tbuckley/cabot-search huggingface dataset:
Variation in the ESR-1 gene as a prognostic marker in early breast cancer survival.
Authors: Danny Houtsma, Stefanie de Groot, Tahar van der Straaten, Renee Baak-Pablo, Cock J.H. van der Velde, Henk-jan Guchelaar, Hans Gelderblom
Journal: Journal of Clinical Oncology (2014)

11074 Background: Variation in the genes coding for the estrogen receptor (ESR-1), CYP2c19 and UGTB15 is associated with worse outcome in tamoxifen treated early breast cancer patients. It is unclear whether this variation is a predictive marker for tamoxifen efficay or if it is a prognostic marker for breast cancer outcome. The aim of this study was to examine if SNP’s in these genes are also associated with survival in early breast cancer patients treated with adjuvant exemestane as to explore a prognostic potential of these markers. Methods: Patients of whom tissue was available were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. DNA was isolated from tumor samples. The following 4 SNPs were genotyped using Taqman assays: rs9340799 and rs2234693 in the ESR-1 gene, rs1902023 in the UGTB15 gene and rs4244285in the CYP2c19 gene. Primary endpoint was relapse-free survival (RFS) and secondary endpoint was overall survival (OS). A Kaplan-Meier analysis was performed and Cox proportional hazards models assessed survival differences. Analyses were adjusted for age at diagnosis, tumor size, nodal status, histological grade, surgery, adjuvant radiotherapy and chemotherapy. Results: 807 patients were included in the analyses and genotypes were obtained in 84%-96% of the samples. No association was found with the primary endpoint of relapse free survival with any of the four SNPS. However, the rs2234693 variant in ESR1 was associated with worse overall survival with an odds ratio of 1,4 (P = 0.016) consistent with a prognostic rather than a predictive drug response effect. Conclusions: Variation in the ESR-1 gene is related to overall survival in early breast cancer patients. Variation in the ESR-1 gene may be used as a prognostic marker of early breast cancer survival regardless of which endocrine treatment is used.
P16.32 Primary cerebral lymphomas. Case report and review of the literature
Authors: E. Unal, V. Antar, T. Hasanov, A. Guzel, K. Kilic
Journal: Neuro-Oncology (2017)

Introduction: The incidence of primary central nervous system lymphoma (PCNSL) has been rising during the past three decades, increasing from 2.5 per million in 1973 to 30 per million in 1997. They constitute the second most frequent primary brain tumor after gliomas. Materials and Methods: Medline and PubMed were queried for primary central nervous system lympohomas. Data was interpreted and is presented along with interesting cases. Results: In the mind of most of the neurosurgeons lymphomas are “good” lesions, corticosteroid treatment make them disappear, biopsy is just what they need and oncologists cure them by chemotherapy. This assumption is far from being correct. First of all they are extremely malignant lesions which can kill the patients in a month after total removal if radiotherapy and chemotherapy is not done. Secondly even if radiotherapy and chemotherapy are administered, median survival is no longer than fourteen to sixteen months. CONCLUSION: We present our cases of PCNSL operated on in our institution and in accordance with some recent publications we communicate our feeling that an attempt at gross total resection is reasonable for patients with solitary lesions that can be removed without morbidity.
P19.05 Safety and tumor inhibitory effect of ketogenic diet for pediatric patients with malignant brain tumors
Authors: N. Shinojima, H. Matsuzaki, A. Maenaka, K. Makino, K. Yamamoto, Y. Takeshima, J. Kuratsu, H. Nakamura, S. Yano
Journal: Neuro-Oncology (2017)

Background: Ketogenic diet (KD) is one of the metabolic therapy which intents low-carbohydrate and high-fat diet, resulting in reduction of serum glucose level and induction of abundant ketone bodies. KD was established as a diet therapy for intractable epilepsy approximately in the 1920s. The metabolism of tumor cells manifests abnormal accentuation of anaerobic glycolysis regardless of oxygen concentration, resulting in assumption of quite abundant glucose for their living, proliferation. KD has been proposed as the diet for the patients with cancers including malignant brain tumors with expectancy of tumor inhibitory effect. Under the KD the normal cells are able to obtain the energy from ketones, while tumor cells are not because lacking critical ketolytic enzymes. Therefore the KD restricting glucose is supposed to selectively starve tumor cells and inhibit tumor growth. Objective: The purpose of this study is to investigate the safety and tumor inhibitory effect of KD for pediatric patients with malignant brain tumors. Methods: Written informed consent was obtained from the patient’s parents. KD treatment was conducted under our protocol approved by the Research Ethics Committee of the Institutional Review Board of Kumamoto University Hospital. Results: Two pediatric patients with infratentorial anaplastic ependymoma underwent KD. A 3-year-old boy underwent surgery followed by radio-chemotherapy. However the uncontrolled tumor progression was found with dural dissemination and palliative care with KD started. Surprisingly he had been still well without any major adverse event and no tumor progression was observed until 13 months later from starting palliative care with KD alone. He could spend the happy time in his home and could survive for 32 months from the date of diagnosis. The other is a 4-year-old girl that underwent surgery followed by radiation and KD. She continued KD without any major side effect for 8 months until she left our hospital. No tumor progression was found 7 months later after RT and she could spend the happy time in her home. Three month later after termination of KD taking, the progression of tumor was found with the dissemination in spinal cord and then she died 4 months later. Conclusions: KD was safe and provided good QOL to the pediatric patients with malignant brain tumors. KD may be an alternative treatment for pediatric patients with malignant brain tumors in palliative care.
P08.67 Defining brain microglia versus peripheral macrophages in a mouse model of glioblastoma using a non-myeloablative conditioning regimen
Authors: K. K. H. Yu, A. S. Youshani, F. L. Wilkinson, C. O’Leary, O. N. Pathmanaban, I. D. Kamaly-Asl, F. Roncaroli, B. Bigger
Journal: Neuro-Oncology (2017)

Central Nervous System (CNS) diseases and lesions are characterised by significant immune cell infiltration. In Glioblastoma Multiforme (GBM), a primary brain cancer, these Tumor Associated Macrophages and microglia (TAMM) may have pro-tumorigenic functions and play a key role in attenuating the host response to glioma. These cells can originate from the CNS itself as microglia or from the peripheral haematopoietic system as macrophages. Techniques currently used to separate the two populations in mice have used partially chimeric transplantation models or head shielded irradiation conditioning, however irradiation in particular leads to confounding pro-inflammatory effects in the peripheral environment. Furthermore, the reliability of using the cell surface markers CD45 high/low coupled with CD11b to distinguish central and peripheral populations has not been rigorously evaluated within the tumour microenvironment using non-irradiative methods. To circumvent these difficulties, we developed a Non-Myeloablative Conditioning (NMC) transplant regimen using low dose busulfan, achieving high CD45.1 donor marked peripheral blood haematopoietic chimerism (93%), without brain chimerism or blood brain barrier damage, thus maintaining CD45.2 marked homeostasis of the resident microglial population in the brain. Subsequent intracranial orthotopic implantation of a syngeneic mouse glioma line and whole brain flow cytometry, allowed us to characterise the proportion and type of peripheral immune cells infiltrating tumours. We observed that the proportion of central or peripheral TAMMs does not change significantly over time once the tumour is initially established. We also demonstrate that CD45/ CD11b, unreliably differentiates between central and peripheral TAMMs in the tumour environment, while the markers CD11b, Ly6C, MHCII, CD64 and MerTK, reliably differentiates subpopulations within peripheral derived TAMMs, (inflammatory monocytes, undifferentiated macrophages and macrophages) and central TAMMs, consisting of microglia, both in the NMC model and in un-transplanted mice with >95% purity. The combination of these techniques provides greater distinction of intra-tumoral myeloid cell subsets than previously described marker sets. The NMC transplantation model is simple and effective way of performing transplantation studies, and a powerful method of investigating immune cell interactions in CNS diseases, where a lack of perturbation of the system is important.
Developing Recommendations for Evidence-Based Clinical Preventive Services for Diverse Populations: Methods of the U.S. Preventive Services Task Force
Authors: Kirsten Bibbins-Domingo, Evelyn Whitlock, Tracy Wolff, Quyen Ngo-Metzger, William R. Phillips, Karina W. Davidson, Alex H. Krist, Jennifer S. Lin, Carol M. Mangione, Ann E. Kurth, Francisco A.R. García, Susan J. Curry, David C. Grossman, C. Seth Landefeld, John W. Epling, Albert L. Siu
Journal: Annals of Internal Medicine (2017)

The U.S. Preventive Services Task Force (USPSTF) summarizes the principles and considerations that guide development of its recommendations for diverse U.S. populations. It uses these principles through each step in the evidence-based guideline process: developing the research plan, conducting the evidence review, developing the recommendation, and communicating to guideline users. Three recent recommendations provide examples of how the USPSTF has used these principles: the 2015 recommendation on screening for abnormal blood glucose and type 2 diabetes; the 2016 recommendation on screening for breast cancer; and the recommendation on screening for prostate cancer, which is currently in progress. A more comprehensive list of recommendations that includes considerations for specific populations is also provided.
Breach of autoreactive B cell tolerance by post-translationally modified proteins
Authors: Jacqueline S Dekkers, Marije K Verheul, Jeroen N Stoop, Bisheng Liu, Andreea Ioan-Facsinay, Peter A van Veelen, Arnoud H de Ru, George M C Janssen, Martin Hegen, Steve Rapecki, Tom W J Huizinga, Leendert A Trouw, René E M Toes
Journal: Annals of the Rheumatic Diseases (2017)

Over 50% of patients with rheumatoid arthritis (RA) harbour a variety of anti-modified protein antibodies (AMPA) against different post-translationally modified (PTM) proteins, including anti-carbamylated protein (anti-CarP) antibodies. At present, it is unknown how AMPA are generated and how autoreactive B cell responses against PTM proteins are induced. Here we studied whether PTM foreign antigens can breach B cell tolerance towards PTM self-proteins.Serum reactivity towards five carbamylated proteins was determined for 160 patients with RA and 40 healthy individuals. Antibody cross-reactivity was studied by inhibition experiments. Mass spectrometry was performed to identify carbamylated self-proteins in human rheumatic joint tissue. Mice were immunised with carbamylated or non-modified (auto)antigens and analysed for autoantibody responses.We show that anti-CarP antibodies in RA are highly cross-reactive towards multiple carbamylated proteins, including modified self-proteins and modified non-self-proteins. Studies in mice show that anti-CarP antibody responses recognising carbamylated self-proteins are induced by immunisation with carbamylated self-proteins and by immunisation with carbamylated proteins of non-self-origin. Similar to the data observed with sera from patients with RA, the murine anti-CarP antibody response was, both at the monoclonal level and the polyclonal level, highly cross-reactive towards multiple carbamylated proteins, including carbamylated self-proteins.Self-reactive AMPA responses can be induced by exposure to foreign proteins containing PTM. These data show how autoreactive B cell responses against PTM self-proteins can be induced by exposure to PTM foreign proteins and provide new insights on the breach of autoreactive B cell tolerance.
P03.17 Immunohistochemical sub-grouping of pediatric and adult medulloblastoma: a preliminary study
Authors: I. Morra
Journal: Neuro-Oncology (2017)

Medulloblastoma (MB) is the most common malignant childhood brain tumor and may affect young adults. Even if today effective therapies are available, patients often suffer from severe long-term adverse effects, relapses and even secondary tumors. Standard therapy is currently based on post-surgical radiotherapy (RT) and chemotherapy. However, exceptions to this protocol might be used to reduce toxicity affecting brain development and consequent cognitive dysfunctions. A more rational therapeutic strategy may be based on targeting signaling pathways that drive MB growth and dissemination. Recently molecular profiling has identified four molecular subtypes of MB. Groups 1 and 2 (WNT and SHH groups) derive from disregulation of these key developmental signaling pathways and Groups 3 and 4 are associated with up-regulation of c-MYC and n-MYC respectively. This subgroup stratification has generated four genetically distinct tumor identities, each with a characteristic clinical presentation and prognosis. Group 3, associated whit the worst prognosis, was recently characterized by increased CD133 positive Cancer Stem Cells and the activation of STAT signaling pathway. The correct sub-classification in the four molecular groups becomes a key step for risk stratification. The use of an appropriate panel of antibodies may help to subclassify MB patients in these molecular groups and to open the possibility of innovative therapies based on specific inhibitors of the signaling pathways involved. To verify the feasibility of the use of Immunohistochemistry (IHC) for the molecular classification of MD and the possible differences between pediatric and adult MB we retrieved form pathology files 21 adult and 22 pediatric MB. We tested the expression of β-catenin, Filamin A, GAB1, KCNA1, YAP1 and NPR3 and compared the results on adult and pediatric MB. Results were somewhat different in the pediatric (Group 1: 36%, Group 2: 48%, Group 3: 8%, Group 4: 8%) from the adult cases (Group 1: 0%, Group 2: 73%, Group 3: 5,3% Group 4: 21%). This preliminary study demonstrates the usefulness of IHC for the application of the molecular classification of MB. Such IHC approach may represent the base for the development of targeted therapies for MB in pediatric and adult patients with the goal of improving cure rate and hopefully decreasing the side effects of Radiotherapy and Chemotherapy.
Mutation In Erythroid Specific Transcription Factor KLF1 Causes Hereditary Spherocytosis In the Nan (Neonatal Anemia) Hemolytic Anemia Mouse Model
Authors: Robert A White, Daniel P. Heruth, Troy Hawkins, Derek Logsdon, Margaret Gibson, Inna Sokolovsky, Ndona Nsumu, Stephanie Major, Barbara Fegley, Gerald Woods, Karen Lewing, Kathleen Neville, Kenneth Cornetta, Kenneth Peterson
Journal: Blood (2010)
P08.47 Crosstalk of the HGF/c-MET and TGF-β pathways in glioblastoma
Authors: E. Papa, M. Weller
Journal: Neuro-Oncology (2017)

Multiple target inhibition has gained considerable interest in combating drug resistance in glioblastoma, however, understanding the molecular mechanisms of crosstalk between signaling pathways and predicting responses of cancer cells to targeted interventions has remained challenging. Despite the significant role attributed to transforming growth factor (TGF)-β family and hepatocyte growth factor (HGF)/c-MET signaling in glioblastoma pathogenesis, their functional interactions have not been well characterized. Using genetic and pharmacological approaches to stimulate or antagonize the TGF-β-pathway in human glioma-initiating cells (GIC), we observed that TGF-β exerts an inhibitory effect on c-MET phosphorylation through the activation of non-canonical, SMAD-independent pathways, including mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB / AKT) pathways. Moreover, a comparison of c-MET-driven and c-MET independent GIC models revealed that TGF-β inhibits stemness in GIC at least in part via its negative regulation of c-MET activity, suggesting that stem cell maintenance may be controlled by the balance between these two oncogenic pathways. Importantly, immunohistochemical analyses of TGF-β and p-c-MET in human glioblastoma specimens supports a concept of negative regulation between these pathways. These novel insights into the crosstalk of two major pathogenic pathways in glioblastoma may explain some of the disappointing results when targeting either pathway alone in human glioblastoma patients and inform on potential future designs on targeted pharmacological or genetic intervention.
P18.07 Holistic needs assessment in an unselected cohort of newly diagnosed brain tumour patients: Use in designing a survivorship event
Authors: E. Molloy, S. Robson
Journal: Neuro-Oncology (2017)

Background: Survivorship programmes, including The NHS England National Cancer Survivorship Initiative Vision (2010) advocate ­survivorship events be offered post oncology treatment to help patients manage their own conditions. A neuro oncology team in a large urban cancer treatment centre sought to meet the psycho-social as well as health needs of our patient group. Little literature is available so investigation was needed. Method: A 48 item neuro-oncology holistic needs assessment (HNA) was offered to all new brain tumour patients at diagnosis and post XRT/Chemotherapy over a 6 month period (Jan-June 2016). Patients ranked each item from 1 (low) to 10 (high). Two thresholds >4 and >7 were used to identify the percentage of patients with specific concerns. Data was also analysed by grade / type of tumour. Results: 104 people completed an assessment at diagnosis. Diagnostic groups were: Grade IV: 55 patients, G III: 8, Low grade: 12, Meningioma: 26. Ranking of the concerns expressed at initial assessment were (in priority order) Grade IV: 1) fatigue 2) sleep 3) fear of tumour recurrence 4) worry,fear,anxiety. Grade III 1) worry,fear,anxiety 2) sleep 3) transport Low grade 1) fear of tumour recurrence 2) worry,fear,anxiety 3) fatigue 4) appearance Meningioma 1) fatigue 2) mobility 3) transport 4) vision Ranking of concerns in 48 people who completed a second assessment were: Grade IV: Fatigue, fear of recurrence, mobility 4) appearance Grade III 1) sleep 2) fear of recurrence 3)fatigue 4) mobility Low grade 1) fear of recurrence 2) anxiety 3) fatigue 4) finance (Insufficient meningioma patients completed a second assessment to draw conclusions). Conclusion: Most concerns were common to all diagnoses indicating a common survivorship programme could be appropriate early in the pathway for brain tumour patients of all tumour grading. One of the limits of this project was the ability to assess the needs of the same patient group later in their treatment, as concerns may alter as people progress through different stages of their disease. Future work will assess needs later in the pathway to identify longitudinal change and inform survivorship programme design.The project was carried out with an innovation grant from Macmillan Cancer Support
Connexin37 reduces smooth muscle cell proliferation and intimal hyperplasia in a mouse model of carotid artery ligation
Authors: Florent Allagnat, Céline Dubuis, Martine Lambelet, Loïc Le Gal, Florian Alonso, Jean-Marc Corpataux, Sébastien Déglise, Jacques-Antoine Haefliger
Journal: Cardiovascular Research (2017)

Intimal hyperplasia (IH) is an abnormal response to vessel injury characterized by the dedifferentiation, migration, and proliferation of quiescent vascular smooth muscle cells (VSMC) to form a neointima layer. Vascular connexins (Cx) are involved in the pathophysiology of various vascular diseases, and Cx43, the main Cx expressed in VSMC, has been shown to promote VSMC proliferation and IH. The aim of this study was to investigate the participation of another Cx, namely Cx37, in the formation of the neointima layer.Wild-type (WT) and Cx37-deficient (Cx37-/-) C57BL/6J mice were subjected to carotid artery ligation (CAL), a model of vessel injury and IH. The neointima developed linearly in WT until 28 days post surgery. In contrast, the neointima layer was almost absent 14 days after surgery in Cx37-/- mice, and twice as more developed after 28 days compared to WT mice. This large neointima formation correlated with a two-fold increase in cell proliferation in the media and neointima regions between 14 and 28 days in Cx37-/- mice compared to WT mice. The CAL triggered Cx43 overexpression in the media and neointima layers of ligated carotids in WT mice, and selectively up-regulated Cx37 expression in the media layer, but not in the neointima layer. The de novo expression of Cx37 in human primary VSMC reduced cell proliferation and P-Akt levels, in association with lower Cx43 levels, whereas Cx43 overexpression increased P-Akt levels.The presence of Cx37 in the media layer of injured arteries restrains VSMC proliferation and limits the development of IH, presumably by interfering with the pro-proliferative effect of Cx43 and the Akt pathway.
P3.02c-060 Dual Positive PD-L1 and CD8+ TIL Represents a Predominant Subtype in NSCLC and Correlates with Augmented Immunogenicity
Authors: Si-Yang Liu, Zhong-Yi Dong, Wen-Zhao Zhong, Si-Pei Wu, Zhi Xie, Hai-Yan Tu, Yi Long Wu
Journal: Journal of Thoracic Oncology (2017)