Mueller, Rohinton Tarapore, Krystal Merdinger, Lee Schalop, Joshua Allen, Wolfgang Oster, Minesh P Mehta
Journal: Neuro-Oncology (2018)

H3 K27M-mutant gliomas have a dismal clinical prognosis and no proven curative therapy. We report the updated clinical experience with ONC201, the first cancer-specific DRD2 antagonist, in adult and pediatric H3 K27M-mutant gliomas. As of May 28, 2018, 26 patients with H3 K27M-mutant glioma have been treated with ONC201: 9 pediatric (<18 years old) and 17 adult patients (>18 years old). Twelve patients had recurrent disease and 14 had previously-treated stable disease prior to initiating ONC201. Patients had 1–4 prior lines of therapy and all received prior radiation. Ten adult patients were enrolled on clinical trials and the other 16 were on compassionate use. ONC201 was orally administered at 625 mg to adults and scaled by body weight for pediatric patients. All patients, except one, were dosed weekly. Fourteen of 26 patients (54%) remain progression-free on ONC201 with a median follow up of 3.6 (range 1.6–24.5) months. No dose modifications or discontinuation due to toxicity have occurred. Among the 12 adult patients with recurrent disease who received single agent ONC201, the estimated PFS6 is 36.5%. Seven patients have experienced radiographic and/or clinical benefit (neurological stabilization or improvement). Among the 5 adults with recurrent thalamic glioma, three have experienced durable complete regression of their thalamic tumors, including the first H3 K27M-mutant glioma patient treated with ONC201 who has experienced 96% regression of her recurrent disease and continues single agent ONC201 for >2 years. Two DIPG pediatric patients who initiated single agent ONC201 6–8 weeks after radiation have experienced radiographic and neurological improvements and exhibited PFS of >13 months from diagnosis. Emerging clinical data suggest that ONC201 exhibits clinical activity for some patients with H3 K27M-mutant glioma.
Results from a Phase 3, Multicenter, Non-Inferiority Study of Ravulizumab (ALXN1210) Versus Eculizumab in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Currently Treated with Eculizumab
Authors: Austin G. Kulasekararaj, Anita Hill, Scott T. Rottinghaus, Saskia Langemeijer, Richard A. Wells, F. Ataulfo Gonzalez-Fernandez, Anna Gaya, Jong-Wook Lee, Emilio Ojeda Gutierrez, Caroline I. Piatek, Jeffrey Szer, Antonio M. Risitano, Shinji Nakao, Eric Bachman, Lori Shafner, Andrew I. Damokosh, Stephan Ortiz, Alexander Röth, Regis Peffault De Latour
Journal: Blood (2018)
Efficacy of a novel inhibitor of vascular adhesion protein-1 in reducing albuminuria in patients with diabetic kidney disease (ALBUM): a randomised, placebo-controlled, phase 2 trial
Authors: Dick de Zeeuw, Ronny W Renfurm, George Bakris, Peter Rossing, Vlado Perkovic, Fan Fan Hou, Masaomi Nangaku, Kumar Sharma, Hiddo J L Heerspink, Alberto Garcia-Hernandez, Tobias E Larsson
Journal: The Lancet Diabetes & Endocrinology (2018)
NCMP-20. TUMOR TYPES, RESECTION AND INCIDENCE OF NEUROPATHY: CURRENT LITERATURE REVIEW
Authors: Sumul Raval, Yash Shah, Sarthak Shah, Vineeta Maddali, Aaryan Raval
Journal: Neuro-Oncology (2018)

PURPOSE: By identifying the individual sub-categorical phenotypes most associated with neuropathy and collectively using to specify a single tumor most associated with neuropathy, the hopes of this literature review are to help clinicians begin treatment for neuropathy before symptoms become severe and perhaps prevent it to the best of their ability. All clinical studies and literature reviews analyzed in this review were obtained through PubMed Central from 1990 through 2017. Characteristics included shape, size, location, approximate estimation of growth period, presence and occurrence of metastasis, and original location of tumor. After a thorough consideration of these characteristics, the specific phenotypes of the tumor for each of these categories most likely to result in any form of neuropathy was determined. Furthermore, the individual subcategory phenotypes were then aggregated to characteristically specify a single tumor most associated with severe neuropathy. The most commonly affected regions of peripheral nerves were analyzed to give better idea of which regions of tumor incidence would be most affiliated with an eventual onset of neuropathy. So certain degree of preventative measures and follow-up with the patient frequently due to the knowledge that neuropathy is very likely to occur. Certain chemotherapies were found to be associated with the most cases of neuropathy. Lung and Breast was found to lead to the most cases of neuropathy. These two cancers were also found to be most associated with brain metastasis which further sheds light on why neuropathy and paraneoplastic disease is occurring in patients with these forms of cancer. CONCLUSIONS: Through a detailed analysis of cancers most associated with neuropathy and paraneoplastic disease, a certain guidelines and risk factors were generated to help prepare for neuropathy following diagnosis of cancers. The warning guideline includes form of chemotherapy, the presence of lung or breast cancer, signs of brain metastasis.
NCMP-08. MANAGEMENT OF RADIONECROSIS AFTER STEREOTACTIC RADIATION FOR BRAIN METASTASES IN THE SETTING OF IMMUNE CHECKPOINT INHIBITORS
Authors: James Jurica, Eric Bernicker, Shraddha Dalwadi, Ivo Tremont-Lukats, Brian Butler, Bin Teh, Andrew Farach
Journal: Neuro-Oncology (2018)

Immune checkpoint inhibitors (ICI) are an increasingly common therapy for metastatic solid tumors. Despite their efficacy, many patients develop brain metastasis requiring stereotactic radiosurgery (SRS) or fractionated stereotactic radiation therapy (SRT). Radiation necrosis (RN) is a known risk. Recent observations suggest that patients receiving SRT/ICI may experience synergism albeit with potential increased risk of symptomatic RN. The best treatment in this setting remains unknown. VEGF inhibitors have demonstrable efficacy in treatment of RN and may be beneficial in treating neurotoxicity associated with combination SRT/ICI. Data were analyzed retrospectively from 169 consecutive patients at a single institution undergoing SRS/SRT for brain metastasis from 2015–2017. 10 patients were eligible for evaluation having received SRT and ICI within a 6 month timeframe and with a minimum 3 months survival for assessment of RN. 7 patients were treated for lung adenocarcinoma, 2 for high-grade neuroendocrine tumor, and 1 with triple-negative breast cancer. 10 patients were treated with SRS (90%), SRT (60%), both (50%), or SRS followed by whole-brain radiation (10%) to a total of 65 brain metastases. ICI (nivolumab, pembrolizumab, atezolizumab, ipilimumab) was administered before, during, or after SRS/SRT. 6 patients (60%) developed symptomatic grade ≥ 1 neurological adverse events. Of these 6, 4 (40%) developed grade 3 RN requiring bevacizumab. Symptoms resolved rapidly in 3 of 4 patients (75%), the 4th patient died of complications of disease shortly after bevacizumab administration. Mean 12 month survival from initial immunotherapy treatment was 89% and mean 18 month survival from initial SRT was 78%. Combination treatment with SRT/ICI for brain metastases appears to be associated with high rates of RN compared to historical standards. Given the prolonged survival seen, appropriate management of this complication is paramount. Short course bevacizumab appears highly effective in treating symptomatic RN associated with ICI. Further evaluation with a larger sample size is warranted.
Interleukin-17-Producing γδ T Cells Originate from SOX13+ Progenitors that Are Independent of γδTCR Signaling
Authors: Nicholas A. Spidale, Katelyn Sylvia, Kavitha Narayan, Bing Miu, Michela Frascoli, Heather J. Melichar, Wu Zhihao, Jan Kisielow, Amy Palin, Thomas Serwold, Paul Love, Michihiro Kobayashi, Momoko Yoshimoto, Nitya Jain, Joonsoo Kang
Journal: Immunity (2018)

Lineage-committed αβ and γδ T cells are thought to originate from common intrathymic multipotent progenitors following instructive T cell receptor (TCR) signals. A subset of lymph node and mucosal Vγ2+ γδ T cells is programmed intrathymically to produce IL-17 (Tγδ17 cells), however the role of the γδTCR in development of these cells remains controversial. Here we generated reporter mice for the Tγδ17 lineage-defining transcription factor SOX13 and identified fetal-origin, intrathymic Sox13+ progenitors. In organ culture developmental assays, Tγδ17 cells derived primarily from Sox13+ progenitors, and not from other known lymphoid progenitors. Single cell transcriptome assays of the progenitors found in TCR-deficient mice demonstrated that Tγδ17 lineage programming was independent of γδTCR. Instead, generation of the lineage committed progenitors and Tγδ17 cells was controlled by TCF1 and SOX13. Thus, T lymphocyte lineage fate can be prewired cell-intrinsically and is not necessarily specified by clonal antigen receptor signals.
Abstract IA11: Gene networks, airway smoke injury, and cancer risk
Authors: Bruce A.J. Ponder
Journal: Clinical Cancer Research (2018)

Abstract Background: Fifteen percent of smokers and former smokers develop lung cancer. This might be chance; an alternative is that some are at greater risk because of different individual responses to airway smoke injury. Several groups have investigated gene expression in normal airway epithelium as a readout of smoke injury and as a stratifier for risk. Questions include, but are not limited to: i) Can nasal epithelium provide a useful and accessible surrogate for bronchial? ii) Is there an inherited component to the injury-related risk? iii) What components of the injury response contribute most to increased risk in current and in former smokers? iv) What is the distribution of injury response in the healthy current and former smoker populations, rather than symptomatic patients, and how does this relate to risk? Results and Work in Progress: We, like others, have based our analysis on gene expression in normal bronchial and nasal epithelium. We use transcription factor-centered gene regulatory networks, derived from normal bronchial and nasal epithelium, to identify the overlying cellular regulatory mechanisms that differ between injury responses. We identify transcriptional “master regulators” (MRs), the activity of which differs between cancer and benign, and confirm the overlap of MRs between nasal and bronchial epithelium. A preliminary pathway analysis suggests the involvement of these MRs in oxidative stress response, DNA repair, immune responses, and developmental processes. Using data from the TRICL consortium, we show that the regulons of a subset of these MRs are enriched in genes located at lung GWAS loci. This suggests that the observed gene expression differences between cancer and benign are in part causal, related to inherited variation rather than secondary to the cancer. Using samples from the Cambridge Bioresource volunteers, we are analyzing data from nasal samples to compare healthy current and former smokers with healthy never-smokers, and so obtain a “smoke injury response.” We will use this to describe the distribution of injury response in the healthy smoker/former smoker populations. Our aim is to test what component of risk-related gene response may be apparent in this healthy asymptomatic smoker population rather than at the “later” symptomatic stages of hospital investigation, and to find which genes or regulatory processes contribute most to this. The results may have implications both for risk prediction and possible interventions in these populations. My talk will be a “work in progress” aimed at stimulating discussion about questions and approaches, rather than a presentation of finished results. Citation Format: Bruce A.J. Ponder. Gene networks, airway smoke injury, and cancer risk [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA11.
Relationship between timing of trial randomization, protocol completion, and clinical outcomes among patients hospitalized for heart failure: from the ASTRONAUT trial
Authors: Stephen J. Greene, Gregg C. Fonarow, Scott D. Solomon, Haris P. Subacius, Muthiah Vaduganathan, Andrew P. Ambrosy, Marat Fudim, Michael Böhm, Aldo P. Maggioni, Eldrin F. Lewis, Faiez Zannad, Javed Butler
Journal: European Journal of Heart Failure (2018)
QOLP-08. A NEURO-ONCOLOGY CAREGIVER SUPPORT GROUP, AN EFFECTIVE WAY TO PROVIDE EMOTIONAL SUPPORT FOR CAREGIVERS
Authors: Margaretta Page, Rosemary Rossi, Marielle Woodall, Susan Chang
Journal: Neuro-Oncology (2018)

Brain tumor support groups provide education and emotional support to patients and families dealing with a brain tumor diagnosis. These groups are beneficial, but at times caregivers report that they must hold back and not speak their truth/reality for fear of hurting the patients feelings. A neuro-oncology caregiver support group is one easy and economical way to provide caregivers with emotional support and foster resilience. A regular attendee reminds us that caregivers need a place to not have to be strong, to not have to be everything all the time, and to be around people that understand. METHOD: A UCSF neuro-oncology caregiver support group is led by a social worker and neuro-oncology RN once a month. The group provides caregivers a safe space to share feelings and focus on their experience of being a caregiver and coping with the emotional aspects of caring for someone with a brain tumor. Participants are invited to acknowledge and share the complicated emotions that they experience. Themes are documented and participants surveyed annually. In 2017–2018, 30 caregivers attended the monthly meetings with an average of 10 attendees. 6 attended all meetings in the last year. Common themes include sorrow, anger, ambiguous loss, guilt, and ways to find joy and humor. Annual survey results demonstrate a mix of male and females, some who travel over 75 miles to be at the meeting. 93% of those responding reported benefit from the opportunity to normalize feelings and learn from each other. 93% reported that the group reduced their sense of isolation and 100% rated the group as beneficial and would recommend the group to others. A neuro-oncology caregiver specific support group is a feasible and economic way to assist caregivers in normalizing complicated emotions, connecting with similar others, and may foster resilience.
Pre-clinical evaluation of the modified Miles assay as a surrogate marker of systemic anti-angiogenic activity
Authors: Andrea Laforme, Dipak Panigrahy, Arja Kaipainen, Michael Fannon, Mark W. Kieran
Journal: Cancer Research (2005)

1173  Background: Vascular endothelial growth factor (VEGF), originally discovered as vascular permeability factor (VPF), is a critical molecule in tumor mediated angiogenesis. A number of novel drugs that specifically inhibit angiogenesis are in clinical trials however, surrogate markers of drug activity are lacking. The Miles assay can be used to assess alterations in vessel permeability mediated by a number of molecules including VEGF. Unfortunately, the administration of VEGF to patients with cancer or other angiogenic dependant diseases may stimulate further disease progression. Histamine is a molecule with a defined activity in vascular leak that is routinely used to quantitate the allergic potential to drugs in normal individuals as well as those with a variety of diseases including cancer. We now report the utilization of the histamine challenge assay as a surrogate marker of activity for anti-angiogenic drugs in a pre-clinical murine model. Methods: All animal experiments were performed in accordance with IRB-approved protocols at Children’s Hospital, Boston using 8 week-old SCID mice. Approximately 1-2 days prior to the experiment, animals were shaved to expose the skin. After recovery of the skin 1-2 days later, animals were anesthetized and injected with Evan’s blue dye either by tail vein or through the orbital plexus. 50ul of 1ng/ul VEGF, 50ul containing 1ug histamine or 50ul of saline were injected intradermally using a 30g needle into the skin over lying the back near the base of the tail. One side received histamine or VEGF, the other saline. Similar experiments were performed injecting approximately 5ul intradermally into the ears. After an appropriate period of time, the skin was opened and exposed to assess the intensity of Evan’s blue dye extravasation. The areas of blue (vascular leak) were quantitated. Results: Animals were treated with a large array of anti-angiogenic agents including drugs that down-regulate bFGF, VEGF, or endothelial cell function. Drugs targeting VEGF or endothelium significantly inhibited the vascular leak induced by intradermal VEGF. More importantly, a similar effect was noted with histamine-induced vascular leak. The inhibition followed a dose response curve. Alterations on the immunohistochemical structure of the skin area correlated with the patterns observed based on the treatment groups. Conclusion: Histamine-mediated vascular leak can be used to evaluate the systemic potency of anti-angiogenic drugs administered in a pre-clinical model. This technique is appropriate for evaluation in human clinical trials of novel anti-angiogenic drugs given the extensive experience with histamine administration in humans. Clinical trials to assess this have been proposed.
GENE-14. DNA METHYLATION AND PROTEOMIC ALTERATIONS IDENTIFY HISTOLOGICALLY-DEFINED TUMOR CELL POPULATIONS AND CHARACTERIZE INTRATUMOR HETEROGENEITY IN GLIOBLASTOMA
Authors: Jean-Pierre Gagner, Scott Kamen, Shruti Nayak, Jonathan Serrano, Varshini Vasudevaraja, Ramona Bledea, Beatrix Ueberheide, Matija Snuderl, Mirna Lechpammer, David Zagzag
Journal: Neuro-Oncology (2018)

Tumor heterogeneity presents a major challenge to cancer diagnosis and treatment. In addition to interpatient tumor variability, intratumoral heterogeneity characterized by distinct molecular and phenotypic profiles is increasingly recognized as a major cause of therapy resistance and cancer recurrence. Because DNA methylation patterns are largely responsible for determining cell-type-specific functioning, we hypothesized that distinct DNA methylation and proteomic alterations could be identified in histologically-defined invasive and proliferative tumor cell populations in human isocitrate dehydrogenase 1 (IDH1)-mutated and wild-type glioblastoma (GBM). Formalin-fixed paraffin-embedded tissue sections of human adult IDH1-mutated and wild-type GBM were laser-microdissected (LM) into perinecrotic pseudopalisading tumor cells (PPCs), non-pseudopalisading tumor core cells (NPPCs), invasive subpial spread (SPS) and perivascular satellitosis tumor cells and brain adjacent to tumor cells prior to analysis and compared to non-microdissected tumor (NMT) and/or germline DNA. Genome-wide DNA methylation and chromosomal copy numbers were determined with Infinium MethylationEPIC 850K BeadChip and intratumoral DNA methylation patterns compared by unsupervised hierarchical clustering. Label-free quantitative liquid chromatography-mass spectrometry of proteins was performed and proteins differentially expressed across LM areas subjected to pathway enrichment analysis. Unsupervised hierarchical classification of DNA methylation patterns for each LM area and NMT demonstrated remarkable clustering for all patients, based on methylation probe and methylated gene patterns. Proteomics analysis showed upregulation of hypoxia-inducible factor-1 inducible proteins in hypoxic PPCs. Out of 1819 proteins quantified, 5 were overexpressed and 9 underexpressed more than 10-fold in SPS compared with NPPCs and associated with alterations in metabolism, transport, extracellular matrix and apoptosis. Correlation of protein expression and DNA methylation patterns was noted. Compared to NPPCs, SPS cells migrating toward the invasive edge share a relatively consistent epigenetic and proteomic signature, suggesting potentially targetable common mechanism(s) of invasion shared among GBM.
EXTH-23. A NOVEL NANOTECHNOLOGY-BASED PLATFORM IMPROVES LASER INTERSTITIAL THERMAL THERAPY FOR INTRACRANIAL TUMORS
Authors: Pakawat Chongsathidkiet, Yang Liu, Hanna Kemeny, Cosette Dechant, Ren Odion, Xiuyu Cui, Kristen Rhodin, Tuan Vo-Dinh, Peter Fecci
Journal: Neuro-Oncology (2018)

Laser Interstitial Thermal Therapy (LITT) is an emerging clinical option for the thermal ablation of intracranial lesions. Current limitations for LITT, however, include the diameter of ablation (< 3cm per trajectory) and lack of inherent specificity for tumor margins. Gold nanoparticles act as “lightning rods” to expand laser treatment coverages. Here, we employ plasmon-activated gold nanostars (GNS) with selective tumor uptake to increase LITT coverage area and tumor specificity in a murine model, and also demonstrate their ability to expand coverage in a clinically-relevant sized model using brain phantoms. CT2A murine glioma cells were implanted into the right cerebral hemisphere. GNS were administered intravenously. Selective GNS uptake in tumors was demonstrated by micro-PET-CT. Microlaser fibers (700um) were used to deliver laser light to tumors. Brain phantoms were composed of agarose gel with embedded 5x5x5 cm3 agarose “tumors” with or without interspersed GNS. A diffuse-tip probe was used to deliver laser light to phantom tumors in the intraoperative MRI suite. MRI thermometry measured temperature change in phantoms. Systemically administered GNS were selectively taken up by tumor compared to surrounding brain. Murine gliomas treated with GNS + laser showed an expanded tumor-conforming zone of cytotoxic edema on small animal MRI compared to tumors treated with laser alone. In phantoms containing GNS, the kill zone (43°C for 10 min) extended to 3.8cm in diameter, compared to 2.0cm in phantoms without GNS. Additionally, the phantoms containing GNS heated faster, reached higher temperatures, and displayed a more homogeneous zone of treatment. We demonstrate the capacity to use nanotechnology to overcome the size and specificity limitations for LITT, both in an in vivo murine intracranial glioma model, as well as in a more relevantly sized brain phantom model. Clinical trials in canine glioma are planned to enable an IDE application.
Under 16s are at highest risk of being stabbed going home from school, UK study finds
Authors: Susan Mayor
Journal: BMJ (2018)

Children under 16 are at the highest risk of being stabbed when going home from school, a large UK study has found.1

“The period immediately after school accounts for a large proportion of [stabbing] incidents in children, and these predominantly occur close to home and school,” said the researchers, led by Paul Vulliamy, from the Centre for Trauma Sciences at Queen Mary University of London.

“This represents an opportunity for targeted preventive strategies,” they said.

The study retrospectively analysed data on all patients aged under 25 presenting to the emergency department of a large trauma centre in London from 2004 to 2014 after deliberate stabbing.

To investigate the epidemiology of knife violence in specific age …