tbuckley/cabot-search huggingface dataset:
QOL-27. THE PEDIATRIC BRAIN AND SPINE TUMOR CENTER AT THE UNIVERSITY CHILDREN’S HOSPITAL IN BASEL, SWITZERLAND
Authors: Uta Tacke, Raphael Guzman, Friederike Prüfer, Alexandros Papachristofilou, Gabor Szinnai, Christine Wondrusch, Janine Gutzwiller, Marianne Heinzelmann, Katja Möschlin, Tamara Diesch, Katrin Scheinemann
Journal: Neuro-Oncology (2018)

Given the complexity of care for children with a CNS tumor a multidisciplinary team approach seems to be the gold standard. Since January 2017 the pediatric brain and spine tumor center has been established, compromised of a multidisciplinary team including neuropediatrics, pediatric neurosurgery, pediatric radiology, radiation oncology, pediatric endocrinology, physio - and occupational therapy, social work and nursing under the leadership of the pediatric neuro-oncologist. All newly diagnosed pediatric CNS tumors as well as all follow up care independent of the treatment received are done for by this team. The multidisciplinary team approach also includes a preoperative discussion and planning for each individual patient as well as a jointly disclosure. A multidisciplinary follow up outpatient clinic takes place twice a month with a tumor board prior to the clinic to discuss all the patients and their different issues. All patients are seen by the needed disciplines. In total 62 patients were seen over a period of 12 months in this clinic with clear improvement of care as well as satisfaction with the care from patients and parents. The center also offers second opinions for patients and parents as well as advice for colleagues from other centers especially in the entity of low grade gliomas. The center also serves as a research platform for clinical as well as basic research projects. The structured implementation of a multidisciplinary team improves significantly the care of pediatric brain tumor patients and close collaboration between medical experts even in a university children’s hospital.
LGG-01. EVALUATION OF COBIMETINIB, A MEK INHIBITOR, IN LOW-GRADE PEDIATRIC BRAIN TUMORS
Authors: Martin Roskoski, Danuta Gasinski, Henry Friedman, Darell Bigner, Stephen Keir
Journal: Neuro-Oncology (2018)

Cobimetinib is an orally bioavailable small-molecule that specifically binds to and inhibits the catalytic activity of MEK, resulting in inhibition of ERK phosphorylation and activation and decreased tumor cell proliferation. Cobimetinib is used clinically in the treatment of BRAFV600-mutant melanoma, and preclinical studies have demonstrated that cobimetinib is effective in inhibiting the growth of cells from other tumor types bearing an activating BRAF mutation. Two low-grade pediatric glioma (pleomorphic xanthoastrocytoma, PXA) xenografts, D-645 PXA, which carries the BRAF V600E mutation, and D-2363 PXA were grown subcutaneously in athymic mice. Tumor-bearing mice were stratified to either the vehicle control or treatment groups based on median tumor volume and were treated with either 1, 5, or 7mg/kg for 21 days. The response to treatment was assessed by delay in tumor growth in days, expressed as a T (Treated) - C (Control) value. Statistical analysis was performed using SAS (a statistical analysis program) and the Wilcoxon rank order test. For D-2363 PXA, T-C values ranged from 2 to 16 days with statistical significance P<0.028 in the 5 and 7mg/kg groups. For D-645 PXA, there were statistically significant (P<0.001) growth delays ranging from 1.00 to 37.61 days with higher doses of cobimetinib correlating to increased growth delay. Our data indicates that cobimetinib is active in delaying tumor growth in low-grade pediatric brain tumors. Enhancement of efficacy was noted in D-645 PXA, which carries the BRAF V600E mutation.
Redox‐Activated Near‐Infrared‐Responsive Polyoxometalates Used for Photothermal Treatment of Alzheimer's Disease
Authors: Mengmeng Ma, Nan Gao, Yuhuan Sun, Xiubo Du, Jinsong Ren, Xiaogang Qu
Journal: Advanced Healthcare Materials (2018)

Abstract Adjustable structure, excellent physiochemical properties, and good biocompatibility render polyoxometalates (POMs) as a suitable drug agent for the treatment of Alzheimer's disease (AD). However, previous works using POMs against AD just focus on the inhibition of amyloid‐β (Aβ) monomer aggregation. In consideration that both Aβ fibrils and reactive oxygen species (ROS) are closely associated with clinical development of AD symptoms, it would be more effective if POMs can disaggregate Aβ fibrils and eliminate ROS as well. Herein, a redox‐activated near‐infrared (NIR) responsive POMs‐based nanoplaform (rPOMs@MSNs@copolymer) is developed with high photothermal effect and antioxidant activity. The rPOMs@MSNs@copolymer can generate local hyperthermia to disaggregate Aβ fibrils under NIR laser irradiation because of POMs (rPOMs) with strong NIR absorption. Furthermore, Aβ‐induced ROS can be scavenged by the antioxidant activity of rPOMs. To the authors' knowledge, there is no report of using rPOMs for NIR photothermal treatment of AD. This work may promote the development of multifunctional inorganic agents for biomedical applications.
RADI-04. COMBINED RADIOLOGICAL, PATHOLOGICAL AND MOLECULAR OUTCOME EVALUATION IN NEWLY DIAGNOSED NON-BRAINSTEM PEDIATRIC HIGH-GRADE GLIOMA FROM THE RANDOMIZED, MULTICENTER HERBY PHASE II TRIAL
Authors: Tim Jaspan, Paul Morgan, Daniel Rodriguez, Daniel Warren, Monika Warmuth-Metz, Esther Sanchez Aliaga, Raphael Calmon, Chris Jones, Alan Mackay, Pascale Varlet, Darren Hargrave, Adela Canete, Maura Massimino, Amedeo Azizi, Marie-Cecil Le Deley, Frank Saran, Raphael Rousseau, Gudrun Zahlmann, Josep Garcia, Gilles Vassal, Jacques Grill
Journal: Neuro-Oncology (2018)

The HERBY trial assessed the efficacy of adding Bevacizumab (BEV) to postoperative radiotherapy/temozolamide (RT/TMZ) in children with newly diagnosed non-pontine high-grade gliomas (HGG). The trial showed no difference in OS or EFS between BEV and non-BEV treatment arms. Radiological, pathological and molecular data were evaluated to characterise pediatric HGG and correlate with outcome measures. 74/124 (59.7%) patients had Cerebral hemispheric and 50/124 (40.3%) Midline tumors. Pathological diagnosis was available in all cases (111 astrocytomas /124), molecular data in 89/124. K27M histone mutations were present in 24/33 Midline cases with molecular data, and G34R/V mutations in 7 Cerebral cases. 116 patients completed treatment (RT/TMZ=56, BEV=60). 54/70 (77%) Cerebral cases underwent total/near-total resection with debulking/biopsy in 16/70 (23%). Fewer (12/46) Midline tumors had total/near-total resections than debulking/biopsy (34/46) (p<0.001). Leptomeningeal (LMM) dissemination occurred more frequently in patients with Midline (17/46) than Cerebral tumors (10/70)(p=0.003). Mean OS (14.27 months) and EFS (9.63) in Midline tumors were significantly lower than mean OS (20.72) and EFS (14.93) in Cerebral tumors (p=0.007, p=0.009). LMM occurred in 9/24 (38%) K27M and 17/57(29%) WT patients, 11/116 (9%) BEV and 16/116 (14%) RT/TMZ cases. Pseudoprogression occurred in 10/116 (9%) cases (RT/TMZ arm=8, Bev arm=2; p=0.017), with no relationship to mutation subtype. K27M mutations, fewer total/near total tumor resections, more frequent leptomeningeal spread and shorter OS/EFS characterizes Midline pediatric HGG. Pseudoprogression occurred less in BEV than in TMZ/RT treated patients, suggesting BEV supresses the treatment response to RT/TMZ therapy, replicating findings in adult populations.
Unmet Need for Adjunctive Dyslipidemia Therapy in Hypertriglyceridemia Management
Authors: Om P. Ganda, Deepak L. Bhatt, R. Preston Mason, Michael Miller, William E. Boden
Journal: Journal of the American College of Cardiology (2018)

Despite the important role of high-intensity statins in reducing atherosclerotic cardiovascular disease events in secondary and primary prevention, substantial residual risk persists, particularly among high-risk patients with type 2 diabetes mellitus, metabolic syndrome, and obesity. Considerable attention is currently directed to the role that elevated triglycerides (TGs) and non-high-density lipoprotein cholesterol levels play as important mediators of residual atherosclerotic cardiovascular disease risk, which is further strongly supported by genetic linkage studies. Previous trials with fibrates, niacin, and most cholesterol ester transfer protein inhibitors that targeted high-density lipoprotein cholesterol raising, and/or TG lowering, have failed to show conclusive evidence of incremental event reduction after low-density lipoprotein cholesterol levels were "optimally controlled" with statins. Although omega-3 fatty acids are efficacious in lowering TG levels and may have pleiotropic effects such as reducing plaque instability and proinflammatory mediators of atherogenesis, clinical outcomes data are currently lacking. Several ongoing randomized controlled trials of TG-lowering strategies with an optimal dosage of omega-3 fatty acids are nearing completion.
Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis
Authors: Shin-Ichi Nureki, Yaniv Tomer, Alessandro Venosa, Jeremy Katzen, Scott J. Russo, Sarita Jamil, Matthew Barrett, Vivian Nguyen, Meghan Kopp, Surafel Mulugeta, Michael F. Beers
Journal: Journal of Clinical Investigation (2018)

Epithelial cell dysfunction is postulated as an important component in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Mutations in the surfactant protein C (SP-C) gene (SFTPC), an alveolar type II (AT2) cell–restricted protein, have been found in sporadic and familial IPF. To causally link these events, we developed a knockin mouse model capable of regulated expression of an IPF-associated isoleucine-to-threonine substitution at codon 73 (I73T) in Sftpc (SP-CI73T). Tamoxifen-treated SP-CI73T cohorts developed rapid increases in SftpcI73T mRNA and misprocessed proSP-CI73T protein accompanied by increased early mortality (days 7–14). This acute phase was marked by diffuse parenchymal lung injury, tissue infiltration by monocytes, polycellular alveolitis, and elevations in bronchoalveolar lavage and AT2 mRNA content of select inflammatory cytokines. Resolution of alveolitis (2–4 weeks), commensurate with a rise in TGF-β1, was followed by aberrant remodeling marked by collagen deposition, AT2 cell hyperplasia, α–smooth muscle actin–positive (α-SMA–positive) cells, and restrictive lung physiology. The translational relevance of the model was supported by detection of multiple IPF biomarkers previously reported in human cohorts. These data provide proof of principle that mutant SP-C expression in vivo causes spontaneous lung fibrosis, strengthening the role of AT2 cell dysfunction as a key upstream driver of IPF pathogenesis.
IMMU-27. Re-MATCH PROTOCOL: PHASE I STUDY OF AUTOLOGOUS TUMOR SPECIFIC LYMPHOCYTE TRANSFER (ALT) + DC VACCINE (DCV) DURING RECOVERY FROM MYELOABLATIVE CHEMOTHERAPY (MAC) AND AUTOLOGOUS STEM CELL RESCUE (HDC + ASCR) OR NON-MYELOABLATIVE CHEMOTHERAPY (NMAC) IN PATIENTS WITH RECURRENT CENTRAL PNETs (r-PNET)
Authors: Sridharan Gururangan, Gerald Grant, Tim Driscoll, Gerald Archer, James Herndon, Henry Friedman, Joanne Kurtzberg, Darell Bigner, John Sampson, Duane Mitchell
Journal: Neuro-Oncology (2018)

We performed a phase I study to assess feasibility, safety, and efficacy of ALT+DCV following HDC +ASCR (group A) or NMAC (group B) in pts with r-PNET. Eligible pts underwent surgery to confirm diagnosis and obtain tumor for vaccine preparation. Pts with local (group A) or metastatic (group B) recurrence received 4 cycles of cytoreductive chemotherapy prior to either MAC (carboplatin + thiotepa + etoposide) (group A) or NMAC (cyclophosphamide + Fludarabine) (group B). Two dose levels of ALT were evaluated [3 x 106 or 3 x 107 cells/kg] with 3 intradermal biweekly DCVs (107cells each). Safety evaluation for DLT assessment was 2 weeks past third DCV with monthly vaccines thereafter as available. Correlative studies for immune response included TCR sequencing and measurement of serum cytokines Ten pts (M5; F5) were treated on protocol (group A 1, group B 9). Nine evaluable pts received immunotherapy; DCV [median 3 doses (3-9)] + ALT [3 x106/kg (n=4) or 3 x 107/kg (n=5)]. There were no DLTs observed. At median of 21 months follow-up, 3 pts are alive with (n=2) or without (n=1) disease 33-42 months following treatment. TCR RNA sequencing demonstrates massive clonal expansion of T cells following ALT+DCV and positive correlation with clinical outcomes. Persistence of tumor-reactive (IFN-gamma secreting) T cell clones in the peripheral blood was observed 4 months after treatment in a patient with long-term disease control. ALT+DCV is feasible, safe, and shows signs of biologic and clinical activity in some pts with r-PNET.
HGCSG1503: A retrospective cohort study evaluating the safety and efficacy of TAS-102 in patients with metastatic colorectal cancer: Analysis of GERCOR index
Authors: K. Suzuki, S. Yuki, S. Nakano, Y. Kawamoto, H. Nakatsumi, K. Hatanaka, T. Ando, K. Furukawa, A. Ishiguro, T. Ohta, K. Eto, J. Nakajima, M. Nakamura, S. Sogabe, K. Kato, M. Tateyama, S. Kato, M. Sekiguchi, Y. Sakata, Y. Komatsu
Journal: Annals of Oncology (2018)
ATRT-04. LATE DEVELOPMENT OF METACHRONOUS ATYPICAL TERATOID/RHABDOID TUMORS (AT/RTS) OR MALIGNANT RHABDOID TUMOR (MRT) IN THREE PATIENTS WITH GERMLINE SMARCB1 MUTATIONS
Authors: Anne Bendel, Helen Toledano, Ian Cohen, Susan Chi, Jaclyn Biegel
Journal: Neuro-Oncology (2018)

Atypical teratoid/rhabdoid tumor (AT/RT) and malignant rhabdoid tumor (MRT) are aggressive malignancies that typically occur in children < 3 years of age and historically have a survival of < 30%. Approximately 25% of patients harbor inactivating germline alterations in SMARCB1, which predispose carriers to develop rhabdoid tumors (RTs) between birth to 5 years (median 5 months). Surveillance guidelines for carriers of SMARCB1 (or SMARCA4) alterations recommend screening with brain MRI, abdominal ultrasound and total body MRI up to 5 years of age. We present 3 survivors of AT/RT with germline alterations in SMARCB1 who developed late primary (metachronous) RTs. Case 1 was diagnosed with a posterior fossa (PF) AT/RT at 3.5 years and developed a metachronous temporal lobe AT/RT at 17.8 years. Case 2 was diagnosed with a PF AT/RT and synchronous renal MRT at 2 months and developed a metachronous thalamic AT/RT at 8 years. Case 3 was diagnosed at 9 weeks with a lateral ventricle AT/RT and developed a metachronous disseminated retroperitoneal MRT at 11.5 years. Genetic analyses confirmed the 2 AT/RTs in case 1, the 2 AT/RTs and 1 MRT in case 2, and the 1 AT/RT and 1 MRT in case 3 to be distinct primary tumors. Due to advances in the treatment of AT/RT and MRT, survival rates are improving. The 3 cases presented in this report suggest that tumor surveillance beyond 5 years of age is indicated for patients with germline alterations who are predisposed to cancer.
Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function
Authors: Brendon L. Neuen, Toshiaki Ohkuma, Bruce Neal, David R. Matthews, Dick de Zeeuw, Kenneth W. Mahaffey, Greg Fulcher, Mehul Desai, Qiang Li, Hsiaowei Deng, Norm Rosenthal, Meg J. Jardine, George Bakris, Vlado Perkovic
Journal: Circulation (2018)

Canagliflozin is approved for glucose lowering in type 2 diabetes and confers cardiovascular and renal benefits. We sought to assess whether it had benefits in people with chronic kidney disease, including those with an estimated glomerular filtration rate (eGFR) between 30 and 45 mL/min/1.73 m2 in whom the drug is not currently approved for use.The CANVAS Program randomized 10 142 participants with type 2 diabetes and eGFR >30 mL/min/1.73 m2 to canagliflozin or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with other cardiovascular, renal, and safety outcomes. This secondary analysis describes outcomes in participants with and without chronic kidney disease, defined as eGFR <60 and ≥60 mL/min/1.73 m2, and according to baseline kidney function (eGFR <45, 45 to <60, 60 to <90, and ≥90 mL/min/1.73 m2).At baseline, 2039 (20.1%) participants had an eGFR <60 mL/min/1.73 m2, 71.6% of whom had a history of cardiovascular disease. The effect of canagliflozin on the primary outcome was similar in people with chronic kidney disease (hazard ratio, 0.70; 95% CI, 0.55-0.90) and those with preserved kidney function (hazard ratio, 0.92; 95% CI, 0.79-1.07; P heterogeneity = 0.08). Relative effects on most cardiovascular and renal outcomes were similar across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/nonfatal stroke ( P heterogeneity = 0.01), as were results for almost all safety outcomes.The effects of canagliflozin on cardiovascular and renal outcomes were not modified by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m2. Reassessing current limitations on the use of canagliflozin in chronic kidney disease may allow additional individuals to benefit from this therapy.URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01032629, NCT01989754.
QOL-08. NEUROPSYCHOLOGICAL ASSESSMENT OF 21 PATIENTS TREATED FOR A CHILDHOOD BRAIN FRONTAL LOBE TUMOUR: ASPECTS OF SOCIAL COGNITION AND THEORY OF MIND
Authors: Audrey Longaud, Mathilde Chevignard, Jacques Grill, Christelle Dufour, Stéphanie Puget, Christian Sainte-Rose, Dominique Valteau-Couanet, George Dellatolas
Journal: Neuro-Oncology (2018)

Frontal lobe function is often evaluated with diffuse lesions such as traumatic brain injury, frontal lobe epilepsy. Few cases study has been reported, evaluating frontal lobe dysfunction after focal lesions, such as tumoral lesions. The aim of the study was to evaluate social cognition and theory of mind performances in 21 patients treated for benign or malignant frontal lobe tumours in childhood. To our knowledge; no study to date has directly measured social cognition aspects and theory of mind aspects in frontal benign or malignant lobe tumours in children and adolescents. 1st ans 2nd order false-belief tests of theory of mind tests (Sally & Ann test, Smarties), facial expression recognition, motor imitation tests were performed. 21 patients (mean age at the time of evaluation: 14.3 years old, mean age at the end of treatments: 9.3 years-old) treated for frontal benign (n=4)/malignant (n=17) lobe tumour during childhood were included in our study. A comparison group of 42 patients were matched on gender, age and level education. Whereas statistical analysis of our study revealed no theory of mind disturbances in 1st and 2nd order false belief in our population, specific measures were identified as discriminating the most patients from controls, such as facial expression recognition test and motor imitation tests. The role and impact of neurons mirrors in our population is discussed.
RONC-01. PILOMYXOID ASTROCYTOMA IN YOUNG PATIENTS: THREE CASE STUDIES AND A LITERATURE REVIEW
Authors: Linbo Cai, Weiping Hong, Yanying Yang, Junjie Zhen, Xiao Xiao, Changguo Shan, Mingyao Lai, Lichao Wang
Journal: Neuro-Oncology (2018)

Pilomyxoid astrocytoma (PMA) is a rare variant of pilocytic astrocytoma (PA) and occurs in children aged 3 months to 2 years. Compared with PA, PMA has more aggressive clinical features, and is associated with higher rates of local recurrence and mortality. We retrospectively analyzed three cases. All three patients underwent subtotal resection (STR). Postoperative pathologic examination confirmed the diagnosis of PMA. After STR, we carried out postoperative observation for the 7-year-old female; the 17-year-old male received CSI combined with TB(IMRT) and 6 courses of TMZ; and the 20-year-old female was treated with IMRT combined with 6 courses of TMZ after STR. The three patients were still alive and received a follow-up examination May, 2017, for a median follow-up time of 27 months. Although the 7-year-old female started CSI treatment because MR imaging performed April 26, 2017 revealed intracranial tumor progression and spinal dissemination, she has survived 33+months. After the completion of chemoradiotherapy following resection, the 20-year-old female has survived 18+ months, and the 17-year-old male also leads a normal life for 27+ months after chemoradiotherapy. PMA is rare in young children and is associated with worse clinical outcomes. Resection is the first choice for the treatment of PMA. The results of our cases and review of the relevant literature suggest that radical resection, followed by chemotherapy and radiotherapy, may narrow the tumor and improve long-term survival. The therapeutic effect of chemotherapy and radiotherapy after the resection of PMA is worthy of further study. Pilomyxoid astrocytoma; radiotherapy; chemotherapy
IMMU-21. TARGETING EGFR IN HYPOMUTATED PEDIATRIC BRAIN TUMORS USING THE D2C7 IMMUNOTOXIN
Authors: Daniel Landi, Eric Thompson, Roger McLendon, Annick Desjardins, Vidya Chandramohan, David Ashley, Darell Bigner
Journal: Neuro-Oncology (2018)

EGFR is a receptor tyrosine kinase that is hyperactivated or overexpressed in many human cancers. Compared with brain tumors in adults, pediatric tumors harbor few somatic mutations, which reduces the antigenic burden and number of potential molecular targets. Compared to checkpoint agents, therapies that elicit innate-based, inflammatory immune responses appear better able to counter tumor-inherent immunosuppression and instigate adaptive antitumor immunity. D2C7-IT is a dual-specific antibody fragment that has a high affinity for both EGFRwt and EGFRvIII-expressing cells fused to a genetically engineered form of the Pseudomonas exotoxin. D2C7-IT has been used to treat 35 adults with malignant glioma on a phase I trial at Duke. D2C7-IT is well-tolerated and preliminarily appears to prolong survival in some patients. We have tested five samples each from several primary pediatric tumor types and found marked, often diffuse EGFRwt overexpression in ependymoma, oligodendroglioma, malignant glioma, low-grade glioma, and pleomorphic xanthoastrocytoma. Because of this data and the potential that D2C7-IT will be even more effective against pediatric tumors with a lower tumor mutational burden (TMB), we are evaluating D2C7-IT delivered by intratumoral infusion in children with any of the above relapsed tumors in a phase I trial. As the primary objective, this study will establish the safety and feasibility of D2C7-IT treatment in children with an EGFRwt-expressing brain tumor. As exploratory objectives, we are assessing the pre-treatment TMB in these pediatric brain tumors and its impact on response to D2C7-IT treatment.
Metachromatic Leukodystrophy: Too Frequent (Mis)Diagnosis?—Reply
Authors: Chujun Wu, Dongsheng Fan
Journal: JAMA Neurology (2018)

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