tbuckley/cabot-search huggingface dataset:
An interpretable classifier for high-resolution breast cancer screening images utilizing weakly supervised localization
Authors: Yiqiu Shen, Nan Wu, Jason Phang, Jungkyu Park, Kangning Liu, Sudarshini Tyagi, Laura Heacock, S. Gene Kim, Linda Moy, Kyunghyun Cho, Krzysztof J. Geras
Journal: Medical Image Analysis (2020)

Medical images differ from natural images in significantly higher resolutions and smaller regions of interest. Because of these differences, neural network architectures that work well for natural images might not be applicable to medical image analysis. In this work, we propose a novel neural network model to address these unique properties of medical images. This model first uses a low-capacity, yet memory-efficient, network on the whole image to identify the most informative regions. It then applies another higher-capacity network to collect details from chosen regions. Finally, it employs a fusion module that aggregates global and local information to make a prediction. While existing methods often require lesion segmentation during training, our model is trained with only image-level labels and can generate pixel-level saliency maps indicating possible malignant findings. We apply the model to screening mammography interpretation: predicting the presence or absence of benign and malignant lesions. On the NYU Breast Cancer Screening Dataset, our model outperforms (AUC = 0.93) ResNet-34 and Faster R-CNN in classifying breasts with malignant findings. On the CBIS-DDSM dataset, our model achieves performance (AUC = 0.858) on par with state-of-the-art approaches. Compared to ResNet-34, our model is 4.1x faster for inference while using 78.4% less GPU memory. Furthermore, we demonstrate, in a reader study, that our model surpasses radiologist-level AUC by a margin of 0.11.
SWK-03. CAREGIVER EXPERIENCES FOR PEDIATRIC BRAIN TUMOR PATIENTS AND THEIR FAMILIES AT A DEDICATED MEDICAL SPECIALTY CAMP
Authors: Ryan Brownfield, Barb Galantowicz, Claire Russell, Jennifer Chabot, Scott Coven
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Medical specialty camps have provided children with unique psychosocial experiences; however, dedicated pediatric brain tumor camps are rare in the United States, except in limited locations. This study aimed to glean caregiver perceptions from a dedicated family brain tumor camp, and to learn about the family experience with navigating a neuro-oncology diagnosis. DESIGN: Flying Horse Farms is a non-profit organization located in Mt. Gilead, Ohio and a member of the SeriousFun Children’s Network, a global community of camps and programs serving children with serious illnesses and their families, at no cost. The institutional review board at Ohio University approved this project at Flying Horse Farms in September 2017. Consent from caregivers was obtained prior to participation in the study, which provided the opportunity to complete three separate phases: a pre-camp survey, attend a semi-structured interview during the weekend, and complete a post-camp survey. RESULTS 11 families were present for the weekend, and 10 families consented to participate in all three phases. For 6 families, this was their first experience at Flying Horse Farms. For 9 of the 10 families, the camp met their expectations. Additionally, 9 out of 10 families reported they would be interested in attending a diagnosis specific camp again in the future. CONCLUSIONS This work demonstrates the feasibility of conducting research at a medical specialty camp without restricting the camp experience. Better understanding of the attendee’s attitudes toward camp may enhance the experience and the neuro-oncology journey in the future.
TBIO-16. NOTCH1 PATHWAY AS TARGET FOR DRUG INTERVENTION FOR HISTONE 3 G34R MUTATED pHGG
Authors: Katie Foot, Anbarasu Lourdusamy, Sofia Christou, Ruman Rahman, Robert Layfield, Richard Grundy, Farhana Haque
Journal: Neuro-Oncology (2020)

Abstract There have been no significant improvements in the treatments for childhood High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), which continue to have a very poor prognosis. These cancers harbor mutations affecting histone 3 (H3) proteins; 80% of DIPGs with histone H3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. We have generated and validated a histone 3.3 G34R mutant-specific antibody and investigated the downstream effects of H3.3 G34R mutations in pHGG. In order to identify the genes that may be deregulated by G34R mutant histone expression, we have performed chromatin immunoprecipitation (ChIP) assays with our H3.3 G34R and wild type H3 antibodies, using pHGG H3 G34R mutant and wild-type cell lines. Initial analyses of ChIP data have implicated deregulation of cell-signaling pathways including Notch1, Hedgehog, PPAR-1, PLC-beta and Androgen, in H3 G34R mutated pHGG. We are currently determining the effects of altered expression of Notch1 pathway components on tumorigenesis of H3 G34R mutated pHGG, through gene and protein expression and inhibition assays. Specifically we find that the Notch1 pathway component HES1 shows increased expression in G34R mutant cells compared to controls, directing our evaluation of the utility of gamma-secretase inhibitors as potential therapeutics. These analyses may underpin development of novel treatment strategies for H3 mutated pHGG.
Clinical Relevance of Alternatively Spliced Isoform AML1-ETO9a in Adult Patients with t(8;21)(q22;q22.1) Acute Myeloid Leukemia (AML): A Study of the German-Austrian AML Study Group (AMLSG)
Authors: Mridul Agrawal, Andrea Corbacioglu, Daniela Weber, Verena I. Gaidzik, Marianne Habdank, Nikolaus Jahn, Thomas Michael Schroeder, Thomas Kindler, Mohammed Amen Wattad, Michael Lübbert, Walter Fiedler, Katharina S. Götze, Mark Ringhoffer, Jan Schleicher, Elisabeth Lange, Michael Pfreundschuh, Martin Griesshammer, Richard Greil, Heinz Kirchen, Elisabeth Koller, Felicitas Thol, Jurgen Krauter, Richard F. Schlenk, Michael Heuser, Arnold Ganser, Lars Bullinger, Peter Paschka, Hartmut Döhner, Konstanze Döhner
Journal: Blood (2017)
Plasma Cell Disease Genotyping with the Liquid Biopsy
Authors: Bernhard Gerber, Martina Manzoni, Valeria Spina, Alessio Bruscaggin, Sonia Fabris, Marzia Barbieri, Gabriella Ciceri, Marta Lionetti, Alessandra Pompa, Gabriela Forestieri, Erika Lerch, Paolo Servida, Francesco Bertoni, Emanuele Zucca, Michele Ghielmini, Agostino Cortelezzi, Franco Cavalli, Georg Stussi, Luca Baldini, Davide Rossi, Antonino Neri
Journal: Blood (2017)
Obligations of the “Gift”: Reciprocity and Responsibility in Precision Medicine
Authors: Sandra Soo-Jin Lee
Journal: The American Journal of Bioethics (2020)

Precision medicine relies on data and biospecimens from participants who willingly offer their personal information on the promise that this act will ultimately result in knowledge that will improve human health. Drawing on anthropological framings of the "gift," this paper contextualizes participation in precision medicine as inextricable from social relationships and their ongoing ethical obligations. Going beyond altruism, reframing biospecimen and data collection in terms of socially regulated gift-giving recovers questions of responsibility and care. As opposed to conceiving participation in terms of donations that elide clinical labor critical to precision medicine, the gift metaphor underscores ethical commitments to reciprocity and responsibility. This demands confronting inequities in precision medicine, such as systemic bias and lack of affordability and access. A focus on justice in precision medicine that recognizes the sociality of the gift is a critical frontier for bioethics.
13P PD-L1 prevalence in advanced urothelial carcinoma by demographic and clinical characteristics
Authors: T.B. Powles, M.S. van der Heijden, A.V. Balar, P. O'Donnell, C. Massard, J. Walker, A. Gupta, N. Angra, J. Cairns, B. Turriziani, M.C. Rebelatto, M. Scott, S. Wildsmith
Journal: Annals of Oncology (2020)
3D organoids derived from the small intestine: An emerging tool for drug transport research
Authors: Yuanjin Zhang, Shengbo Huang, Weiguo Zhong, Wenxia Chen, Bingyi Yao, Xin Wang
Journal: Acta Pharmaceutica Sinica B (2020)

Small intestine in vitro models play a crucial role in drug transport research. Although conventional 2D cell culture models, such as Caco-2 monolayer, possess many advantages, they should be interpreted with caution because they have relatively poor physiologically reproducible phenotypes and functions. With the development of 3D culture technology, pluripotent stem cells (PSCs) and adult somatic stem cells (ASCs) show remarkable self-organization characteristics, which leads to the development of intestinal organoids. Based on previous studies, this paper reviews the application of intestinal 3D organoids in drug transport mediated by P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2). The advantages and limitations of this model are also discussed. Although there are still many challenges, intestinal 3D organoid model has the potential to be an excellent tool for drug transport research.
PATH-09. NEXT-GENERATION SEQUENCING OF GLIOBLASTOMA MULTIFORME ‘EXTREME RESPONDERS’
Authors: Mohammed Zameer, Cassie Fives, Niamh Peters, Niamh Birmingham, Dearbhaile Collins, Seamus O’Reilly, Richard Bambury
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma Multiforme (GBM) is the most common primary brain among adults. Despite steady advances in treatment, the outcome remains universally lethal. Median overall survival in a population-based study is approximately 10 to 12 months. Prognostic factors in GBM patients include age, performance score, extent of surgical resection, IDH1 mutation status and MGMT methylation status. Survival &amp;gt; 2 years is rare; for the purpose of this study we have defined these patients ‘extreme responders.’ This study aims to identify genomic signatures and gene alterations that may have contributed to ‘extreme response’ to standard adjuvant chemoradiotherapy. METHODS A total of 12 out of 141 primary GBM patients were identified as ‘extreme responders’ as part of a retrospective chart review between 2005 - 2016. Of the 12 suitable for NGS testing, 9 were analyzed using the Foundation One CDx® (next-generation sequencing platform) which interrogates 324 genes, microsatellite status and tumour mutational burden (TMB). Baseline demographics, clinical characteristics, and NGS results were compared. RESULTS Of the 9 patients tested, over half were female (5, 55%) and median age at diagnosis was 53 years. Gross total resection was performed at diagnosis in 3 cases. MGMT status was available for 5 patients and was methylated in 3. NGS results revealed: MSI stable in all patients, median TMB 3 muts/Mb and most common gene alterations were TP53 (5/9); ATRX (4/9); EGFR (3/9); CDKN2A/B (3/9); IDH1(3/9); PIK3R1(3/9) and PTEN (3/9). CONCLUSION Acknowledging the fact that our sample size was small and no control group was tested, our study infers a higher incidence of IDH1, TP53 and ATRX mutations which are more common in secondary glioblastomas and this may be a contributing factor towards longer survival in our cohort. We did not identify any universal molecular marker predictive of improved prognosis or exquisite sensitivity to chemoradiotherapy.
LGG-22. EVALUATION OF IMMUNE AND GENOMIC CHARACTERISTICS IN PEDIATRIC OPTIC NERVE GLIOMA (ONG)
Authors: Ashley A Campbell, Andrew M Silverman, Hanna Moisander-Joyce, Cheng-Chia Wu, Mahesh Mansukhani, George Zanazzi, Andrew Turk, Peter D Canoll, James H Garvin, Michael Kazim, Robyn D Gartrell-Corrado
Journal: Neuro-Oncology (2020)

Abstract Pediatric optic nerve glioma (ONG) is a rare, sight-threatening tumor. We previously reported clinical, radiologic, histopathologic, and molecular characteristics of pediatric ONG patients treated at Columbia University Medical Center between 2000–2017. Here we evaluate this cohort and one additional patient using quantitative multiple immunofluorescence (qmIF) and next generation sequencing (NGS) using the Columbia Combined Cancer Panel (CCCP). For qmIF, 4 micron immuno-blank slides were stained for CD3, CD8, CD68, CD163, HLA-DR, and Olig2. QmIF images were analyzed and data were processed in R studio and compared based on tumor mutation and treatment history. QmIF failed in 1 case and CCCP failed in 2 cases. CCCP confirmed KIAA1549:BRAF fusions in 2 patients, identified NF1 in 2 patients, and demonstrated both a KIAA1549:BRAF fusion and SETD2 mutation in the added case. Qualitative analysis showed immune infiltrate across cases included macrophages (CD68+, 1.6–6.5% of all cells) and T cells (CD3+, 0.4% to 1.5%). Non-cytotoxic T cells (CD3+CD8-) comprised 60.7–100% of the T cell compartment. There was no difference when comparing mutation groups. However, patients who previously received radiation had increased CD3+, specifically CD3+CD8- cells compared to non-irradiated patients (p=0.01 and p&amp;lt;0.01, respectively) while CD3+CD8+ and CD68+ cells were not different between groups (p=0.49 and p=0.27, respectively). In summary, qmIF analysis showed increased tumor infiltration by non-cytotoxic T cells in previously irradiated pediatric ONG patients compared to non-irradiated patients, while there was no difference in macrophages of cytotoxic T cells. This type of analysis may be useful in designing immunotherapeutic strategies for pediatric ONG.
BIOM-34. CLINICAL, RADIOGRAPHIC, AND PATHOLOGIC PREDICTORS OF RESPONSE TO ANTI-PD-1 AND ANTI-PD-L1 THERAPY IN IDH-WILDTYPE GLIOBLASTOMA PATIENTS
Authors: Bryan Iorgulescu, Mary Jane Lim-Fat, Lei Qin, Gareth Grant, Raymond Huang, Geoffrey Young, David Reardon
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Although monoclonal antibodies targeting PD-1 and its ligand PD-L1 have improved overall survival (OS) for many cancers, recent trials of anti-PD-(L)1 in glioblastoma revealed no OS benefit. However, a small subset of patients appears to benefit, warranting evaluation of predictive markers of improved survival. METHODS We evaluated 108 patients managed at Dana-Farber Cancer Institute for IDH-wildtype glioblastoma, who received anti-PD-(L)1 therapy and had complete clinical, pathologic, and radiographic data. OS was measured from anti-PD-(L)1 initiation to death or censored at last follow-up. Predictors of OS were evaluated by multivariable Cox regression, adjusted for age at diagnosis, sex, disease setting (newly-diagnosed vs. recurrent), MGMT status, chemotherapy and bevacizumab before/during anti-PD-(L)1, extent of resection prior to anti-PD-(L)1, and, at anti-PD-(L)1 initiation: KPS, dexamethasone use, absolute lymphocyte count (ALC), ADC mean value, FLAIR volume, T1 post-contrast volume. RESULTS Of 108 patients, 28 (25.9%) were newly-diagnosed, 80 (74.1%) were treated in the recurrent setting, and 100 died (92.3%). In multivariable analysis, unmethylated MGMT (HR 2.31, 95%CI: 1.38–3.88, p=0.002), and, at the time of anti-PD-(L)1 initiation, baseline dexamethasone use (HR 1.79, 95%CI: 1.07–3.00, p=0.03), lower ADC mean values (reference 2nd quartile [1,130-1,262 10-6mm2/s]; 3rd quartile [1,268–1,388] HR 0.32, 95%CI: 0.15–0.67, p=0.002; 4th quartile [1,402–11,966] HR 0.30, 95%CI: 0.14–0.66, p=0.003), and higher T1 post-contrast volumes (reference 2nd quartile [4,121–8,157mm3]; 3rd quartile [8,701–14,663mm3] HR 2.08, 95%CI: 1.03–4.19, p=0.04; 4th quartile [15,566-64,362mm3] HR 3.15, 95%CI: 1.49–6.69, p=0.003) independently predicted worse OS. Older age (HR 1.02/year, 95%CI: 1.00–1.05, p=0.07) and lower ALC (HR 0.66/unit, 0.40–1.10, p=0.11) trended towards worse OS. CONCLUSION Unmethylated MGMT, and, at the time of starting anti-PD-(L)1, baseline dexamethasone, low ADC mean value, and high T1 post-contrast volume may be predictive of worse OS in IDH-wildtype glioblastoma patients treated with anti-PD-(L)1. These findings may help better select patients who could benefit from PD-(L)1 inhibitors.
BIOM-43. GLUTAMATE RECEPTOR AND GLUTAMINE METABOLISM PROFILING BY GENE EXPRESSION ANALYSIS AMONG PATIENTS WITH HIGH GRADE GLIOMA (HGG)
Authors: Michael Castro, Nilofar Badra-Azar, Thomas Kessler, Moritz Schütte, Bodo Lange, Marie-Laure Yaspo
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glutaminolysis and excessive glutamate production are among the metabolic hallmarks of HGG. In addition to a probable role in causing seizures, autocrine stimulation of metabotropic and ionotropic (NMDA, AMPA, and kainate) receptors are capable of activating intracellular signaling pathways that are tumorigenic and contribute to drug and radiation resistance. While hints of a survival benefit from glutamate receptor targeting have occasionally emerged from the clinic, no single strategy has consistently demonstrated efficacy. Hence, we sought to characterize the magnitude of glutamate receptor overexpression and its diversity across a population of HGG patients. METHODS A set of 41 genes related to glutamate metabolism was selected from the literature. RNA gene counts for TCGA glioblastoma multiforme (N=163) and Grade 3 glioma samples (Astrocytoma=82, Oligodendroglioma=47, Oligoastrocytoma=39) were downloaded from https://portal.gdc.cancer.gov/. Annotation on subtypes and PFS values were obtained from PMID: 24120142 and 26061751. Gene expression normalization as FPKM and hierarchical clustering were performed using R-3.6.0 genes. RESULTS A heatmap with hierarchical clustering for glutamate and glutamine-related genes for the TCGA GBM and grade III glioma samples cohort was generated including colored annotation for the subtype and progression free survival. The graph shows a rough separation into two groups, with grade III gliomas and proneural samples tentatively clustering together and showing higher expression for most of the glutamate related genes. The magnitude of glutaminolysis-related gene over-expression varied significantly across the cohort suggesting a wide variety in the extent of glutamine addiction. CONCLUSION Specific glutamate receptors are commonly upregulated in HGG patients, however the heterogeneity underlying this phenomenon suggests that uniform drug strategies are unlikely to succeed in a diverse population. However, gene expression analysis has utility to identify specific glutamate receptor and glutamine profiles and to inform the treatment strategies for discrete subsets of patients using drugs that are already in the armamentarium.
Abstract #4362: MUC17 is a potential tumor suppressor gene in colorectal adenocarcinoma
Authors: Venkat Katkoori, Chandrakumar Shanmugam, Brittnee L Lucas, Surindra K Batra, William E Grizzle, Gene Siegal, Upender Manne
Journal: Cancer Research (2009)

Background: Mucins are the major secreted glycoproteins of the gastrointestinal tract including the colorectum. Aberrant expression of mucins has been known to play a role in colorectal carcinogenesis. Increased expression of MUC17, a recently identified membrane tethered mucin, has been reported in pancreatic tumor tissues and in cancer cell lines of pancreas and colon. Nevertheless, the role of MUC17 and its clinical significance in colorectal adenocarcinomas (CRCs) have not been studied. Methods: One hundred and thirty six formalin-fixed paraffin-embedded tissue specimens of CRCs, were evaluated for phenotypic expression of MUC17 using anti-human MUC17 rabbit polyclonal antibody and horse-radish peroxidase detection method. The expression levels and patterns were correlated with key clinicopathologic features and patient outcomes. We also performed in vitro cell based assays for cell growth, cell cycle arrest, cell migration and invasion to understand the tumor suppressor function of MUC17 by stable interference of MUC17 in the CRC cell line, LS174. Results: In our immunohistochemical analysis, we observed uniform MUC17 staining in the cytoplasm, specifically in the supra-nuclear position (punctate pattern), in all benign (normal) colonic epithelial tissues. Whereas in CRCs we observed either punctate staining (60 of 136, 44%), a complete lack of staining (null) or diffuse low levels of cytoplasmic staining (76 of 136, 56%). The cases in which the CRCs exhibited diffuse cytoplasmic or null staining pattern were considered as aberrant expressors of MUC17. The aberrant expression of MUC17 was significantly correlated with poor tumor differentiation (\#967;2, p=0.021) and with larger tumor size (\#967;2, p=0.011). Also, these patients had a trend towards short overall patient survival (log rank, p=0.072). In vitro cell based analyses have suggested that cells with stable inhibition of MUC17 by siRNA had significantly decreased cell cycle arrest in G0/G1 or S phase and had higher rates of cell proliferation and cell migration as compared to uninhibited control (scramble RNAi) cells. Conclusion: These preliminary results suggest that the loss of punctate immunostaining pattern of MUC17 was associated with an aggressive behavior of CRCs and shortened patient survival. Additionally, the cell-based experimental data suggests that MUC17 may be the protein product of a potential tumor suppressor gene in colorectal cancer.This work is supported by funds from the National Institute of Health/National Cancer Institute (RO1-CA98932-01, 2U54-CA118948-03, and the Early Detection Research Network, U24-CA086359).  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4362.
EPID-31. CONTEMPORARY MANAGEMENT OF GRADE 2 AND 3 GLIOMA IN ALBERTA AND MANITOBA, 2012–2016: COMPARISON OF TOLERABILITY AND OUTCOMES ACROSS CHEMOTHERAPY REGIMENS
Authors: Emily Walker, Jay Easaw, Faith Davis, Marshall Pitz
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Grade II/III glioma are a significant source of morbidity and mortality, with disease behaviour ranging from relatively mild to aggressive. Phase 3 clinical trial data informed contemporary treatment paradigms, but the perceived differences in tolerability between temozolomide-based regimens and procarbazine, CCNU, and vincristine (PCV)-based regimens has resulted in different treatment approaches across centres. We compared the frequency of progression and adverse drug events (ADE) among patients given these two regimens. METHODS Grade II/III glioma patients were identified through cancer registries in Alberta and Manitoba. Clinical data was obtained through electronic medical records. We estimated the distribution of patient age and sex, molecular data, treatment details, ADE, and patient outcomes across groups treated by temozolomide or PCV. RESULTS From 2012–2016, 344 patients were identified. Of these, 51% received chemotherapy: 26 received PCV (5/6 cycles completed by 85%), 142 received temozolomide (5/6 cycles completed by 78%). PCV resulted in grade 3/4 ADE in 38% of cycles, most commonly bone marrow toxicity. Temozolomide resulted in grade 3/4 ADE in 6% of cycles, most commonly nausea and rash. Clinical progression events occurred in 23% and 30% of PCV and temozolomide patients, respectively. Radiological progression events occurred in 50% and 52% of PCV and temozolomide patients, respectively. CONCLUSION Systemic therapy is commonly given to patients with grade II/III glioma, with more temozolomide use compared to PCV. All patients had high completion rates of treatment despite more frequent grade 3/4 adverse events in patients treated with PCV. The frequency of progression was similar across groups.