tbuckley/cabot-search huggingface dataset:
NO way! Nasal nitric oxide measurement in infants
Authors: Jane S. Lucas, Woolf T. Walker
Journal: European Respiratory Journal (2018)

Primary ciliary dyskinesia (PCD) generally causes symptoms from the first weeks of life, but diagnosis is usually delayed for years or can be missed altogether. Referral for diagnostic testing is often late because key symptoms, such as wet cough, chronic rhinitis and recurrent upper and lower respiratory tract infection, are non-specific. An international survey of patients reported that 37% had >40 visits to medical professionals due to PCD-related symptoms before being referred for diagnostic testing [1]. Approximately 50% of children with PCD have situs inversus, a rare condition in the general population, and it is therefore not surprising that these patients are investigated earlier. A European survey found that age of diagnosis was at 3.5 years in those with situs inversus and 5.8 years in children with normal situs [2]. Assuming a prevalence of 1 in 10 000 [3], we expect ∼1180 diagnosed children in England (childhood population ∼11.8 million); however, there are currently only ∼340 children in the National Paediatric PCD Service. This highlights a huge proportion of undiagnosed patients even in a country with a national PCD service [4]. This is in stark contrast to cystic fibrosis (CF) where neonatal screening programmes ensure that diagnosis occurs in early infancy in many countries, with positive impact on clinical outcome [5]. Young children with PCD have similarly impaired forced expiratory volume in 1 s to children with CF [6], and require multidisciplinary treatment. Early diagnosis facilitates a management plan, including regular airway clearance physiotherapy, surveillance for airway pathogens with treatment of respiratory exacerbations, genetic counselling for families, audiology monitoring and management of conductive hearing loss [7, 8]. We expect that early diagnosis would delay respiratory decline and ensure specialist treatment of ear, hearing and nasal issues, thereby optimising health, psychological, social and educational outcomes. Nasal nitric oxide (NO) measurement is feasible in infants, potentially allowing earlier diagnosis of primary ciliary dyskinesia <http://ow.ly/9K0a30kpcZU>
ATRT-06. CLINICAL AND MOLECULAR RISK FACTORS IN CHILDREN WITH ATYPICAL TERATOID/RHABDOID TUMOUR (AT/RT) - EVIDENCE FROM THE EU-RHAB REGISTRY
Authors: Michael Fruehwald, Martin Hasselblatt, Reinhard Schneppenheim, Karolina Nemes, Susanne Bens, Pascal Johan, Peter Hauser, Eduardo Quiroga, Palma Solano-Paez, Veronica Biassoni, Maria Joao Gil-da-Costa, Martha Perek-Polnik, Marianne van de Wetering, Martin Ebinger, Gudrun Fleischhack, Rhoikos Furtwaengler, Pablo Hernaiz-Driever, Harald Reinhard, Stefan Rukowski, Paul-Gerhardt Schlegel, Irene Schmid, Beate Timmermann, Uwe Kordes, Joachim Gerss, Kornelius Kerl, Karsten Nysom, Reiner Siebert, Marcel Kool, Norbert Graf
Journal: Neuro-Oncology (2018)

AT/RT is a challenging entity due to a dearth of controlled clinical trials and lack of biological samples. We aimed to identify clinical and molecular risk factors in a carefully characterised series of AT/RT. We enrolled 142 patients from 13 European countries (06/2009 to 08/2017). Median age at diagnosis was 17,5 months (25th /75th percentile: 9/26,5 months). Therapy followed a consensus regimen. Tumors were investigated for SMARCB1 and SMARCA4 mutations using FISH, MLPA and/or sequencing (n=87/142). Blood was examined for germline mutations (GLM) (n=114/142). Molecular subgroups (ATRT-TYR, -SHH or -MYC) were determined in tumors using Illumina BeadChip based DNA-methylation profiling (n=102/142). Preliminary 5y-OS- and EFS-estimates of this cohort are 20 ± 5% and 26 ± 5%. In a multivariate model, patients (a) below 1 year at diagnosis with (b) M+-disease, (c) synchronous tumours and (d) incomplete resection (no GTR) had the worst prognosis (p<0.05). Most samples had allelic somatic partial/whole gene deletions (55%), while SNVs were observed in 45%. GLM were detected in 26%. Subgroup analyses detected 57% ATRT-SHH, 30% ATRT-TYR, and 13% ATRT-MYC tumors. Children of the TYR-subgroup had a superior outcome. Patients can be divided into two defined risk strata: a) infants with metastatic or synchronous tumors and potentially a GLM and/or features of the non-TYR subgroups; b) older patients with a GTR who achieve a CR. This risk model warrants validation and expansion within future clinical trials. EU-RHAB is supported by grants to MCF by the “Deutsche Kinderkrebsstiftung” DKKS 2010.03 and the parents organization Lichtblicke, Augsburg.
DEV-03. RISK OF PROGRESSION/RELAPSE IN PEDIATRIC INTRACRANIAL EPENDYMOMA: SINGLE-CENTER EXPERIENCE FROM A DEVELOPING COUNTRY
Authors: Anirban Das, Suman Paul Chowdhury, Rimpa Basu Achari, Lateef Zameer, Saugata Sen, Gopal Achari, Arpita Bhattacharya
Journal: Neuro-Oncology (2018)

Intracranial ependymoma, the 3rd-most common pediatric brain tumor, has poor long-term survival. Our aim was to study the risk-factors for progression/relapse in a new cancer hospital in eastern India. Retrospectively extracted data from case records between 2012–17 were analyzed. Eighteen children were enrolled (median age: 39.5 months, males: 55%). Median symptom-diagnosis interval was 8 weeks. Symptoms included headache (8; 44%), vomiting (10; 55%), unsteadiness (8; 44%), seizures/altered sensorium (4; 22%). Location was posterior fossa (12; 67%), or supra-tentorial (6; 33%). Spinal/leptomeningeal spread was documented in 4/14 (28.5%). Complete excision was performed in 4/16 (25%); second-look surgery was feasible in one. Histopathology was anaplastic (14; 78%) or grade II (4; 22%). Sixteen children received adjuvant treatment: 11 (69%) radiotherapy alone, 5 (31%) additional chemotherapy. One each, refused treatment (died), and chose homeopathy (alive). Median survival was 30 months. 3-year progression-free survival was 39.5 ± 1.7%. Patterns of failure were local in 5/6, and combined (local and metastatic) in one. One child is on salvage treatment, rest died. Age, gender, symptom-diagnosis interval, location, subtotal resection, anaplastic histology, leptomeningeal dissemination and nature of adjuvant therapy were not predictive of failure (p>0.05). Two/4 children who had complete resection relapsed 30 and 14 months after completing treatment. There was no treatment-related mortality. Pediatric ependymoma remains a difficult disease to treat, with failures, predominantly local, occurring despite complete resection and adjuvant therapy, several months after completing treatment. Novel treatment strategies based on molecular classification, and regular surveillance for detecting relapse early, may improve outcome.
QOL-59. THE DEVELOPMENT OF A SCHOOL ‘BRAIN AID KIT’ BOX
Authors: Jade Ryles, Faye Fraser, Simon Bailey, Gail Halliday
Journal: Neuro-Oncology (2018)

The purpose of developing the school ‘Brain Aid Kit’ box (school BAK box) was to empower neuro-oncology patients and their families in survivorship. Within the North East of England, a multi-disciplinary school meeting takes place at diagnosis, relapse and transition in education only. A questionnaire was sent to twenty schools and parents who had received previous school meeting input. The results identified there was a need for education staff to have support and up to date health information at the start of each school year. It is unachievable for professionals to complete a school meeting each school year for every patient in survivorship. Three workshops took place where the information included in the school ‘BAK’ box was created. Both written and visual information on diagnosis, treatment and side effects, which can be individualised for each patient was added. The information is given in a plain box for patients to decorate, promoting ownership. The school ‘BAK’ box is being trialled in forty schools within the North East of England, with questionnaire feedback from both schools and parents. All questionnaires will be collated by May 2018, with the aim to offer a school ‘BAK’ box to every neuro-oncology patient. Preliminary feedback has indicated families have been able to information share appropriate and key information with their schools confidently and competently. There is currently no other known tool across England that addresses on-going issues of education in survivorship within the neuro-oncology services. The hope is the school ‘BAK’ box will fill this void.
DIPG-35. A NOVEL HDAC INHIBITOR IN NEW PATIENT-DERIVED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) MODELS
Authors: Matthew Biery, Carrie Myers, Emily Girard, Shelli Morris, Savanna Carmack, Alyssa Noll, Jay Sarthy, Eric Ferguson, Andrew Mhyre, Andrew Strand, James Olson, Nicholas Vitanza
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) remains a universally fatal childhood cancer with a median survival of less than 1 year. Focal radiation remains the standard of care as surgical resection is impossible and conventional cytotoxic chemotherapy has very limited efficacy. Building on the success of other autopsy-derived DIPG cell cultures, we have created a novel patient-derived cell culture, PBT-14FHTC, characterized by mutations in H3FA3, TP53, and amplifications in PDGFRα and cKIT. Previous work has demonstrated the efficacy of panobinostat, a pan-HDAC inhibitor, against DIPG in vitro and in vivo, though resistance develops. Due to this resistance, as well as the limited blood-brain barrier penetration of panobinostat, it is critical to identify other epigenetic agents able to target DIPG. A screen of next generation HDAC inhibitors identified quisinostat, an HDAC inhibitor with a greater selectivity of HDAC1. In vitro studies demonstrate a IC50 < 50 nM against well-characterized patient-derived DIPG cell cultures SU-DIPG-XIII and SU-DIPG-XVII, as well as similar low nM efficacy in other patient-derived cultures such as SU-DIPG-IV, VUMC-DIPG-10, and our new PBT-14FHTC. For in vivo testing, we developed an orthotopic xenograft model using patient-derived DIPG cells transformed with CMV-mCherry-luciferase that can be evaluated by bioluminescence IVIS imaging without harming or euthanizing the subject. In vivo efficacy studies of quisinostat as a single agent, in combination with other epigenetic modulating agents, and in combination with radiation are currently underway using our patient-derived orthotopic xenograft DIPG mouse model.
NSRG-21. BRAIN TUMORS OF THE FIRST YEARS OF LIFE: TEN YEARS OF IOP/GRAACC/UNIVERSIDADE FEDERAL DE SAO PAULO EXPERIENCE
Authors: Patricia Dastoli, Jardel Nicácio, Marcos Costa, Andrea Cappellano, Frederico Silva, Nasjla Silva, Sergio Cavalheiro
Journal: Neuro-Oncology (2018)

Management of brain tumors in neonates and infants is very challenging. To analyze the several treatment strategies and outcomes of brain tumors in the first year of life in a single institution. The authors retrospectively evaluated 63 infants with brain tumors treated between 2007 and 2017, at IOP/GRAACC/UNIFESP. Data regarding initial clinical presentation, treatment modalities and outcomes were collected. From 63 patients treated, 61 were eligible for evaluation and 2 were excluded for loss of follow-up. Thirty were girls and 31 boys. The mean age at treatment was 6 months (range: 1 day-12 months). Twenty-nine babies presented with signs and symptoms of intracranial hypertension, 11 babies with epileptic seizures and 8, cranial nerves deficits. Forty-five tumors were located in the supratentorial compartment and 16 were infratentorially. Nine patients were diagnosed with tuberous sclerosis, 2 with neurofibromatosis type 1, 2 diagnosed with Li Fraumeni and 1 with Gorlin syndrome. The most common histological types were: 11 rhabdoid teratoid, 9 low grade astrocytoma, 5 choroid plexus carcinoma and 5 glioblastoma. Surgery is the treatment of choice. Ten patients underwent more than one surgery (2 to 6 resections) Eight deaths occurred. The mean follow-up was 3y10m (range: 2 days- 7y9m). Gross total resection is the goal of surgical treatment, but sometimes it is impossible in the first approach. To decrease the high intraoperative mortality of malignant tumors, these patients can undergo as many surgeries as necessary for total tumor resection, alternating with cycles of chemotherapy.
Nonviral RNA chimeric antigen receptor–modified T cells in patients with Hodgkin lymphoma
Authors: Jakub Svoboda, Susan R. Rheingold, Saar I. Gill, Stephan A. Grupp, Simon F. Lacey, Irina Kulikovskaya, Megan M. Suhoski, J. Joseph Melenhorst, Brandon Loudon, Anthony R. Mato, Sunita Dwivedy Nasta, Daniel J. Landsburg, Matthew R. Youngman, Bruce L. Levine, David L. Porter, Carl H. June, Stephen J. Schuster
Journal: Blood (2018)
CCR4 mutations associated with superior outcome of adult T-cell leukemia/lymphoma under mogamulizumab treatment
Authors: Yuma Sakamoto, Takashi Ishida, Ayako Masaki, Takayuki Murase, Kentaro Yonekura, Yukie Tashiro, Masahito Tokunaga, Atae Utsunomiya, Asahi Ito, Shigeru Kusumoto, Shinsuke Iida, Ryuzo Ueda, Hiroshi Inagaki
Journal: Blood (2018)
LGG-09. LONG-TERM OUTCOMES OF SYMPTOMATIC OPTIC PATHWAY GLIOMA: 32 YEARS OF EXPERIENCE AT A SINGLE TERTIARY CENTER
Authors: Mumtaz Khan, Robert Lethridge, Revathi Rajagopal, Sharon Lee, Gabriel Lee, Mandy Taylor, Alycea McGrath, Nicholas G Gottardo
Journal: Neuro-Oncology (2018)

To evaluate the long-term outcomes in patients diagnosed with symptomatic optic pathway gliomas (OPGs). Retrospective review of all patients with symptomatic OPG treated in a single center from 1984 to 2016. Thirty-seven patients were identified with a median follow-up of 13.74 years (range 1.0-29.6). Eleven (29.7%) of them had NF1. The mean age was 5.8 years and female: male ratio was 1.8:1. Decreased visual acuity was the commonest symptom (75.7%) at presentation. Six cases underwent surgical debulking, 13 were biopsied, and 2 had cosmetic orbital decompression. Histopathological subtypes were pilocytic astrocytoma (n=18) and ganglioglioma (n=1). Seventeen patients received chemotherapy and 18 had radiotherapy. The progression-free survival (PFS) was 53 ± 8.3% at 5 years and 49.7 ± 8.4% at 10, 20 and 25 years. The overall survival (OS) was 97.2 ± 2.7% at 5 and 10 years, 86.1 ± 7.8% at 20 and 77.5 ± 10.8% at 25 years. Twenty-two (59.5%) patients without initial evidence of endocrinopathy developed hormonal defects following therapy. Vision remained unchanged in 15 (40.5%) patients, 14 (37.8%) had visual deterioration at least in one eye, whilst improvement of vision and normal vision were seen in 5 (13.5%) and 3 (8.1%) cases respectively. Second brain tumour was observed in 3 patients at 20.6, 25.3 and 28.7 years post-diagnosis. All 3 had received prior radiotherapy. Whilst the PFS remained static after 10 years, the OS dropped after 20 years, due to the occurrence of second malignant brain tumours in patients who received radiotherapy. Significant long-term morbidities were observed in the majority of survivors.
DIPG-48. DIFFUSE INTRINSIC PONTINE GLIOMA CELLS ARE INTERCONNECTED BY ‘TUMOR MICROTUBES’
Authors: Shawn Gillespie, Surya Nagaraja, Michelle Monje-Deisseroth
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor characterized by resistance to therapy. While much progress has been made in mapping the genetic and epigenetic landscapes of DIPG, this newfound knowledge has yet to translate into durable clinical benefit for patients. The recent identification and in vivo characterization of ‘tumor microtubes’, membranous extensions that physically connect neighboring cancer cells via gap junctions in adult astrocytoma (Winkler et al., 2015) suggests that a similar mechanism may operate in pediatric high-grade gliomas (pHGG) such as DIPG, potentially contributing to the observed resistance to therapy. Here, we interrogated primary human DIPG samples, patient-derived DIPG orthotopic xenografts and cell cultures for the presence of putative ‘tumor microtubes’ (TMs). Immunohistochemistry and high-resolution confocal microscopy revealed long filamentous structures connecting DIPG cells that exhibit microanatomical parameters consistent with the TMs described in adult astrocytoma. Neuroligin-3 (NLGN3), a critical microenvironmental determinant of glioma progression, induces expression of several genes implicated in the formation of TMs such as TTYH1 and GAP-43. We find that NLGN3 exposure augments the formation of TM-like structures when applied to DIPG cells in vitro. The role that DIPG cell interconnections via TMs play in DIPG resistance to therapy remains to be tested, but may represent a non-cell-intrinsic mechanism of resistance by which DIPG cells form a cooperative network to adapt and survive therapeutic interventions.
The Urinary Proteome Reflects Proximal Tubule Stress In Type-1 Diabetics With Microalbuminuria and Early Renal Function Decline
Authors: John Klein, Andrzej Krolewski, James Warram, Brad Rovin, Grier Page, Clinton Bertram, Daniel Wilkey, Linda Ficociello, Bruce Perkins, Grzegorz Boratyn, Michael Merchant
Journal: Journal of the American Society of Nephrology (2009)
Calcium channel blocker use and gastrointestinal tract bleeding among older adults
Authors: Robert C Kaplan, Susan R Heckbert, Thomas D Koepsell, Frits R Rosendaal, Curt D Furberg, Lawton S Cooper, Bruce M Psaty
Journal: Circulation (2001)

P56     Previous studies suggest that calcium channel blockers (CCBs)  may be associated with bleeding complications. We examined the  association between CCB use and hospitalization for gastrointestinal  (GI) tract bleeding among hypertensive older adults in the  Cardiovascular Health Study (CHS). Within the CHS population of adults  >=65 years old, a cohort of pharmacologically-treated hypertensive  individuals was identified (n=2,189 at baseline). Hospitalized GI tract  bleeding events during follow-up (n=121) were identified using  computerized data and validated using medical records. Information on  medication use and other risk factors for bleeding was assessed at  yearly examinations. The adjusted hazard ratio (HR) was estimated using  Cox proportional hazards regression with time-dependent predictor  variables. Compared with use of other antihypertensive medications, use  of CCBs was associated with a HR of 1.37 (95 % confidence interval  (CI) = 0.95-1.98) for any hospitalized GI tract bleeding, after  adjustment for age and cardiovascular disease status. Further  adjustment for other known risk factors for GI tract bleeding had  little effect. The HRs associated with each of the major CCB subclasses  and release formulations were similar. Subjects who used the lowest  daily doses of CCBs had the highest risk. The HR associated with CCB  use was 1.32 for upper GI tract bleeding (95% CI = 0.82-2.13),  1.19 for lower GI tract bleeding (95% CI = 0.64-2.23), 1.49 for  peptic ulcer-related bleeding (95% CI = 0.70-3.20), and 1.98 for  “life-threatening” bleeding (95% CI = 1.08-3.63). In this  study, the HR associated with CCB use was consistent with a moderately  elevated risk of hospitalized GI tract bleeding but was not  significantly different from the null. Ongoing clinical trials will  help to clarify whether CCBs cause bleeding  complications.
Neutrophil to lymphocyte ratio and platelet to lymphocyte ratio are independent prognostic factors for overall survival in Hispanic patients with gastric adenocarcinoma
Authors: A. Ramos-Esquivel, D. Brenes, E. Cordero, W. Alpizar-Alpizar
Journal: Annals of Oncology (2018)

Introduction: High values of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are associated with poor prognosis in patients with gastric adenocarcinoma. However, the majority of these findings have been carried out in Asian countries. It is well known that outcomes of gastric cancer are different among regions, with better outcomes in patients from Asia in comparison to Western populations. Besides, recent trials have acknowledged that values of white cells can vary according to ethnicity. Therefore, in this retrospective study we aim to determine the prognostic value of NLR and PLR in Hispanic patients from Costa Rica where gastric cancer occupies the third cause of cancer-related death in both sexes. Methods: We reviewed consecutive gastric cancer patients treated in four major hospitals in Costa Rica from 2009 to 2012. Pre-treatment (before surgery or systemic treatment) NLR and PLR, as well as clinical variables were collected from medical records. Univariate and multivariate Cox regression analyses were performed to assess the relationship between NLR, PLR, overall survival (OS) and disease-free survival (DFS). The best cutoff point was based on the maximization of the Log-rank test statistic. Results: A total of 490 patients were included in this trial. Median follow-up was 26 months. Mean age was 61.8 ±16.6 years. A total of 282 patients were male (57.6%). Surgery was performed in 309 patients (63.1%) and the most frequent procedure was partial or total gastrectomy with D2 dissection (84.1%). Clinical stage distribution was as follows: stage I: 2.8%, stage II: 27.9%, stage III: 34.8%, and stage IV: 34.5%. The optimal cutoff point for NLR and PLR was set at 5 and 350, respectively. In univariate analysis, a NLR higher than 5 was associated with reduced DFS (Hazard Ratio (HR): 2.31; 95% Confidence Interval (CI): 1.78-3.00; p < 0.001) and poor OS (HR: 2.24; 95% CI: 1.72-2.92; p < 0.001). Similarly, a PLR higher that 350 was associated with worse DFS (HR: 2.28; 95% CI: 1.70-3.06; p < 0.001) and poorer OS (HR: 2.33; 95% CI: 1.73-3.13; p < 0.001). In the multivariate analysis, after adjustment for potential confounders and interactions such as clinical stage and performance status, only the NLR higher than 5 was independently associated with worse DFS (HR: 1.84; 95% CI: 1.33-2.56) and OS (HR: 1.61; 95%CI: 1-16-2.25). Conclusion: A NLR greater than 5 was independently associated with worse OS and DFS in Hispanic patients with gastric cancer. This cheap and easy to obtain biomarker can predict long-term outcomes in our population.
ATRT-02. THE AURORA KINASE A (AURKA) INHIBITOR ALISERTIB ACTS SYNERGISTICALLY WITH A POLO-LIKE KINASE 4 (PLK4) INHIBITOR TO TARGET ATYPICAL TERATOID / RHABDOID TUMOR (AT/RT) CELLS
Authors: Anders Bailey, Amreena Suri, Connor Dyer, Clara Horn, Tadanori Tomita, Simone Sredni
Journal: Neuro-Oncology (2018)

Previously, we observed that CRISPR/Cas9-induced mutations in the PLK4 gene, a critical regulator of centriole duplication, significantly impaired proliferation and survival of AT/RT cells. We established that PLK4 is overexpressed in AT/RT and inhibiting PLK4 resulted in impaired proliferation, survival, migration and invasion. It also induced polyploidy increasing AT/RT susceptibility to DNA-damaging drugs. The inhibition of AURKA, also overexpressed in AT/RT by alisertib, is currently in phase II clinical trial for the treatment of rhabdoid tumors (RT) (NCT02114229). We hypothesized that associating alisertib with a PLK4 inhibitor (PLK4i) would improve the efficacy of each drug. We tested association of alisertib with the PLK4i CFI-400945 in three RT cell lines (MON, BT-12 and BT-16). Multiple concentrations for each inhibitor alone and in combination were tested. PrestoBlue viability and MTT proliferation assays were performed. Median effect plots showed that CFI-400945 associated with alisertib significantly decreased the concentration of both inhibitors needed to affect proliferation and viability in all cell lines tested. While alisertib alone required 200-500nM and CFI-400945 alone required 3.000–6.000nM to inhibit 50% proliferation and viability (IC50), combination of the two drugs required only 10-40nM of alisertib (13–20 times less) and 5-10nM of CFI-400945 (over 500 times less) to produce the same effect (p-value<0.001 in at least two cell lines for each assay). The PLK4i acts synergistically with alisertib to target RT cells. This association can represent a novel, less toxic strategy to treat AT/RT. The Musella Foundation for Cancer Research.