tbuckley/cabot-search huggingface dataset:
Abstract 19620: Impact of D-dimer for Prediction of Occult Cancer in Patients With Unprovoked Venous Thromboembolism
Authors: Donghee Han, In-Jeong Cho, Chi Young Shim, Hyuk-Jae Chang, Geu-Ru Hong, Jong-Won Ha, Namsik Chung
Journal: Circulation (2015)

Introduction: Unprovoked venous thromboembolism (VTE) is related higher incidence of occult cancer. However, routine screening for cancer in this population is still controversial. D-dimer is a biomarker reflecting the activation of hemostasis and fibrinolysis. D-dimer is clinically used to exclude VTE, also related in patients with malignancy. Hypothesis: We aimed to explore the predictive value of d-dimer level for detecting occult cancer in patients with unprovoked VTE. Methods: We retrospectively analyzed 840 patients who diagnosed deep vein thrombosis or pulmonary thromboembolism. Among them, 175 (20.8%) patients who diagnosed with unprovoked VTE selected to participate in this study. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated for incidence of occult cancer as well as d-dimer level reference to patient without occult cancer. Results: During follow-up for 5.0±1.9 years, 30 of 840 patients diagnosed cancer in this population. The primary origin of tumor was 6 (20%) of stomach, 6 (20%) of lung, 4 (13%) of colon and others. Number of patients with metastatic cancer was 17 (57%). Log d-dimer was significantly higher in occult cancer group than unprovoked VTE without cancer (3.5 ± 0.5 vs. 3.2 ± 0.5, p=0.009). When the patients with unprovoked VTE were divided by d-dimer according to Youden index, high d-dimer (≥2432) was associated with higher prevalence of occult cancer (26.9% vs. 9.2%, p=0.002). In logistic regression analysis, d-dimer is independently associated with occult cancer (OR: 3.93, 95% CI: 1.46-10.54, p=0.007) after adjusted gender, age, type of VTE (i.e., deep vein thrombosis or pulmonary thromboembolism) and tumor markers. In addition, d-dimer is more significantly associated with patients who diagnosed cancer with distant metastasis (OR: 4.31, 95% CI: 1.16-15.99, p=0.029) Conclusions: High level of d-dimer concentrations are indicator of an increased risk of occult cancer in patients with unprovoked VTE.
Laparoscopic liver resection for tumors in proximity to major vasculature and the impact of neo-adjuvant systemic therapy
Authors: M. D'Hondt, E. Willems, I. Parmentier, H. Pottel, C. Verslype, C. De Meyere, F. Vansteenkiste, M. Besselink
Journal: Annals of Oncology (2018)

Introduction: Only small case series have been published regarding laparoscopic liver resection (LLR) for tumors in proximity to major vessels (MVs). The aim of this study is to compare peri-operative outcomes of LLR for tumors < 20 and ≥ 20mm from MVs. Methods: Retrospective analysis of a prospectively collected database of consecutive LLR (October 2011 – August 2017) performed by a single surgeon. Proximity to MVs was defined as a distance of 20 mm or less to the caval vein, hepatic veins and portal vein (main trunk and first branches). Results: A total of 235 LLR were performed, of which 60 patients (24%) had lesions in proximity to major vasculature, median distance to MV 10 mm (range 0-17 mm). Significantly more patients in the close-to-major-vessels group (CTMV) received neo-adjuvant chemotherapy (36.7% vs 24.2%, p = 0.0094). In the CTMV group, the median Difficulty Score for LLR was significantly higher (8.5 (IQR: 6.0-9.0) vs 5.0 (IQR: 3.0-6.0), p < 0.001) as was the use of CUSA (p < 0.001) and Pringle manoeuver (8.3% vs 1.7%; p = 0.028). Operative time was significantly longer (180min (IQR: 140-210) vs 120min (IQR: 75-150), p < 0.001) and blood loss was significantly higher (190ml (IQR: 100-325) vs 75ml (IQR: 50-220), p < 0.001) in the CTMV group. This did not result in a difference in perioperative blood transfusion (3.3% vs 1.7%, p = 0.60) or in postoperative morbidity (15.0% vs 14.3%, p = 0.89). There was no mortality in both groups. There was no significant correlation between the distance to MVs and blood loss (p = 0.80) or operative time (p = 0.95). Correlation between central venous pressure drop and blood loss was borderline significant (p = 0.06). There was a significantly higher R1 resection rate in the CMTV group (10% vs 1.7%, p = 0.0098). On long-term follow-up, there were no significant differences in 5-year overall survival (41% VS 69%, p = 0.12) and 5-year disease-free survival (31% VS 20%, p = 0.98) between the CTMV group and the other group. Conclusion: In selected patients, LLRs of lesions in proximity to MVs is safe and feasible with acceptable long-term and oncological results. These patients received more neo-adjuvant systemic therapy.
A pilot trial of PEGPH20 (Pegvorhyaluronidase alfa) in combination with avelumab (anti-PD-L1 MSB0010718C) in chemotherapy resistant pancreatic cancer (PDAC) - Trial in progress
Authors: L. Medina Rodriguez, C. Guillén-Ponce, J. Feliu, M. Hidalgo
Journal: Annals of Oncology (2018)

Introduction: PDAC is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure, resulting in tumor vascular collapse, hypoxia, blocking chemotherapeutic agent perfusion and immune cells. Consequently, checkpoint inhibitors and immunotherapy strategies have failed in PDAC. PEGPH20 targets tumors that accumulate HA. Enzymatically depleting HA from the extracellular matrix (ECM), resulting in decompression of intratumoral blood vessels and increased penetration of antitumor agents. In preclinical models, depletion of HA in the tumor microenvironment has been shown to inhibit the growth of tumors characterized by accumulation of HA. PEGPH20 has been evaluated in a phase II trial in combination with gemcitabine and nab–paclitaxel (PAG) versus gemcitabine plus nab–paclitaxel (AG). For patients with high HA expression on baseline biopsies, the combination arm with PEGPH20 increased progression-free survival (PFS) by 4 months (9.2 vs. 5.2 months; HR 0.51; p = 0.048). Our study tests the hypothesis that elimination of HA in tumor microenvironment by PEGPH20 will result in stromal remodeling and may facilitate the activity of checkpoint inhibitors like avelumab, by at least two mechanisms including increase in drug delivery and increasing immune infiltrate. Methods: A pilot, open label, multicenter, pharmacodynamics, safety, and efficacy study of PEGPH20 in combination with avelumab in chemotherapy resistant advanced or locally advanced PDAC. PEGPH20 3 microg/Kg dose will be administered on days 1, 4, 8, 11, 15, 18 during the first cycle (28 days) and days 1 and 15 thereafter. Avelumab at dose of 10 mg/Kg will start on day 15 after 4 doses of PEGPH20 and continued to be administered every 2 weeks during the study. Enoxaparin will be administered to all subjects to minimize the risk of thromboembolic events (TE) associated to PEGPH20 administration. Pharmacokinetics (Pk) samples for PEGPH20 will be collected. Other assessments: serum CA 19-9 and tissue biomarkers (including collagen content, cancer associated fibroblasts [CAF], and immune infiltrate). Objectives: Primary: To determine the objective response rate (ORR) as per RECIST v1.1 criteria. Secondary: To determine the overall survival (OS), progression free survival (PFS) and CA19-9 tumor marker response. Exploratory: To determine the effect of PEGPH20 in HA content in plasma and paired tumor biopsies. Key inclusion criteria: progression to first line treatment for locally advanced or advanced disease, life expectancy ≥ 3 months and no clinical evidence of prior TE within 12 months or other known TE during the screening.
HGG-19. BONE MORPHOGENETIC PROTEIN 4 DIFFERENTIATES GLIOMA STEM CELLS TO INCREASES CHEMOSENSITIVITY VIA DECREASING H3K4me3 IN PEDIATRIC HIGH GRADE GLIOMAS
Authors: Sonali Nayak, Benamin Best, Emily Hayes, Barbara Mania-Farnell, Tadanori Tomita, Guifa Xi
Journal: Neuro-Oncology (2018)

Glioma stem cells (GSCs), with neural stem cell (NSC) like properties are key factors behind therapeutic resistance in pediatric high-grade gliomas (HGG), the second most formidable childhood cancers. Targeting GSCs is a promising pathway for enhancing therapeutic effect and improving patient outcomes. Histone post-translational modifications (PTMs) regulate gene expression patterns dictate stem cell fate and regulate drug resistance. Tri-methylation on histone 3 lysine 4 (H3K4me3) has been associated with human NSCs and GSCs, with its reduction results in cell differentiation and increases chemotherapeutic efficacy in pediatric HGGs. Human SETD1A facilitates H3K4me3 on active gene promoters. Levels of SETD1A and H3K4me3 are high in NSCs and malignant gliomas, highlighting potentially novel treatment targets. BMP4 increases cell sensitivity to cytotoxic therapies. However, BMP4 effects on H3K4me3 in human NSCs and pediatric HGGs are unknown. In this study, cellular phenotype, levels of H3K4me3 and SETD1A following BMP4 treatment in human NSC and pediatric HGGs are investigated. The results indicate BMP4 promotes differentiation and decreases H3K4me3 and SETD1A levels, as well as H3K4me3 occupancy on stemness and drug resistant genes’ promoters decreased in NSC and pediatric HGGs, respectively. BMP4 also increases chemosensitivity in pediatric HGGs. The results demonstrate that BMP4 differentiates human NSCs and increases chemotherapy sensitivity through regulation of SETD1A by altering H3K4me3 levels at key stemness and drug resistance genes’ promoter. Subsequently, targeting SETD1A concomitantly with conventional chemotherapy may provide novel therapeutic strategies to improve prognosis for children with HGGs.
First study in North Africa: Screening colorectal cancer
Authors: C. Mazouzi, K. Bouzid
Journal: Annals of Oncology (2018)

Introduction: In Algeria in 2015 colorectal cancer represents the 2nd cause of cancer mortality after lung cancer in men and after breast cancer in women. The increasing CRC incidence and mortality can be reduced by screening and treating adenomas and early cancers. A pilot CRC screening programme using immunochemical faecal occult blood testing (iFOBT) and colonoscopy for test-positives were implemented in Béjaia a northeast district of Algeria. This study aims to evaluate the acceptability, feasibility, validity of screening tests, and scaling-up of screening in Algeria. This report describes the implementation, coverage and performance indicators of this pilot project. Methods: This is a pilot study for colorectal cancer screening with an immunological test of an average risk population aged [50-74] over a 20-month period. A target population aged 50–74 years was informed about and invited to undergo CRC screening by community –clinics. faecal sample collection kits were provided through local primary care units for home sample collection. iFOBT-positive persons were referred for colonoscopy at the Béjaia University hospital, and endoscopic polypectomy/biopsies were performed according to the colonoscopies findings. Those with confirmed CRC received appropriate treatment. Results: Of the 10,000-target population, 2562 (26%) were screened using iFOBT between January 2016 and November 2017. The main issue in the program was accessing people living in study areas due to lack of valid registry system. Of those screened, 156 (6.11%) were found positive; positivity was equitably between men and woman, a rate of 39.4% polyps among the pathological colonoscopies, 6 cancers are found which corresponding 3.7% of positive tests and a colorectal cancer detection rate of 2.35%. The high false positive rate in our study would be investigated during the next stage through assessment of several kits in Algeria to compare their validity. Conclusion: The successful implementation of the pilot CRC screening with satisfactory process measures indicate the feasibility of scaling-up organized CRC screening through existing health services In Algeria. More work is needed in assessment of kits to be used in the national program. Also, the process of identification of the population based on their residential access will be evaluated further. An economic evaluation for the program to be conducted before the end of 2018.
DIPG-06. IDENTIFICATION OF GENES FUNCTIONALLY INVOLVED IN THE DETRIMENTAL EFFECTS OF MUTANT HISTONE K27M-H3.3 USING DROSOPHILA MELANOGASTER
Authors: Johannes Berlandi, Amel Chaouch, Isabel Tegeder, Katharina Thiel, Claudia L Kleinman, Margret Shirinian, Nicolas De Jay, Astrid Jeibmann, Paul Lasko, Nada Jabado, Martin Hasselblatt
Journal: Neuro-Oncology (2018)

Histone H3 mutations (K27M, G34R and G34V) have been identified as driver mutations in malignant gliomas, but little is known about targetable downstream signaling pathways. We thus aimed at identifying genes playing a functional role in the detrimental effects of histone H3 mutations using a Drosophila model. Ubiquitous and midline glia specific expression of K27M-H3.3 (but not wildtype H3.3) caused pupal lethality, morphological alterations and decreased H3K27me3. In Gal4/UAS modifier screens, shRNA knockdown of 17/194 candidate genes resulted in a positive shift of lethality to later stages of development. These included genes encoding histone modifying and chromatin remodeling proteins as well as downstream genes regulating cell differentiation and proliferation. Single sample gene set enrichment analysis revealed human orthologues of candidate genes to be enriched in K27M-H3-mutant diffuse midline gliomas. Three candidate genes, i.e. HMGB2, BMI1 and ELP3 were significantly over-expressed in K27M-H3-mutant diffuse midline gliomas. These results suggest that fly models can be employed for the identification of functionally relevant genes involved in the detrimental effects of mutant histone H3. Supported by IZKF Münster (Ha3/019/15)
Generation and primary characterization of iAM-1, a versatile new line of conditionally immortalized atrial myocytes with preserved cardiomyogenic differentiation capacity
Authors: Jia Liu, Linda Volkers, Wanchana Jangsangthong, Cindy I Bart, Marc C Engels, Guangqian Zhou, Martin J Schalij, Dirk L Ypey, Daniël A Pijnappels, Antoine A F de Vries
Journal: Cardiovascular Research (2018)

The generation of homogeneous cardiomyocyte populations from fresh tissue or stem cells is laborious and costly. A potential solution to this problem would be to establish lines of immortalized cardiomyocytes. However, as proliferation and (terminal) differentiation of cardiomyocytes are mutually exclusive processes, their permanent immortalization causes loss of electrical and mechanical functions. We therefore aimed at developing conditionally immortalized atrial myocyte (iAM) lines allowing toggling between proliferative and contractile phenotypes by a single-component change in culture medium composition. Freshly isolated neonatal rat atrial cardiomyocytes (AMs) were transduced with a lentiviral vector conferring doxycycline (dox)-controlled expression of simian virus 40 large T antigen. Under proliferative conditions (i.e. in the presence of dox), the resulting cells lost most cardiomyocyte traits and doubled every 38 h. Under differentiation conditions (i.e. in the absence of dox), the cells stopped dividing and spontaneously reacquired a phenotype very similar to that of primary AMs (pAMs) in gene expression profile, sarcomeric organization, contractile behaviour, electrical properties, and response to ion channel-modulating compounds (as assessed by patch-clamp and optical voltage mapping). Moreover, differentiated iAMs had much narrower action potentials and propagated them at >10-fold higher speeds than the widely used murine atrial HL-1 cells. High-frequency electrical stimulation of confluent monolayers of differentiated iAMs resulted in re-entrant conduction resembling atrial fibrillation, which could be prevented by tertiapin treatment, just like in monolayers of pAMs. Through controlled expansion and differentiation of AMs, large numbers of functional cardiomyocytes were generated with properties superior to the differentiated progeny of existing cardiomyocyte lines. iAMs provide an attractive new model system for studying cardiomyocyte proliferation, differentiation, metabolism, and (electro)physiology as well as to investigate cardiac diseases and drug responses, without using animals.
QOL-12. SPORTS FOR ALL – MOTIVATING NEURO-ONCOLOGY PATIENTS TO ENGAGE IN SPORTING ACTIVITY
Authors: Sharon Beardsmore, Jane Guest, Alison Cooper, Sian Phillips, Jenny Adamski
Journal: Neuro-Oncology (2018)

Our observation and experience is that many paediatric brain and spinal tumour patients do not engage in sporting activity. The majority have some level of physical or neurocognitive disability and low confidence, which may inhibit participation in sports. The role that physical activity plays in the physical, social and psychological wellbeing of children is vital to their on-going care, rehabilitation and long term health. The Neuro-Oncology team at Birmingham Childrens Hospital, U.K, are exploring ways patients can continue and enhance their rehabilitation through normal and accessible physical activities. The aim is to encourage children with disabilities due to a brain or spinal tumour to engage in sport by providing information and enabling active participation to build confidence. A resource noticeboard and information folder was generated to provide easily available information about accessible sporting opportunities in local areas. Staff engaged with families to provide information on the benefits of ‘sports-for-all’ and patients were invited to ‘taster’ days of accessible multisport activities with local disability sports providers. Questionnaires confirmed that many patients struggle with physical activities. Feedback following the active information campaign and attendance at the multisport days showed that patients valued ‘being given the chance to get involved’ with ‘activities on offer that were at the right level’. The active promotion of sporting activities in Neuro-Oncology patients has been positively received. Accessible multisports taster sessions will continue with plans to expand to specific accessible sports sessions (boxercise/ballet) in conjunction with regional social enterprises.
TBIO-06. B7-H3 EXPRESSION AS A POTENTIAL BIOMARKER OF PROGNOSIS AND TARGET IN PEDIATRIC GLIAL AND NON-GLIAL CNS TUMORS
Authors: Uday Bhanu Maachani, Zhiping Zhou, Daniel Martinez, Mariarita Santi, Nadia Dahmane, Mark Souweidane
Journal: Neuro-Oncology (2018)

B7-H3, which belongs to the B7 superfamily, has been shown to be an important factor in down-regulating host tumor immune responses, and is aberrantly expressed in many human malignancies. Beyond immune regulatory roles, its overexpression has been linked to invasive, metastatic potential and poor prognosis in cancer patients. Recent unconventional antibody-dependent cell-mediated cytotoxicity strategies targeting B7-H3 are in development and early phase clinical trials have shown encouraging preliminary results. We previously reported B7-H3 immunoreactivity and overexpression in diffuse intrinsic pontine glioma (DIPG) and the potential for antibody-based targeted therapy against B7-H3. However, the expression of this protein in other pediatric CNS malignancies has not been comprehensively investigated. This study examines whether B7-H3 could also be a potential target in a diverse set of pediatric glial and non-glial CNS tumors. Tissue microarrays containing formalin-fixed pediatric high and low grade gliomas (LGG), ependymomas, primitive neuroectodermal tumors (PNET), neuroepithelial, atypical teratoid/rhabdoid tumors (AT/RT) and choroid plexus tumors (CPT) were examined by immunohistochemistry for levels and extent of B7-H3 expression. We report that B7-H3 overexpression is universal in these tumors, and significant overexpression was found in several malignant brain tissues relative to normal human specimens. Expression levels of B7-H3 correlated with grade of tumor aggressiveness and high expressing patients showed significantly poor prognosis, especially in pHGG (p=0.026) and medulloblastomas (p=0.05). In summary, B7-H3 is aberrantly overexpressed in various pediatric CNS tumors and can act as a novel diagnostic marker and potential therapeutic target for better clinical management of patients with these malignancies.
NURS-04. NUTRITION RISK CLASSIFICATION AND INTERVENTION DECISION TOOL FOR CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Rachel Hill, Mandy Mansell, Danielle Johnson, Ashleigh Hines
Journal: Neuro-Oncology (2018)

During childhood cancer treatment, nutrition screening and timely intervention is vital because malnutrition negatively impacts survival, treatment tolerance, infection risk, quality of life, and cost of care. Though some central nervous system (CNS) tumors present a greater nutritional risk than others, no specific classification system has been published, and there is no standardized decision-making process between institutions or providers. Additionally, despite aggressive efforts, many parents report conflict and guilt when their child experiences anorexia and is unable to maintain an appropriate nutritional status. Early education and the use of a proactive nutrition intervention decision tool could optimize intervention timing, standardize care between patients, and alleviate tension between the parent, patient, and medical team. Based on diagnosis, treatment intensity, and patient-specific characteristics including age, dysphagia, and nutritional status at diagnosis, an algorithm was developed to classify CNS tumor patients into three risk categories (low, intermediate, and high risk for malnutrition). Each category has a unique intervention pathway, including timing of dietitian consult, use of appetite stimulants and high calorie diets and/or supplements, and timing of nutrition support. Discussion points include selecting the most appropriate route of nutrition support when indicated, since surgically-placed feeding devices may potentiate problems during cancer treatment. Additional factors considered are dysphagia, age, expected enteral feeding duration, and nasoenteric feeding tolerance. This decision tool will be piloted to evaluate its utility. Quality of parental education and preparedness for nutrition intervention will be evaluated by a questionnaire. The tool will then be revised and validated.