tbuckley/cabot-search huggingface dataset:
PATH-09. CLINICAL CHARACTERISTICS OF ADULTS WITH H3 K27M-MUTANT GLIOMAS AT UCSF
Authors: Robin Buerki, Sarah Lapointe, David Solomon, Joanna J Phillips, Arie Perry, Javier Villanueva-Meyer, Annette Molinaro, Nancy Ann Oberheim Bush, Jennie Taylor, Nicholas Butowski, Susan Chang, Jennifer Clarke
Journal: Neuro-Oncology (2018)

Histone H3.3 or H3.1 mutant protein is commonly expressed in pediatric and adult diffuse midline gliomas, including diffuse intrinsic pontine gliomas (DIPGs), and portends a poor prognosis, regardless of histologic features. As such, “Diffuse midline glioma, H3-K27M-mutant” (DMG-H3K27M) was added to the 2016 WHO Classification as a grade IV entity. Knowledge of the clinical experience and natural history of this recently defined tumor in adults is limited. We retrospectively reviewed the pathology of adult (age ≥ 18) DMG-H3K27Ms diagnosed at our institution either via H3-K27M mutant-specific immunohistochemistry or via the UCSF500 targeted next-generation sequencing panel that includes the H3F3A, HIST1H3B, and HIST1H3C genes. Treatment, outcome, and imaging characteristics were reviewed. We identified 26 adults with DMG-H3K27M and 2 with non-midline-H3K27M. Tumor locations included thalamus/basal ganglia (15), hypothalamus (2), pineal region (1), cerebellum (3), brainstem (2), spinal cord (2), mesial temporal (1), and non-midline sites (2). MRI imaging for 21/25 evaluable cases demonstrated enhancement. Of the 26 DMG-H3K27M cases, median age was 35 years (22–68 years). Of these, 17 patients had biopsy only. Median OS was 41 months (95%-CI 31-NA). In the 22 DMG-H3K27M patients with available clinical treatment data, 21 received radiation (19 with temozolomide) at initial diagnosis. At progression/recurrence, 11 patients received bevacizumab, 5 were re-treated with temozolomide, 8 received other chemotherapy, and 8 received > 1 course of re-irradiation. While still poor overall, clinical outcome in adults with DMG-H3K27M is often better than that of pediatric DIPGs and other IDH-wildtype high-grade gliomas, such as glioblastoma. This may reflect a different cell of origin or other distinct biologic differences. Further investigation of both DMG-H3K27M and non-midline H3K27M mutant tumors in adults is warranted to study the genetic and epigenetic features of these rare tumors, as well as optimal treatment strategies.
Chemiluminescent immunoassay and LC/MS-MS methodology for the determination of vitamin D status in infants at high risk for developing allergic diseases: Is there any analytical bias?
Authors: K. Rueter, L. Black, B. Max, M. Clarke, C. Gamez, E. Lim, D. Palmer, S. Prescott, A. Siafarikas
Journal: Allergy (2017)
PDTM-19. TUMOUR TREATING FIELDS (TTFIELDS) EXHIBIT EFFICACY ON HIGH-GRADE PAEDIATRIC BRAIN TUMOUR CELL LINES
Authors: Joshua Branter, Maria de los Angeles Estevez Cebrero, Richard Grundy, Surajit Basu, Stuart Smith
Journal: Neuro-Oncology (2018)

INTRODUCTION The EF-14 trial of the Optune system which utilises Tumour Treating Fields (TTFields) has shown positive results in adult Glioblastoma multiforme (GBM) patients. These results have given strength to the feasibility of TTFields being added to existing chemotherapy and radiation therapy for brain tumour patients. Here we present the data showing the efficacy of TTFields on a panel of paediatric GBM, Medulloblastoma and Ependymoma cell lines. METHODS The Inovitro system is the laboratory testing system used to develop the clinically approved Optune system. Inovitro was used to deliver TTFields over a range of clinically relevant frequencies (100-400kHz) to our panel of high grade paediatric cell lines. The effects of TTFields on cell viability was assessed using metabolic viability tests, and cell cycle analysis was performed using flow cytometry. Gene expression analysis was performed via Affymetrix microarray. RESULTS TTFields have significant efficacy on all of our cell lines, and the extent of this is dependent upon frequency. Cells treated with TTFields were re-seeded and growth rates were compared to control cells. The treated cells experienced up to 75% slower growth rates following treatment. Cell cycle analysis revealed that TTFields treated cells have significantly greater levels of G2/M phase accumulation relative to control, and this coincides with previous observations in adult GBM cell lines. The efficacy of TTFields may be significantly increased with the addition of the mitotic inhibitor, paclitaxel. The effects of TTFields treatment on gene expression will be discussed. CONCLUSIONS TTFields treatment has demonstrated efficacy against our panel of paediatric GBM, Medulloblastoma and Ependymoma cell lines - further investigation is warranted so that this may be translated into the clinic.
DRES-01. ZEB1-MEDIATED INVASIVE MESENCHYMAL TRANSITION AT THE SINGLE CELL LEVEL PROMOTES ANTI-ANGIOGENIC THERAPY RESISTANCE IN GLIOBLASTOMA
Authors: Ankush Chandra, Arman Jahangiri, William Chen, Garima Yagnik, Joseph Garcia, Alan Nguyen, Jacob Weiss, Kayla Wolf, Jung-Ming Lin, Soeren Mueller, Jonathan Rick, Aaron Diaz, Luke Gilbert, Sanjay Kumar, Manish Aghi
Journal: Neuro-Oncology (2018)

Bevacizumab responsiveness in glioblastoma is transient. The time course and upstream regulators of resistance still remain undefined. There is also conflicting evidence as to whether the resistance is driven by upregulated VEGF-independent angiogenic pathways or adaptation to treatment-induced hypoxia involving perivascular invasion. We analyzed paired patient specimens before and after bevacizumab-resistance and two xenograft models of bevacizumab-resistance: (1) a multigenerational model that replicates the lengthy treatment duration in patients and (2) PDXs replicating patient tumor resistance. Transcriptional changes were studied using microarray and qPCR. Morphological changes were assessed by immunostaining; invasion was assessed by bioengineered 3D models of perivascular vs. parenchymal invasion. Stem cell enrichment was confirmed by stem cell reformation assays. Despite upregulated VEGF-independent pro-angiogenic genes, immunostaining revealed increased hypoxia and decreased vessel density in resistant xenografts and patient specimens, suggesting tumor growth despite effective bevacizumab-induced devascularization. Microarrays revealed overexpression of the mesenchymal subtype gene signature across resistant xenograft generations and in resistant PDXs, replicating patient specimens whose elevated mesenchymal gene signature correlated with bevacizumab treatment duration. Single-cell sequencing of bevacizumab-resistant patient specimens revealed these mesenchymal changes to arise in early cell clones with fewer mutations. Xenograft and patient specimen microarray analysis implicated ZEB1, a key mediator of mesenchymal transition and glioma-stemness, as a potential regulator of this change, with ZEB1 increasing across xenograft generations (P< 0.001). Late-generation resistant-xenografts revealed lower form factor (p< 0.001), increased perivascular and parenchymal invasion in 3D bioengineered models (p< 0.001 and p< 0.05), and larger neurospheres (p= 0.002) with higher stem cell counts (p< 0.001) versus to early-generations. CRISPR targeting of ZEB1 reversed the morphology, stem cell neurosphere formation, and mesenchymal gene expression changes defining resistance to that of bevacizumab-sensitive tumors. We identified ZEB1 as a targetable regulator of the mesenchymal change and associated perivascular invasion and stem cell enrichment defining bevacizumab resistance.
High prevalence of carriage of mcr-1-positive enteric bacteria among healthy children from rural communities in the Chaco region, Bolivia, September to October 2016
Authors: Tommaso Giani, Samanta Sennati, Alberto Antonelli, Vincenzo Di Pilato, Tiziana di Maggio, Antonia Mantella, Claudia Niccolai, Michele Spinicci, Joaquín Monasterio, Paul Castellanos, Mirtha Martinez, Fausto Contreras, Dorian Balderrama Villaroel, Esther Damiani, Sdenka Maury, Rodolfo Rocabado, Lucia Pallecchi, Alessandro Bartoloni, Gian Maria Rossolini
Journal: Eurosurveillance (2018)

Background The mcr-1 gene is a transferable resistance determinant against colistin, a last-resort antimicrobial for infections caused by multi-resistant Gram-negatives. Aim To study carriage of antibiotic-resistant bacteria in healthy school children as part of a helminth control and antimicrobial resistance survey in the Bolivian Chaco region. Methods From September to October 2016 we collected faecal samples from healthy children in eight rural villages. Samples were screened for mcr-1 - and mcr-2 genes. Antimicrobial susceptibility testing was performed, and a subset of 18 isolates representative of individuals from different villages was analysed by whole genome sequencing (WGS). Results We included 337 children (mean age: 9.2 years, range: 7–11; 53% females). The proportion of mcr-1 carriers was high (38.3%) and present in all villages; only four children had previous antibiotic exposure. One or more mcr-1 -positive isolates were recovered from 129 positive samples, yielding a total of 173 isolates (171 Escherichia coli , 1 Citrobacter europaeus , 1 Enterobacter hormaechei ). No mcr-2 was detected. Co-resistance to other antimicrobials varied in mcr -positive E. coli . All 171 isolates were susceptible to carbapenems and tigecycline; 41 (24.0%) were extended-spectrum β-lactamase producers and most of them (37/41) carried bla CTX-M -type genes. WGS revealed heterogeneity of clonal lineages and mcr -genetic supports. Conclusion This high prevalence of mcr-1 -like carriage, in absence of professional exposure, is unexpected. Its extent at the national level should be investigated with priority. Possible causes should be studied; they may include unrestricted use of colistin in veterinary medicine and animal breeding, and importation of mcr-1 -positive bacteria via food and animals.
Abstract P083: Qualitative Evidence Supporting a New Model of Health Behavior Change for African American Men in a Faith-Based Community
Authors: Sohye Lee, Ruth Lindquist
Journal: Circulation (2017)

Purpose: Programs of behavior change with education targeting application to lifestyle habits may result in changes in risk-related behavior and improved cardiovascular disease (CVD) outcomes. The purpose of this abstract is to describe the changes, as evidenced in the qualitative analyses of transcripts of 14 sessions of a 6-month peer support group intervention to foster risk-related behavioral change, and in final program interviews. Method: African American men (N=8), aged 45-83 years, from one Baptist church in NE U.S. participated in a peer-led behavior change program targeting Life’s Simple 7 (get active, control cholesterol, eat better, manage blood pressure, lose weight, reduce blood sugar, stop smoking), over a 6-month period. Research staff monitored the hour-long peer intervention sessions by phone and recorded and transcribed the sessions. Qualitative analysis comprised thematic analyses of the textual content of the peer group sessions and transcripts of follow-up interviews to identify evidence in the text supporting the existence of shifting stages of change within the group over time. Self-reported stages of readiness to change related to the 7 CVD behavioral risk areas were also quantified using 7 contemplation ladders with rungs ranging from zero (“no thoughts of changing”) to 10 (“taking action to change”). Results: Over the course of the 6-month intervention, changes in group participants’ stages of change were evident. Six key themes emerged from the group sessions, including: (1) individuals’ resistance to change behaviors (weeks 1-2); (2) engagement through peer discussion of challenges and barriers (weeks 2-5); (3) awareness of physical benefits of change (weeks 2-24); (4) peer group cooperation for problem solving (weeks 3-24); (5) initiating health promotion inclusive of family and community (weeks 11-24); and (6) teaching others (weeks 18-24). The median difference in change in the contemplation ladders was &lt;0; likely due to a ceiling effect due to the recruitment of motivated men who were ready to change. In the 6-month interviews, although men have changed behaviors positively over time, participants still reported challenges to changing and maintaining behaviors in different areas. This reveals that behaviors are continuing to evolve, and that in this shifting, behavior change is still an ongoing process as the men become more aware of their behaviors and increasingly view them in context of family and community. Conclusions: In this 6-month, intensive peer-led intervention, the micro-culture of the peer support group transformed from self-focused resistance to cohesion, then to other-oriented action. The data moved beyond Prochaska’s Stages of Change Model to break out and define a new paradigm of change that affected family and community and which will likely lead to longer term, continued changes and ongoing reinforcement.
EXTH-02. DUAL DRUG MODIFIED NANOVESICLES FOR ENHANCING THE THERAPEUTIC EFFICACY OF DOXORUBICIN TOWARDS GLIOBLASTOMA AND MPNST
Authors: A B Madhankumar, Oliver Mrowczynski, Robert Maurer, Becky Slagle-Webb, Elias Rizk, Brad Zacharia, James Connor
Journal: Neuro-Oncology (2018)

Doxorubicin is a topoisomerase II inhibitor demonstrated to be effective in several cancers including malignant peripheral nerve sheath tumors (MPNST) and glioblastoma in cell culture, but at higher dose causes adverse effects like cardiotoxicity in patients. This minimizes the therapeutic dosage of doxorubicin administered for such cancers. To overcome this issue we have developed novel lipid based nanovesicles carrying doxorubicin with certain chemosensitizing agents like farnesyl thiosalicylic acid (FTS), a Ras inhibitor and dexrazoxane (DEX) in the lipid bilayer component of the nanovesicles using a microfluidic encapsulation method. FTS modified nanovesicles with doxorubicin in the core demonstrated an enhanced cytotoxic potential in glioma cells and neurofibromatosis type-1 associated MPNST cells (NF-1 MPNST). To determine the in vivo therapeutic efficacy, U87-Luc subcutaneous tumor bearing mice were injected twice weekly with 4mg/kg body weight dose of FTS-LIP-DOX or LIP-DOX (n=8) for 6 weeks. After 6 weeks of treatment, the median tumor volume in the control group reached 3212 mm3 and that of LIP-DOX and FTS-LIP-DOX reached a mean volume of 111 mm3 and 64.4 mm3 respectively. In a second formulation, doxorubicin was combined with dexrazoxane (DEX), a metal chelator and topoisomerase inhibitor in a liposome formulation. In our pilot study in vivo investigation we treated mice with DOX-DEX-liposomes(n=3) or DOX-liposomes (n=2) at a dose of 7 mg/kg body weight with respect to doxorubicin, twice weekly for 5 weeks in a MPNST mouse model. In the first 3 weeks, a slower tumor progression in the DOX-DEX liposomes group was observed compared to DOX-liposomes formulation, beyond which the tumor progression in both groups approached each other. We didn’t observe any adverse effect based on serum chemistry analysis. This novel therapy provides an opportunity for doxorubicin dose escalation in MPNST mouse model with improved therapeutic efficacy.
CMET-44. PREDICTORS OF SURVIVAL IN NEURO-METASTATIC MERKEL CELL CARCINOMA
Authors: Maya Harary, Vasileios Kavouridis, Manisha Thakuria, Timothy Smith
Journal: Neuro-Oncology (2018)

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy of neuroendocrine origin, with about 30 cases of brain metastasis (BM) reported in the literature. Historically, the treatment of neuro-metastatic MCC has largely included chemotherapy (CT) and radiotherapy (RT). The aim was to investigate predictors of overall survival (OS) in neuro-metastatic MCC. In this retrospective study, we surveyed institutional databases and additionally conducted a systematic review of the literature to identify cases reporting on management of distant MCC BM. A pooled analysis was performed on the institutional and literature cases to assess predictors of OS. Survival analysis was done on R (ver 3.4.0) using a Log Rank statistic and cox proportional hazard ratio. Forty cases were included for analysis, describing operative (14) and non-operative (26) management. Median time from initial MCC diagnosis to CNS involvement was 17.0-mos (IQR 10.5- 26.5), and most patients had a single BM (62.5%). Management of intracranial disease included RT (84.2%), systemic therapy (59.5%) and surgical resection (35%). Operative management was associated with a lower intracranial burden of disease (BoD, single BM: op 92.9% vs. non-op 46.2%, p=0.004), but similar systemic BoD. Median OS was longer in patients treated with neurosurgery (73-mos, 95%CI:31–115 vs. 25-mos, 95%CI:17–44, p ‹ 0.001). Both neurosurgery (HR 0.18, 95%CI:0.06–0.54, p=0.002) and having a single BM (multiple BM or leptomeningeal disease: HR 2.51, 95%CI:1.12–5.6, p=0.03) conferred an OS benefit on risk-unadjusted analysis. On multivariable analysis, only neurosurgical resection was an independent predictor of OS (HR 0.16, 95%CI:0.04–0.59, p=0.006), controlling for age, BoD and RT. Systemic therapy and RT were not associated with OS. CONCLUSIONS: Resection of MCC BM may confer a survival benefit relative to non-operative management given appropriate patient selection. Prospective investigation of multimodal management of neurometastatic MCC is warranted, especially given the promise of new immunotherapy agents in treating MCC.
RARE-23. PRIMARY INTRA-AXIAL CENTRAL NERVOUS SYSTEM INFLAMMATORY MYOFIBROBLASTIC TUMOR, ALK NEGATIVE: A RARE ENTITY
Authors: Nicholas Pflederer, John Gross, Julia Bridge, Cam Nguyen, Thomas Ruma
Journal: Neuro-Oncology (2018)

Inflammatory myofibroblastic tumor (IMT) is a rare spindle cell neoplasm with admixed inflammatory cells which occurs mainly in the abdomen or thoracic cavity of children or young adults. Primary CNS IMT is exceedingly rare with roughly 100 reported cases in the world literature, most of which are extra-axial and occur as a dural-based mass. Herein, we describe a rare case of intra-axial primary CNS IMT. A 24 year-old healthy female presented to the ER after falling and striking her head. A CT scan revealed an acute intraparenchymal hemorrhage, as well as a mass within the right frontoparietal lobe. Subsequent MRI was performed further characterizing the lesion as a 3.0 cm intra-axial tumor. Craniotomy was performed displaying a circumscribed neoplasm with relatively bland spindle cells arranged in fascicles with an admixed lymphoplasmacytic infiltrate. Mitotic activity was present but limited. Immunohistochemistry (IHC) was positive for TLE1 and vimentin but negative for GFAP, ALK, SMA, MUC4, KIT and β-catenin. Additional molecular testing by FISH for ALK (2p23) rearrangement was negative. We report a rare case of intra-axial primary CNS ALK Negative IMT. Approximately half of all IMTs harbor a clonal translocation that activates the anaplastic lymphoma kinase (ALK)-receptor tyrosine kinase at the 2p23 locus. As a result, ALK is overexpressed and can be detected by IHC or via molecular diagnostics (FISH, RNA sequencing or RT-PCR). Since this case was processed, additional novel anomalies involving rearrangements in ROS1, RET, ETV6 and/or NTRK3 genes have been described and could lead to promising therapeutic targets in the future.
CMET-35. DIFFUSION AND PERFUSION FEATURES OF METASTATIC BRAIN LESIONS
Authors: Ararat Chakhoyan, Catalina Raymond, Jason Chen, Jodi Goldman, Tania Karpealian, Nader Pouratian, Benjamin Ellingson
Journal: Neuro-Oncology (2018)

To determine clinically relevant MRI features of various metastatic brain lesions using classical and advanced post-processing techniques of both diffusion and perfusion-weighted MR images. One hundred twenty-three brain metastases including breast (27), non-small cell lung cancer (NSCLC, 43) and other (44) were retrospectively assessed prior to radiation treatment with standard anatomical, diffusion and perfusion-weighted MRI. A total of 346 individual lesions were manually segmented. Complementary to tumor volume, apparent diffusion coefficients (ADC) and relative cerebral volume (rCBV) measurements, an independent component analysis (ICA) was performed with dynamic susceptibility contrast (DSC) in order to assess arterio-venous components and their overlap region relative to tumor volume and time to peak of T2* signal from each component. Results suggests that no differences are observable for either ADC or rCBV features (median value) across metastatic subtypes. Interestingly, ICA-derived arterial component was higher in breast and NSCLC compared to other patients, while the venous component was higher in breast compared to all other groups. No difference in the overlap component was observed between groups. Within the other group, we found that overlap has higher volume than venous and arterial components. For other group, the difference between arterial and venous components was as well significant. Median time to peak of arterial and venous components were 8.4s and 12.6s with no differences between lesion types. Additionally, the overlap component was positively related to rCBV in all groups. However, no correlation was found for arterial and venous components with respect to rCBV values. CONCLUSIONS: Advanced ICA-derived component analysis demonstrates perfusion differences in metastatic brain lesions not observable with classical ADC and optimized rCBV post-processing approaches.
Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer
Authors: Delphine Goehrig, Jérémy Nigri, Rémi Samain, Zhichong Wu, Paola Cappello, Gaëlle Gabiane, Xinyi Zhang, Yajie Zhao, In-San Kim, Marie Chanal, Roberta Curto, Valerie Hervieu, Christelle de La Fouchardière, Francesco Novelli, Pascale Milani, Richard Tomasini, Corinne Bousquet, Philippe Bertolino, Ana Hennino
Journal: Gut (2018)

Objective Pancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer. Design We performed studies with p48- Cre; Kras G12D , pdx1 -Cre; Kras G12D ;Ink4a / Arf fl/fl , pdx1 -Cre; Kras G12D ; p53 R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy. Results We identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8 + T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8 + T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment. Conclusions Our data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer.