tbuckley/cabot-search huggingface dataset:
Serum angiogenesis associated proteins and clinical outcome in metastatic colorectal cancer patients receiving bevacizumab
Authors: G. Marisi, E. Scarpi, A. Passardi, O. Nanni, F. Pagan, M. Valgiusti, A. Casadei Gardini, C. Molinari, G. Frassineti, D. Amadori, P. Ulivi
Journal: Annals of Oncology (2018)

Introduction: Bevacizumab (B) plus chemotherapy (CT) is a common choice for first-line treatment of metastatic colorectal cancer (mCRC). Molecular predictors of B efficacy have not been identified yet. Previous studies have assessed circulating levels of pro- and anti-angiogenic factors at baseline and during therapy in relation to B response with conflicting results. We analyzed the potential role of 22 angiogenesis associated proteins (FGF-basic, HGF, sTIE-2, sVEGFR-1, sVEGFR-2, Ang-2, EGF, IL-6, IL-8, PLGF, VEGF-A, VEGF-C, VEGF-D, PDGF-bb, Ang-1, SDF-1alpha, MDC, Galectin, TSP-1, Endocan, eNOS, HIF-1alpha) in relation to patient outcomes. Methods: Serum samples collected at different times (baseline, first clinical evaluation and disease progression) were available for 58 patients treated by CT (FOLFOX4/FOLFIRI) with B out of the 176 patients enrolled in the randomized multicenter ITACa trial (NCT01878422). Levels of all serum proteins were determined using a Bio-Plex 200 array reader, based on Luminex X-Map Technology. Baseline marker expression levels and their modulation during therapy were correlated with objective response (OR), progression-free survival (PFS) and overall survival (OS). Results: Higher baseline vascular endothelial growth factor C (VEGF-C) levels and macrophage-derived chemokine (MDC) levels were associated with higher OR rate (Odd Ratio=7.69, 95% CI 2.13-27.78, p = 0.002 and Odd Ratio=3.58, 95% CI 1.12-11.37, p = 0.031, respectively). Baseline IL-8 levels were associated with PFS and OS, in particular patients with IL-8 <145 pg/mL showed a better median PFS and OS compared to those with higher levels (12.6 vs 6.5 months; Hazard Ratio [HR] 5.09, 95% CI 2.00-12.97, p < 0.001 and 28.8 vs 8.7 months, HR 6.06, 95% CI 2.12-17.37, p < 0.001, respectively). Moreover, patients with thrombospondin-1 (TSP-1) levels ≥12000 ng/mL showed a better median OS compared to those with lower levels (34.5 vs 13.1 months, HR 0.43, 95% CI 0.23-0.8, p = 0.007). Regarding serum proteins modulation during therapy, patients with a > 20% reduction from baseline to first clinical evaluation in IL-8 levels showed a better PFS and OS compared to those with a < 20% reduction or an increase (HR 0.41, 95% CI 0.22-0.77, p = 0.005 and HR 0.43, 95% CI 0.23-0.79, p = 0.007, respectively). Conclusion: Our data suggest that baseline IL-8 and TSP-1 levels could represent potential prognostic markers in patients with mCRC receiving B-based chemotherapy and that IL-8 modulation from baseline to the first clinical evaluation may indicate better clinical outcomes.
Prognostic impact of K-RAS mutational status and primary tumour location in patients undergoing resection for colorectal cancer liver metastases: A METHEPAR analysis (multicentre study in Argentina)
Authors: J. O’Connor, E. Huertas, F. Sanchez Loria, F. Brancato, J. Grondona, M. Fauda, O. Andriani, P. Sanchez, P. Barros Schelotto, V. Ardiles, E. de Santibañes
Journal: Annals of Oncology (2018)

Introduction: Even though RAS mutations are known to imply aggressive tumour biology, their objective impact on survival is still controversial. The purpose of this study is to determine the impact of KRAS mutational status in the overall survival (OS) and recurrence free survival (RFS) of patients undergoing surgery for colorectal liver metastases (CLM). Methods: Patients with resected CLM from a multicenter collaborative database (METHEPAR) and known KRAS mutational status were included in the present study. Survival outcomes were compared between patients with mutated KRAS (mt-KRAS) versus wild-type KRAS (wt-KRAS). Results: From a total of 662 patients evaluated, 174 patients (26,3%) were mt-KRAS, while 488 (73,7%) were wt-KRAS. At a median follow-up of 37 months, patients with mt-KRAS had significantly less RFS than those with wt-KRAS (HR 1,42; 95% c.i. 1,10 – 1,84). Regarding the location of the primary tumour, 73,3% had left tumours and 25,5% had right tumours, and only 1,2% had both, without differences between the two groups. In multivariable analysis, a mt-KRAS along with positive lymph nodes, >1 metastases, >5 cm tumours, synchronic tumours and R1-R2 resections were independently associated with worse survival. Conclusion: KRAS mutational status seems useful for the prediction of RFS. In our Multicentric Study we couldn't confirm location of the primary tumour, as a prognostic factor in pts. with resected liver metastases. In pts. with CRC after curative resection of CLM, KRAS mutation status may be used to individualize multidisciplinary approach.
QOL-01. THE EFFECT OF VIRTUAL REALITY EXERCISES ON BALANCE IN CHILDREN WITH BRAIN TUMORS
Authors: Müberra Tanriverdi, Fatma Karantay Mutluay, Fatma Betül Çakir
Journal: Neuro-Oncology (2018)

Balance disorders has seen in children with brain tumors. Purpose of our study is to examine the effects of balance education and compare the efficiency of video game exercise systems to conventional methods. 30 patients between 6-18 years of age included in the study and they are randomized into two groups; Wii Fit and conventional. Both groups received their exercises under supervision of a physiotherapist for 8 weeks total, twice a week 1 hour per session. Assessments performed at the beginning of the exercise program and at the end of the 8th week including disease affect, timed performance, functional capacity, balance and daily living activities. There was no significant difference between two groups and in group assessment of disease affect (p>0,05). There were significant differences in groups for timed performance (p<0,05) and functional capacity (p<0,05) but there was no difference between the two groups. Both groups results for balance improved and there was no significant difference between groups even though the Wii Fit group improved more statistically (p≈0). There was no difference between total scores of daily living activities but only social communication score was better in favor of Wii Fit group. Treatment program has no effect on the disease affect instruments yet timed performance tests, functional capacity and balance skills of the patients improved. These improvements were even better for the Wii Fit group. These results show that physiotherapy and rehabilitation is beneficial for children with brain tumor even though it doesn’t have any effects on the disease itself.
Abstract 352: Using Extracellular Matrix Biomolecules to Modify Poly(vinyl alcohol) Vascular Graft Surface Properties
Authors: Katie P Truong, Deirdre E Anderson, Evelyn K Yim, Monica T Hinds
Journal: Circulation Research (2017)

The demand for biosynthetic vascular grafts is increasing due to the growing prevalence of occlusive arterial disease in the population. Autologous vessels are often used for treatment but are limited due to a patient’s pre-existing condition or previous surgeries. There is a clinical need for engineered small diameter blood vessel grafts with mechanical and physiologic properties that mimic native arteries. Poly(vinyl alcohol) hydrogel (PVA) has been previously shown to be a suitable biomaterial for grafting. However, its hydrophilic and bioinert properties prevent in vivo endothelialization. Previously, our work has shown that modification of the PVA surface with different biomolecules can alter endothelial growth and function. Coating with gelatin exhibited a pro-endothelial environment for tissue growth but displayed pro-thrombotic properties. When cyclicRGD (cRGD) peptide was incorporated in the PVA graft, we observed increased endothelial cell viability without an increase in platelet adhesion. We hypothesize that short peptide sequences of the basement membrane extracellular matrix will produce peak endothelial cell growth without compromising the hemocompatibility of the graft. Planar PVA underwent surface modification with different basement membrane proteins and peptides including collagen, laminin, cRGD, and YIGSR. To characterize the hydrophobicity of the material, we measured the static water contact angle on the surface of the PVA. Cell attachment and proliferation of primary endothelial cells were quantified with immunohistochemistry by staining for nuclei, actin, and VE-cadherin. Initial results showed increased hydrophobicity and cell attachment with the surface modifications. Currently, we are assessing thrombotic potential by obtaining plasma clotting time, and platelet attachment and activation during incubation with platelet rich plasma. In the future, we will measure cell migration and retention under flow and characterize the cell phenotype under pro-thrombotic and anti-thrombotic flow conditions using real time PCR. This work is a significant step toward advancing the fabrication of biosynthetic vascular grafts for the treatment of cardiovascular disease
MBRS-27. DIFFERENCES IN RNA AND MIRNA EXPRESSION BETWEEN PTCH AND SUFU MUTATED MEDULLOBLASTOMA IN TWO PATIENTS WITH GORLIN’S SYNDROME
Authors: Sivan Gershanov, Helen Toledano, Nitza Goldenberg-Cohen, Mali Salmon-Divon
Journal: Neuro-Oncology (2018)

A percentage of sonic hedgehog (SHH) medulloblastomas will carry a germline mutation in PTCH1 (upstream) or SUFU (downstream) as part of Gorlin’s syndrome. It has been suggested that the tendency to develop medulloblastoma is greater in those with SUFU and that the syndromic features are different depending on the gene involved. We compared the gene and microRNA expression profile of the tumors of two patients with germline mutations - one in PTCH and one in SUFU. We performed RNA and microRNA sequencing from fresh tumor samples followed by ingenuity pathway analysis. We identified several differences in expression of genes and microRNA: the miRNAs miR-130a-3p and miR-181-5p showed lower expression in the SUFU sample with resultant increased expression of DICER1 either directly or indirectly. Other genes that exhibit decreased expression in the SUFU sample included Connexin involved in Gap junction signaling and Metalloproteinase involved in axonal guidance signaling. Genes that display higher expression in the SUFU sample included GABAR-A in the GABA receptor signaling pathway and Cahedrin in the beta-catenin signaling pathway. These findings need confirmation in a larger sample of tumors and may help to find treatable molecular targets for these types of medulloblastoma. This is vital since radiation - a standard component of treatment for medulloblastoma - is contraindicated in Gorlin’s due to the risk of basal cell carcinoma. In addition SHH inhibitors are ineffective for SUFU medulloblastoma as they inhibit upstream of the mutation.
Adult Glioma Incidence and Survival by Race or Ethnicity in the United States From 2000 to 2014
Authors: Quinn T. Ostrom, David J. Cote, Mustafa Ascha, Carol Kruchko, Jill S. Barnholtz-Sloan
Journal: JAMA Oncology (2018)

Glioma is the most commonly occurring malignant brain tumor in the United States, and its incidence varies by age, sex, and race or ethnicity. Survival after brain tumor diagnosis has been shown to vary by these factors.
Bright spots, physical activity investments that work: Vitality Active Rewards—a smartphone app that incentivises programme members to be physically active
Authors: Deepak N Patel, Craig Nossel, Jon Patricios, Joel Maboreke
Journal: British Journal of Sports Medicine (2018)

Country/locality/coverage: A smartphone app-based programme that has been activated by more than 415 000 people in South Africa.Target Population: Adult members of Vitality, a health promotion and disease prevention programme linked to medical and life insurance plans What modes/types/domains of physical activity does the programme promote?The Vitality Active Awards (VAR) programme promotes, facilitates and incentivises all modes of physical activity, including walking, gym-based activities such as yoga, aerobics, aqua-aerobics; social walking and running programmes; and endurance events such as marathons, cycle races and triathlons. Which of the 7 best investments the program addresses?The VAR programme encourages active transport (Investment 3), community-wide programs involving multiple settings and sectors and that mobilise and integrate community engagement and resources (investment 6) and sports systems and programs that promote 'sport for all' and encourage participation across the life span (investment 7)
DIPG-07. GENOMIC ANALYSIS METHODS FOR IDENTIFICATION OF CANCER DRIVER PATHWAYS IN CHILDHOOD BRAIN TUMORS
Authors: Lauren Sanders, Brittany Rose-Dey, Holly Beale, Jacob Pfeil, Ellen Kephart, Katrina Learned, Ann Durbin, Isabel Bjork, Rob Currie, Olena Morozova, Sameer Agnihotri, Sofie Salama, David Haussler
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is a rare and invasive pediatric brain tumor with limited treatment options. The Treehouse Childhood Cancer Initiative at UC Santa Cruz has developed a comparative gene expression analysis method which identifies outlier genes in gene expression data from tumor samples. This method may be useful for identifying consistently activated pathways in difficult-to-treat tumors such as DIPG. We show here that this method can be used to identify HARS and HMGCR as over-expressed genes in a cohort of DIPG patient tumor samples. Differential expression analysis demonstrates that these genes are significantly over-expressed in DIPG tumors as compared to normal brain tissue, indicating that they may be therapeutically relevant. Targeting these genes in vitro with FDA-approved drugs significantly reduces cell line viability, and targeting both genes at once in combinatorial therapy is more effective than targeting each gene separately. Testing these drugs in human astrocytes and neural stem cells shows no reduction in cell viability. Pathway enrichment analyses demonstrate that the cholesterol biosynthesis pathway, which is driven by HMGCR expression and is a known driver pathway in gliomas, is enriched in DIPG cell lines and in DIPG patient samples. Our results indicate that the cholesterol biosynthesis pathway may be enriched in a subset of DIPG tumors and may be a viable therapeutic target. Future experiments will test our results on a larger cohort of DIPG cell lines.
Imaging of Chemokine Receptor CXCR4 in Mycosis Fungoides Using 68Ga-Pentixafor PET/CT
Authors: Serkan Kuyumcu, Ebru Yilmaz, Fikret Büyükkaya, Zeynep Gözde Özkan, Seher Nilgün Ünal
Journal: Clinical Nuclear Medicine (2018)

A 52-year-old woman diagnosed with mycosis fungoides was referred for F-FDG PET/CT before treatment for the evaluation of disease severity. The patient also underwent Ga-pentixafor PET/CT for further evaluation. FDG uptake was observed in cervical, axillary, and pelvic lymph nodes and multiple widespread skin lesions throughout the body, suggestive of extensive involvement of mycosis fungoides. All lesions were visually identifiable with high target-to-background ratio on Ga-pentixafor PET/CT which demonstrated marked CXCR4 expression in all lesions that were detected using F-FDG PET/CT.
Association of Platelet Count and Mean Platelet Volume with Overall Survival in Patients with Cirrhosis and Unresectable Hepatocellular Carcinoma
Authors: Bernhard Scheiner, Martha Kirstein, Sabine Popp, Florian Hucke, Simona Bota, Nataliya Rohr-Udilova, Thomas Reiberger, Christian Müller, Michael Trauner, Markus Peck-Radosavljevic, Arndt Vogel, Wolfgang Sieghart, Matthias Pinter
Journal: Liver Cancer (2018)

Platelets have been reported to influence tumor biology and may promote metastasis. Traditionally, thrombocytopenia, a hallmark of cirrhosis, was associated with hepatocellular carcinoma (HCC) development. However, the impact of platelet count on outcome in patients with established HCC is not well studied.Outcomes of patients with cirrhosis diagnosed with HCC between 1995 and 2013 (derivation cohort) and 2000-2016 (validation cohort) who were not eligible for surgical treatment and did not receive antiplatelet therapy were retrospectively studied. Thrombocytopenia was defined as platelet count < 150 g/L. High mean platelet volume (MPV) was defined as ≥median value of the respective cohort (derivation cohort: ≥11 fL; validation cohort: ≥10.6 fL).Among 626 patients with unresectable HCC, thrombocytopenia was present in 378 (60.4%) and was associated with favorable baseline tumor characteristics: lower diameter of the largest nodule (5.6 ± 3.2 vs. 7.6 ± 4.2 cm), less extrahepatic spread (9.5 vs. 20.2%, both p < 0.001), less macrovascular invasion (21.2 vs. 31.0%, p = 0.005), and lower BCLC stages (63.0 vs. 73.4% BCLC C/D; p = 0.007) as compared to patients with normal platelet count. On univariate analysis, thrombocytopenia and larger MPV were associated with longer overall survival (OS) (thrombocytopenia: median OS [95% CI], 11.5 [9.3-13.8] vs. 5.5 [3.8-7.1] months; p = 0.001; MPV ≥11 fL: 11.7 [9.1-14.2] vs. 6.0 [4.4-7.6] months; p < 0.001). In multivariate analysis, the combined variable of thrombocytopenia and larger MPV was independently associated with longer OS (HR [95% CI], 0.80 [0.65-0.98]; p = 0.029). These results were confirmed in an independent external validation cohort of 525 patients with cirrhosis and HCC. Again, patients with thrombocytopenia and high MPV had significantly longer OS (15.3 [11.7-18.9] vs. 9.3 [7.4-11.2] months; p < 0.001).Thrombocytopenia and higher MPV are associated with better outcome in patients with advanced HCC. These findings may prompt further clinical research on additive antiplatelet therapy in the prevention and management of HCC.
EPEN-13. NOVEL LSD-1 INHIBITOR VALIDATION IN NEWLY ESTABLISHED PFA EPENDYMOMA PATIENT-DERIVED ORTHOTOPIC XENOGRAFT (PDOX) MODELS
Authors: Sibo Zhao, Huiyuan Zhang, Lin Qi, Holly Lindsay, Yuchen Du, Frank Braun, Mari Kogiso, Sarah Injac, Yongcheng Song, Xiao-Nan Li
Journal: Neuro-Oncology (2018)

Posterior fossa A (PFA) ependymoma (EPN) has one of the worst prognosis in children and is primarily driven by epigenetic changes. In this study, we established a series of PFA EPN PDOX models from fresh surgical patient specimens. We also examined the therapeutic efficacy of SYC-836, a novel LSD-1 inhibitor compound, in these models. EPN patient samples obtained from Texas Children’s Hospital were directly implanted into NOD/SCID mouse brains. Tumorigenic xenograft tumors were serially subtransplanted for 5 generations. Detailed morphologic, histologic, and molecular comparisons were completed between xenograft and patient tumors. To examine in vitro activities, primary cultured cells from a PFA EPN cell line were subjected to SYC-836 at various concentrations (0-25uM). Cell viability and proliferation were measured over 14 days. To validate the drug’s in vivo efficacy, 2 PDOX models were utilized. 40 SCID mice/model were implanted with tumor cells and divided into 4 treatment groups each: 1) control, 2) radiation, 3) SYC-836 only, and 4) combination (radiation + SYC-836). Animal survival times were analyzed using log rank analysis. We successfully developed 6 posterior fossa EPN xenografts models. It can be cryopreserved for long-term maintenance of tumorigenicity. Xenograft tumors precisely replicated characteristics of the patient tumors. SYC-836 demonstrated effective cell killing in vitro. IC50 was ~7.5uM. There were no survival benefit with either XRT or SYC-836 only when compared to the control group; however, when used in combination, the treatment strategy lead to significant improvement in animal survival. SYC-836 was well tolerated in mice.
Pathogenic Citrulline‐Multispecific B Cell Receptor Clades in Rheumatoid Arthritis
Authors: Philip J. Titcombe, Gustaf Wigerblad, Natalie Sippl, Na Zhang, Anna K. Shmagel, Peter Sahlström, Yue Zhang, Laura O. Barsness, Yogita Ghodke‐Puranik, Azar Baharpoor, Monika Hansson, Lena Israelsson, Karl Skriner, Timothy B. Niewold, Lars Klareskog, Camilla I. Svensson, Khaled Amara, Vivianne Malmström, Daniel L. Mueller
Journal: Arthritis & Rheumatology (2018)

Objective Anti–citrullinated protein antibodies ( ACPA s) have proven highly useful as biomarkers for rheumatoid arthritis ( RA ). However, composition and functionality of the associated autoreactive B cell repertoire have not been directly assessed. We aimed to selectively investigate citrullinated autoantigen–specific B cell receptors ( BCR s) involved in RA and initiate studies on their pathogenicity. Methods Blood samples were obtained from patients in a University of Minnesota cohort with ACPA ‐positive RA (n = 89). Tetramer sets bearing citrullinated filaggrin peptide cfc1 or citrullinated α‐enolase peptide were constructed to specifically capture autoreactive B cells from the unaltered, polyclonal repertoire in RA patients. Citrullinated peptide tetramer–bound B cells were subjected to flow cytometric cell sorting and single‐cell IGH , IGK , and IGL gene sequencing for B cell lineage determinations. BCR gene sequences were also expressed as recombinant monoclonal antibodies ( mA b) for direct evaluation of citrullinated autoantigen binding and effector functionality. Results Using citrullinated peptide tetramer enrichment to investigate single autoreactive blood B cells, we identified biased V‐region gene usage and conserved junction arrangements in BCR s from RA patients. Parsimonious clustering of related immunoglobulin gene nucleotide sequences revealed clonal expansions of rare individual B cell clades, in parallel with divergent sequence mutations. Correspondingly, recombinant mA b generated from such BCR lineages demonstrated citrulline‐dependent cross‐reactivity extending beyond the citrullinated peptides used for B cell capture. A pair of citrullinated autoantigen–specific mA b with cross‐reactive binding profiles also promoted arthritis in mice. Conclusion Our findings suggest that broad ACPA specificities in RA arise from a restricted repertoire of evolving citrulline‐multispecific B cell clades with pathogenic potential.
MBRS-12. INTERFERENCE WITH THE FUNCTION OF MYC IN GROUP 3 MEDULLOBLASTOMA
Authors: Jonas Ecker, Venu Thatikonda, Ina Oehme, Gintvile Valinciute, Florian Selt, Juliane L Buhl, Diren Usta, Cornelis M van Tilburg, Christel Herold-Mende, Martina Schnölzer, Uwe Warnken, Marcel Kool, Natalie Jäger, Stefan M Pfister, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2018)

High-risk medulloblastoma (MB) is a deadly disease with poor overall survival. Survivors suffer from severe treatment-associated morbidity. Patients with Group 3 MB with an amplification of MYC show particularly poor outcome. Therefore novel therapies tailored to this subgroup are urgently needed. We have previously shown that MYC amplified MB cell lines are highly susceptible to inhibition of class I histone deacetylases (HDACs), including HDAC2. We here explore the functional interaction of HDAC2 and MYC. Chromatin immunoprecipitation with pulldown of MYC, HDAC2, RNApolII and H3K27ac, followed by DNA-sequencing was performed in n=3 primary MYC amplified Group 3 MB tumors and correlated with gene expression profiles (GEP). The GEP of MYC amplified MB cell line HD-MB03 was determined after class I HDAC inhibition. MYC stability upon HDACi treatment was assessed in immunofluorescence microscopy and cycloheximide chase experiments. MYC-HDAC2 interaction was analyzed in co-immunoprecipitation and mass spectrometry studies. In primary tumors 90% of MYC DNA binding sites are co-occupied by HDAC2. Compared to MYC- or HDAC2-only bound genes, MYC-HDAC2 co-bound genes show strong recruitment of RNApolII and higher expression levels. In HD-MB03 cells MYC and HDAC2 show overlapping DNA binding sites of 80%, both proteins are co-localized in a multi-protein complex. GEP analysis revealed a significant downregulation of MYC target genes after treatment with class I HDAC inhibitor MS-275, coinciding aberrant MYC protein levels. Our data suggests that MYC functions directly depend on class I HDAC activity. Inhibiting HDAC2 may offer a therapeutic option to target the currently undruggable oncoprotein MYC.