tbuckley/cabot-search huggingface dataset:
CD271+ Cells Are Diagnostic and Prognostic and Exhibit Elevated MAPK Activity in SHH Medulloblastoma
Authors: Lisa Liang, Ludivine Coudière-Morrison, Nazanin Tatari, Margaret Stromecki, Agnes Fresnoza, Christopher J. Porter, Marc R. Del Bigio, Cynthia Hawkins, Jennifer A. Chan, Timothy C. Ryken, Michael D. Taylor, Vijay Ramaswamy, Tamra E. Werbowetski-Ogilvie
Journal: Cancer Research (2018)

Abstract The extensive heterogeneity both between and within the medulloblastoma subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH medulloblastoma subgroup. Here, we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH medulloblastoma using IHC analysis and transcriptome data across 763 primary tumors. RNA sequencing of CD271+ and CD271− cells revealed molecularly distinct, coexisting cellular subsets, both in vitro and in vivo. MAPK/ERK signaling was upregulated in the CD271+ population, and inhibiting this pathway reduced endogenous CD271 levels, stem/progenitor cell proliferation, and cell survival as well as cell migration in vitro. Treatment with the MEK inhibitor selumetinib extended survival and reduced CD271 levels in vivo, whereas, treatment with vismodegib, a well-known smoothened (SMO) inhibitor currently in clinical trials for the treatment of recurrent SHH medulloblastoma, had no significant effect in our models. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH medulloblastoma tumors and reveals a novel role for MEK inhibitors in targeting CD271+ SHH medulloblastoma cells. Significance: This study identifies CD271 as a specific and novel biomarker of SHH-type medulloblastoma and that targeting CD271+ cells through MEK inhibition represents a novel therapeutic strategy for the treatment of SHH medulloblastoma. Cancer Res; 78(16); 4745–59. ©2018 AACR.
ATRT-29. SUCCESS OF HIGH DOSE CHEMOTHERAPY IN INFANTS PRESENTING WITH ATYPICAL TERATOID RHABDOID TUMOURS (ATRT)
Authors: Patricia O’Hare, Mette Jorgensen, Anthony Michalski, Olga Slater, Kim Phipps, Kristian Aquilina, Owaase Jeelani, Yen-Ch’ing Chang, Jenny Gains, Amy Fairchild, Jess Pickles, Thomas Jacques, Darren Hargrave
Journal: Neuro-Oncology (2018)

ATRT is an aggressive tumour of infancy with a historically poor prognosis. In very young patients radiotherapy is avoided due to neurocognitive toxicity, however high dose chemotherapy (HDC) is used as an alternative treatment strategy in this group of patients. This is a retrospective review of 30 patients diagnosed with ATRT from 2009–2016, 24 of whom received adjuvant treatment. 5 received radiotherapy upfront, of whom 3 remain alive. 19 patients received adjuvant chemotherapy (median age at diagnosis 10 months, 38% with germline mutation). 6/19 patients didn’t proceed to HDC. One patient progressed and was salvaged with radiotherapy and remains alive. The other 5 patients progressed on chemotherapy after 5, 6 (n=3) or 9 cycles of treatment. 13 patients proceeded to HDC (of whom 8 remain alive). 5 patients achieved gross total resection with surgery, 4 of whom remain alive post HDC. A further 2 patients, who had subtotal resection at diagnosis, achieved CR prior to commencing HDC, and both of these patients are alive. Of the remaining 6 patients who received HDC, one patient achieved CR only after HDC but is disease free 40 months post HDC. A further patient who relapsed within 6 months of HDC was salvaged with focal radiotherapy and remains in remission with 18 months of follow up. Treatment related mortality is 15%. HDC offers significant chance of prolonged survival for infants with ATRT, without the need for radiotherapy. CR achieved either with surgery or chemotherapy is an important prognostic factor.
EPEN-24. YAP1 FUSION PROTEINS MEDIATE ONCOGENIC ACTIVITY IN EPENDYMOMA VIA INTERACTION WITH TEAD TRANSCRIPTION FACTORS
Authors: Kristian W Pajtler, Konstantin Okonechnikov, Mikaella Vouri, Sebastian Brabetz, David T W Jones, Andrey Korshunov, David Capper, Lukas Chavez, Stefan M Pfister, Marcel Kool, Daisuke Kawauchi
Journal: Neuro-Oncology (2018)

In a previous study we identified two molecular groups of supratentorial (ST) ependymoma in pediatric patients driven by distinct gene fusions involving either the NF-κB effector RELA or the HIPPO signaling regulator YAP1, designated ST-EPN-RELA and ST-EPN-YAP1, respectively. The lack of adequate models for ST-EPN-YAP1, which predominantly occurs in very young children, has so far hindered the development of effective targeted therapies for these tumors. In an attempt to model this group, the most frequent fusion type, YAP1-MAMLD1, was cloned into a Luciferase-carrying transposable vector. Oncogenicity was subsequently tested using an electroporation-based in vivo gene transfer approach following injection of the vector into the lateral ventricle of E13.5 wildtype mouse embryos. After birth, YAP1-MAMLD1-expressing tumors, monitored using luciferase-based in vivo bioluminescence imaging, developed rapidly with 100% penetrance, indicating that the fusion alone is sufficient to initiate tumors. To further investigate the role of this fusion in human EPNs, we performed YAP1 ChIP-seq analyses on human ST-EPN-YAP1 and ST-EPN-RELA primary tumors. Despite similar gene expression levels of YAP1 in both molecular groups, our comparative analyses found that putative binding sites of TEADs, transcriptional factors interacting with YAP1, were significantly enriched in ST-EPN-YAP1-specific YAP1 target sites. In vivo validation further confirmed that interaction between YAP1-MAMLD1 and TEADs is crucial for oncogenicity of the fusion, since prevention of YAP1-TEAD binding did not result in tumor formation. Thus, targeting the YAP1-TEAD interaction might represent a promising therapeutic approach for this devastating infant disease.
QOL-11. SYMPTOM BURDEN EXPERIENCED BY CHILDREN WITH BRAIN TUMORS AND ITS INFLUENTIAL FACTORS
Authors: Jin-Shei Lai, Jennifer Beaumont, Peter Manley, Stewart Goldman
Journal: Neuro-Oncology (2018)

Children with brain tumors (BT) could experience symptom burden throughout their disease continuum, from on-therapy to long-term survivorship. This study evaluated symptom burden reported by BT and the potentially influential factors. Data from 230 BT children aged 7-22 (mean age=14 yr; 52% boys; 76% white) were analyzed. Average years since last treatment =2.6 (87%<=1 year). 49% attended a regular classroom without individualized educational plan (IEP). Symptom burden was assessed using Patient Reported Outcomes Measurement Information System (PROMIS) – Anxiety, Depression, Fatigue, Mobility, Upper Extremity Function (UE), Peer Relationship (PR), and Cognition. Patients and parents completed Symptom Distress Scales (SDS). Test-statistics and ANOVA were used to evaluate relationships between PROMIS measures and potentially influential variables. Significant results (p<0.01) showing impact of symptom burden included: PROMIS measures correlated with SDS reported by patients and parents on all comparisons; Fatigue, Mobility and UE were associated with Karnofsky functional performance status, number of treatment modalities (0-3), and time since last treatment (<=1 yr, >1 yr); Fatigue and Cognition were associated with educational program (regular classroom without IEP versus those that had an IEP); Mobility and UE were associated with time since last radiation; Mobility, UE and Anxiety were associated with time since last chemotherapy. Treatment type and time since treatment impacted BT's symptom burden. Significant planned associations were found between PROMIS measures and other variables, including SDS, functional performance, and educational programs. Validity of using PROMIS to evaluate BT's symptom burden in patients' follow-up care was also supported.
EPID-07. A PRECISION MEDICINE STRATEGY TO AVOID THE HARM OF BRAIN INJURY IN SURVIVORS OF CHILDHOOD BRAIN TUMOURS
Authors: David Walker, Jo-Fen Liu, Ruman Rahman, Emma Campbell, Sophie Wilne, Donald MacArthur, Thomas Chu, Richard Grundy
Journal: Neuro-Oncology (2018)

60% of childhood brain tumour survivors suffer disability due to prolonged pre-diagnostic intervals with raised intra-cranial pressure (50%) and the risk of visual impairment (<6%); sight threatening visual pathway glioma (VPG); post-operative cerebellar mutism syndrome (CMS) affecting up to 30% of cerebellar tumour patients, and the consequences of CNS-directed adjuvant radiotherapy. Four projects investigating ways to minimise brain injury have been submitted to this meeting: 1) the HeadSmart awareness campaign seeking to accelerate brain tumour diagnosis, linked to a population data linkage study of visual impairment certification, 2) an international consensus to develop eligibility criteria for VPG trial design, 3) a professional consensus process to validate and develop a predictive scoring tool for cerebellar mutism 4) an international drug delivery consortium to raise awareness of the need for new drug delivery systems. 1) since 2009 the UK total diagnostic interval has reduced from median 13.4 to 6.5 weeks, and UK certifications of blindness reduced from 5.8-3.5% (2007-2011); 2) an international consensus process identified visual outcome criteria and case selection criteria for a new era of VPG trials; 3) CMS predictive scoring system is being validated and developed with 10 leading centres; 4) a strategy to engage with academia, pharmaceutical industry, research charities and government institutes to prioritise drug delivery system research has been launched in Europe and US. Using targeted awareness strategies, professional consensus techniques and record linkage methods, it is possible to promote rapid change in clinical practice and research prioritisation with the potential to directly enhance measurable qualities of survivorship.
Pancreatic Cancer Following Incident Diabetes in African Americans and Latinos: The Multiethnic Cohort
Authors: Veronica Wendy Setiawan, Daniel O Stram, Jacqueline Porcel, Suresh T Chari, Gertraud Maskarinec, Loïc Le Marchand, Lynne R Wilkens, Christopher A Haiman, Stephen J Pandol, Kristine R Monroe
Journal: JNCI Journal of the National Cancer Institute (2018)

Diabetes has been proposed to be a risk factor for and a consequence of pancreatic cancer (PC). The relationship between recent-onset diabetes and PC is not well understood, and data in minorities are sparse. We examined the relationships between recent-onset diabetes and PC incidence in African Americans and Latinos in the Multiethnic Cohort.
Hyperthermic intraperitoneal chemotherapy (HIPEC) in combined treatment of locally advanced and disseminated gastric cancer: Results of a single-centre study
Authors: R. Yarema, M. Ohorchak, Y. Oliynyk, M. Matusak, M. Zubarev, P. Gyrya, Y. Kovalchuk, V. Safiyan, I. Karelin, T. Semotuk, T. Novicka, L. Laba, M. Yarysh, T. Fetsych
Journal: Annals of Oncology (2018)

Introduction: Patients with locally advanced gastric cancer (GC) and/or peritoneal metastases have a poor prognosis despite systemic chemotherapy or palliative surgery. The aim of this retrospective comparative non-randomized study was to evaluate aggressive cytoreduction in combination with hyperthermic intraperitoneal chemoperfusion (HIPEC) as a novel treatment strategy for patients with intraperitoneal disseminated and locally advanced GC. Methods: 59 GC patients with serosal invasion (n = 24), limited peritoneal metastases (n = 25), or disseminated peritoneal metastases and tense ascites (n = 10) underwent combination therapy with HIPEC. Three matched control groups undergoing standard therapies were retrospectively identified. Results: Combination therapy for serosa-invasive GC reduced the level of metachronous peritoneal carcinomatosis from 75% in the surgical control subgroup to 33.3% (p = 0.004) and increased median survival from 13,3 months to 32.5 months (р=0.0006). The median and 1-year survival rates for intraperitoneal disseminated GC patients undergoing therapy with the use of HIPEC were 12 months and 54.2% compared with 8,4 months and 20%, respectively (p = 0.004) for control subgroup patients (palliative chemotherapy). For patients with complete cytoreduction median survival was 14 months, one patient (4%) alive more than 5 years. The symptomatic use of HIPEC in GC patients with diffuse peritoneal carcinomatosis complicated by symptomatic ascites does not significantly increase survival, it allows effective elimination of recurrent ascites. The independent prognostic factors in GC patients with peritoneal metastases undergoing combined treatment with HIPEC are the stage of peritoneal dissemination in compliance with the classification of the Japanese Gastric Cancer Association and the score of cytoreduction completeness. Conclusion: HIPEC is an effective method of adjuvant therapy for gastric cancer with high risk of intraperitoneal progression. Cytoreduction followed by HIPEC improves survival in patients with limited peritoneal carcinomatosis of gastric origin.
MBRS-46. JERANTININE: A NOVEL TUMOUR-SPECIFIC ALKALOID FOR THE TREATMENT OF PAEDIATRIC MEDULLOBLASTOMA
Authors: Sophie J Roper, Amy F Lloyd, Paul J Scotting, Tracey D Bradshaw, Beth Coyle
Journal: Neuro-Oncology (2018)

Medulloblastoma is the most common malignant paediatric brain tumour. Standard treatment includes a combination of surgery, craniospinal radiotherapy and adjuvant chemotherapy. The chemotherapy agent Vincristine causes potent inhibition of tumour growth, however, high levels of toxicity and intrinsic drug resistance mechanisms, limit its clinical use. Jerantinine is a novel aspidosperma indole alkaloid that, like Vincristine, works by destabilising microtubule growth and hence blocks cell division. Here, we tested the hypothesis that Jerantinine would be an effective alternative to Vincristine in medulloblastoma. Jerantinine, like Vincristine, caused a dose-dependent decrease in cell viability and colony formation in medulloblastoma cell lines. Cytotoxicity of Vincristine could be potentiated with the ABCB1 inhibitor Verapamil, however there was no potentiation of Jerantinine’s activity indicating that Jerantinine functions independently of intrinsic ABCB1 expression and is able to circumvent this drug resistance mechanism. The effect of Jerantinine treatment was also assessed in 3D spheroid culture. Spheroid viability decreased with increasing concentrations of Jerantinine, as measured using the CellTiter-Glo® 3D cell viability assay. Automated imaging analysis (Celigo® cytometer) also showed an increase in cell death at a range of Jerantinine concentrations over 48 hours. Confocal microscopy showed comparable effects of Jerantinine and Vincristine in medulloblastoma cell lines, including cytoskeletal defects, inhibition of tubulin polymerisation and defective cell division. However unlike Vincristine, Jerantinine caused no visible disruption to cellular morphology of neural stem cells. These results suggest that Jerantinine is an effective, tumour-specific alternative to Vincristine in the treatment of paediatric medulloblastoma.
NAVIGATE II: Randomized, double-blind trial of the exhalation delivery system with fluticasone for nasal polyposis
Authors: Donald A. Leopold, David Elkayam, John C. Messina, Colette Kosik-Gonzalez, Per G. Djupesland, Ramy A. Mahmoud
Journal: Journal of Allergy and Clinical Immunology (2018)

Chronic rhinosinusitis is common and sometimes complicated by nasal polyps (NPs). Corticosteroid nasal sprays are often unsatisfactory because they are ineffective at delivering medication to high/deep sites of inflammation.We sought to assess whether an exhalation delivery system with fluticasone (EDS-FLU) capable of high/deep drug deposition improves outcomes.Patients (n = 323) 18 years and older with moderate-to-severe congestion and NPs were randomized to twice-daily EDS-FLU (93, 186, or 372 μg) or exhalation delivery system (EDS)-placebo for 24 weeks (16 double-blind plus 8 open-label when all received 372 μg). Coprimary end points were change in nasal congestion/obstruction at 4 weeks and summed bilateral polyp grade at 16 weeks. Secondary end points included symptoms, polyp elimination, and functioning.EDS-FLU was superior on both coprimary end points (P < .001 vs EDS-placebo, all doses). Mean polyp grade improved continuously through week 24 (P < .009, all comparisons), with polyps eliminated on at least 1 side in approximately 25% of patients at week 24 versus 8.7% with EDS-placebo (P ≤ .014, all comparisons). Sino-Nasal Outcomes Test scores also improved significantly versus those in patients receiving EDS-placebo (-21.1 to -21.4 vs -11.7 at week 16, P < .05 all doses). At the end of the double-blind period, EDS-FLU (all doses) significantly improved all 4 defining disease symptoms. In most patients (68%), those receiving EDS-FLU reported "much" or "very much" improvement. The number of patients eligible for surgery decreased by 62%-67%. The safety profile was similar to that reported in prior trials evaluating conventional corticosteroid nasal sprays in comparable populations.EDS-FLU produces clinically and statistically significant improvement in all 4 diagnostically defining disease symptoms, polyp grade, and quality of life in patients with chronic rhinosinusitis with NPs.
CRAN-05. EATING BEHAVIOR AND OXYTOCIN IN CHILDHOOD-ONSET CRANIOPHARYNGIOMA PATIENTS
Authors: Anna Daubenbüchel, Anika Hoffmann, Monika Warmuth-Metz, Maria Eveslage, Jale Özyurt, Hermann L Müller
Journal: Neuro-Oncology (2018)

Severe obesity due to disease and/or treatment-related hypothalamic lesions (HL) frequently impairs quality of life in childhood-onset craniopharyngioma patients (CP). CP often show eating restraints or binge eating. Oxytocin, a peptide hormone produced in the hypothalamus and secreted by posterior pituitary gland, plays a major role in the regulation of eating behavior and body composition. SUBJECTS AND 34 CP and 73 healthy controls participated in a cross-sectional study which aimed to investigate associations between eating behavior/eating disorders, HL and OSC (oxytocin saliva concentrations). OSC were measured before and after standardized breakfast by immunoassay. Eating behavior was assessed using the Inventory for Eating Behavior and Weight Problems and the Inventory for Eating Disorders. CP with anterior plus posterior HL (grade 2) scored more pathological with regard to eating behavior and eating disorders associated with obesity than CP with a lower HL grade and healthy controls. Eating behavior in CP with anterior HL (grade 1) was more similar to that of healthy controls except their tendency for high dietary restraints. Decreases in postprandial compared to fasting OSC were associated with adverse eating behavior in CP and healthy controls and with higher BMI SDS in CP. This is the first study to show that different grades of HL are associated with distinct patterns of eating behavior. In addition, our results suggested that reduced postprandial compared to fasting OSC is associated with weight problems in CP and with adverse eating behavior and eating disorders in both CP and healthy controls.
CRAN-22. IMPROVED ENDOCRINE OUTCOME WITH CONSERVATIVE SURGERY AND EARLY ADJUVANT RADIATION STRATEGY IN CHILDHOOD CRANIOPHARYNGIOMA: A REVIEW BY TREATMENT DECADE IN A SINGLE CENTRE
Authors: Chiara Guzzetti, Laura Losa, Richard Hayward, Kristian Aquilina, Yen-Ching Chang, Helen A Spoudeas
Journal: Neuro-Oncology (2018)

Neuroendocrine morbidity after Craniopharyngiomas may result from tumour position, recurrence/invasion and treatment. Over the last decades, our treatment policy has changed from aggressive tumour resection before 1995 to ‘hypothalamic-sparing’ surgery and, if required, early adjuvant radiation. We aimed to evaluate tumour recurrence and prevalence of endocrinopathy across treatment decades. 30 (22M) newly diagnosed children, median age 7.6(1.1–17.2)yrs (Group1), presenting between 2008–2015, underwent dynamic endocrine testing at diagnosis and were followed for 4.0(0.3–7.4)yrs. After urgent decompressive surgery if required, patients were conservatively managed in a neurooncology MDT setting with access to radiotherapy (either photon or proton therapy). Prevalence of Recurrence (PR) and endocrinopathy in Group1 were compared with those in our previous cohorts, [Group2a 1998–2010 (40 patients (18M) aged 8.6(7.2–10.0)yrs, followed for 6.0(4.8–7.2)yrs and Group3b 1973–1994 (75 patients (42M) aged 6.7(1–16.3)yrs, followed for 6.7(1.5–19.8)yrs], by chi-square statistics. PR of Group1(16.7%) and Group2(12.5%) was lower than Group3(41%, X2=5.8 and 10.1, p≤0.01). GHD was evident at diagnosis in 95% of Group1. Prevalence of post-treatment GHD and TSHD were similar across groups but life threatening ACTHD [Group1(56.7%) vs Group3(85.3%, X2=10.0, p≤0.01); Group2(72.5%), p=ns] and DI [Group1(56.7%) and Group2(55%) vs Group3(80%, X2=6.0 and 8.0, p≤0.01)], and Panhypopituitarism (Group1(56.7%) and Group2(50%) vs Group3(85.3%, X2=10.0 and 16.5, p≤0.01)] were lower in recent decades despite radiation. Dynamic testing at diagnosis confirms high rates (>95%) of occult pre-treatment GHD. A conservative surgical strategy protects against ACTHD, DI and Panhypopituitarism despite radiation, and similarly stabilises disease. aIkazoboh et al. SIOP 2011 abstract PM008 bDeVile et al. Arch Dis Child 75(2):108-114,1996
RADI-08. DIAGNOSTIC VALUE OF EARLY POSTOPERATIVE MR IMAGING AND DIFFUSION-WEIGHTED IMAGING FOLLOWING TRANSSPHENOIDAL RESECTION OF NON-FUNCTIONING PITUITARY MACROADENOMAS
Authors: Mohamed M Arnaout, Hanan A Hassan, Manar A Bessar, Islam R Herzallah, Adrienne M Laury, Mohamed A Basha
Journal: Neuro-Oncology (2018)

BACKGROUND AND The value of early contrast enhanced magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) in differentiating residual pituitary adenoma from postoperative surgical changes has not been established. PATIENTS AND We prospectively studied 30 patients with non-functioning pituitary macroadenomas who were undergoing transsphenoidal adenomectomy. Patients were imaged with both MRI and DWI in the early postoperative period, as well as 6 months post-surgery. Patterns of postoperative contrast enhancement were described (non-enhancement, peripheral enhancement, and nodular enhancement). Apparent diffusion coefficient (ADC) maps were utilized to select the region of interest (ROI) for ADC calculations. Seventeen patients had postoperative surgical granulation tissue and 13 had residual adenoma based on the 6 month follow up imaging. Mean ADC values of postoperative granulation tissue and residual adenoma were 1.476 ± 0.476 x 10 -3 mm2/s and 0.855 ± 0.190 x 10 -3 mm2/s, respectively, in the early postoperative period, and 1.357 ± 0.416 x 10 -3 mm2/sand 0.829 ± 0.201x 10 -3 mm2/s, respectively, at the 6 month follow-up. ADC values of granulation tissue were significantly different from that of residual adenoma at both time points (P< 0.001). Sensitivity, specificity, positive and negative predictive values of early MRI were 84.6%, 94.1%, 91.7%, and 88.9% respectively, and of early DWI were 91%, 97%, 94.3%, and 93%, respectively. Early postoperative DWI after transsphenoidal resection of pituitary macroadenomas may be more helpful than early MRI in differentiating residual adenoma from post-surgical changes.