tbuckley/cabot-search huggingface dataset:
From Antimicrobial Peptides to Antimicrobial Poly(α‐amino acid)s
Authors: Wei Shen, Pan He, Chunsheng Xiao, Xuesi Chen
Journal: Advanced Healthcare Materials (2018)

Abstract Conventional small‐molecule antibiotics are facing a significant challenge of the rapidly developed drug resistance of pathogens. In contrast, antimicrobial peptides (AMPs), an important component for innate host defenses, are now under intensive investigation as a promising antimicrobial agent for combating drug resistant pathogens. Most AMPs can effectively kill a broad spectrum of pathogens via physical disruption of microbial cellular membranes, which is identified to be difficult to develop resistance. However, the clinical applications of AMPs are still greatly limited by several inherent impediments, such as high cost of production, potential hemolysis or toxicity, and liability to proteinase degradation. Recently, cationic poly(α‐amino acid)s with structures mimicking the AMPs are found to have excellent antimicrobial activity. These polymers, termed “antimicrobial poly(α‐amino acid)s (APAAs),” have some advantages over AMPs, such as easy production and modification, prolonged antimicrobial activity, low cytotoxicity, and enhanced stability to protease degradation. Here, a brief introduction of mechanisms and affecting factors of microbial killing by AMPs is first presented, followed by a systematic illustration of recent advances in design and preparation of biomimetic APAAs and a perspective in this field.
Abstract 11816: Sustained Ventricular Fibrillation During CPR as the Strongest Predictor for the Favorable Neurological Outcomes in Out-of-hospital Cardiac Arrest Patients; The Multicenter Prospective Study of SAVE-J
Authors: Takahiro Nakashima, Yoshio Tahara, Satoshi Yasuda, Naoto Morimura, Ken Nagao, Yasufumi Asai, Hiroyuki Yokota, Mamoru Hase, Takahiro Atsumi, Tetsuya Sakamoto
Journal: Circulation (2015)

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) has been reported to be effective in out-of-hospital cardiac arrest (OHCA) patients in whom ventricular fibrillation (VF) as an initial rhythm were refractory to conventional cardiopulmonary resuscitation (CPR). However, it remains unclear whether ECPR is effective even though cardiac rhythm would change from VF to non-VF during CPR. Methods: This multicenter prospective observational study was conducted in 46 hospitals. A total of 457 patients with OHCA aged 20-74 years in whom initial rhythm was VF and the duration from collapse to hospital arrival was within 45 minutes were originally registered. After given CPR for more than 15 minutes in hospital, these patients received combination therapy with ECPR including therapeutic hypothermia (TH), or not received. The patients underwent ECPR (n=250) were classified into the following 2 groups according to rhythm changes during CPR; Group-A (sustained VF; n=127) and Group-B (changing from VF initially to non-shockable rhythm; n=123). The endpoint was a favorable outcome defined as Cerebral Performance Category 1-2 at 6 months after collapse. Results: There were no significant differences of age, sex, time from collapse to ECPR start and the rate of TH between the 2 groups. The rate achieving favorable outcome was significantly higher in Group-A than Group-B. (19.7% vs. 3.3%, p&lt;0.001) (Figure1). When focusing on sustained VF (Group-A), the rate achieving favorable outcome improved about 5.5-fold by ECPR (ECPR, n=127; 19.7% vs. non-ECPR, n=55; 3.6%, p&lt;0.001) (Figure2). In the multivariate logistic-regression analysis, sustained VF during CPR was the strongest predictor for the favorable outcomes among the pre-hospital parameters including age, bystander CPR and time from collapse to ECPR (Odds ratio 4.43, p=0.018). Conclusions: These findings indicates that the patients with sustained VF seem to be a particular population that could merit ECPR.
EPEN-06. ANTIANGIOGENIC METRONOMIC THERAPY FOR CHILDREN WITH RECURRENT EPENDYMOMA
Authors: Daniel Alderete, Lorena Baroni, Claudia Sampor, Candela Freytes, Carla Pennella
Journal: Neuro-Oncology (2018)

Patients with relapse ependymoma have few therapy options and a short median survival time regardless of salvage treatment. The aim of this study is to evaluate the activity of multidrug antiangiogenic treatment in recurrent ependymoma patients. We evaluated the use of biweekly intravenous bevacizumab in combination with five oral drugs (thalidomide, celecoxib, fenofibrate, and oral etoposide/cyclophosphamide) in 9 recurrent ependymoma patients between September 2015 and August 2017. The median aged at beginning of treatment was 7.7y (3.7–11.8). 8 patients began therapy for progression disease (6 local/2 metastatic; 1 first/7 multiple) and 1 because residual tumor after conventional treatment. Objective tumor response was 88% (8), including 5 with partial response and 3 with stable disease. Best response was observed 4.4 months (2.8–5.4) since starting treatment. The median treatment time was 10.6 months (3.4–21). Median time to progression(PFS) was 10.7 months. Median overall survival(OS) was 14.4 months (3.4–27.8). The OS and PFS after 6 months was 100% and 87% respectively; and after 12 months 50% and 37%. At last follow-up, 4 patients (44%) are alive including 2 still undergoing treatment. One patients remain alive and progression free at 16 months and another is alive with disease at 27 months. Therapy was generally well tolerated. This 5-drug regimen plus Bevacizumab produces objective responses with minimal toxicity in children with recurrent ependymoma. This antiangiogenic metronomic therapy could be an evolving alternative approach to recurrent ependymoma and it would be included as part of conventional treatment for unresectable ependymoma.
Patient selection and timing of allogeneic hematopoietic stem cell transplantation for relapsed follicular lymphoma
Authors: Mike Fillon
Journal: CA A Cancer Journal for Clinicians (2018)

Key Points Approximately 20% of patients with FL relapse within 2 years of diagnosis with decreasing sensitivity to treatment. Allo‐HCT is more effective in patients who are in earlier phases of the disease. Autologous hematopoietic cell transplantation should be considered as an option for high‐risk patients who experience failure of chemoimmunotherapy after initial lines of therapy.
DIPG-19. PROLONGED SURVIVAL AND EVENTUAL DEATH BY DISSEMINATED PULMONARY METASTASIS IN A PEDIATRIC PATIENT WITH DIFFUSE PONTINE H3.1K27M GLIOMA: A CASE REPORT
Authors: Christina Coleman, Tabitha Cooney, Arie Perry, Hua Guo, David Solomon, Joseph Torkildson
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine gliomas (DIPG) with H3.1K27M mutation are associated with dismal prognosis and median survival of 15.0 months. We present a patient with diffuse H3.1K27M pontine glioma treated with craniospinal irradiation and anti-angiogenic therapy, who survived 38 months and ultimately died of pulmonary disease. A previously healthy 7-year-old female presented with headache and altered mental status. Neuroimaging revealed T2/FLAIR hyperintensity centered within the pons, as well as enhancement along ventral C6-T5 spinal cord concerning for synchronous metastatic disease. Ventriculoperitoneal shunt placement and brainstem biopsy were performed, biopsy revealed infiltrative astrocytoma with positive nuclear histone H3-K27M staining. She received 6 weeks of craniospinal irradiation followed by 10 months of therapy with thalidomide, celecoxib and etoposide per modified Angiocomb protocol. She eventually developed interstitial lung disease with no concurrent clinical signs of CNS disease progression. She died of respiratory failure 38 months from diagnosis. Next generation sequencing performed on diagnostic tissue found HIST1H3B p.K28M hotspot and PTPN11 gene missense mutations, lung biopsy prior to death revealed the same H3.1K27M and PTPN11 mutations, as well as frameshift mutations in NF1 and CREBBP genes. Postmortem examination revealed presence of metastases in lungs, kidneys, liver, fallopian tube, perihepatic soft tissue, diaphragm, and progression of her primary disease. Our case is the first report of documented DIPG pulmonary metastasis and subsequent death by pulmonary disease, and the longest documented survival of HIST1H3B K27M pontine glioma by several months. Further thought should be given to whether cerebrospinal fluid diversion and radiation strategy affected her clinical course.
Clinico-pathological and molecular characterization of BRAF mutant metastatic colorectal cancer (mCRC): Are all mutations created equal?
Authors: M. Schirripa, P. Biason, F. Cortiula, M. Pino, F. Urbano, C. Antoniotti, S. Corallo, F. Gelsomino, A. Orlandi, S. Lonardi, F. Bergamo, G. Munari, U. Malapelle, M. Rugge, C. Mescoli, L. Reggiani Bonetti, G. Lanza, A. Dei Tos, G. De Maglio, V. Zagonel, F. Loupakis, M. Fassan
Journal: Annals of Oncology (2018)

Introduction: Functional studies on preclinical models (Yao et al. Nature 2017) identified 3 classes of BRAF mutations: activating RAS -independent BRAF mutations signaling as monomers (class 1- BRAF V600E) or as dimers (class 2-codons 601/597) and RAS -dependent BRAF mutations with impaired kinase activity (class 3-codons 594/596). While clinico-pathological and molecular features of class 1 mutation are well known, limited data are available with regard to class 2 and 3 mutations, due to their rarity in CRC. Methods: Clinico-pathological, molecular and outcome data from BRAF mutated (codons 594, 596, 597, 600, 601) mCRC patients were collected. A group of BRAF wild-type patients was included as control. IHC analyses were performed to determine the consensus molecular subtypes (CMS). Clinical features were compared by chi-square or fisher's exact test. PFS and OS were evaluated by Kaplan-Meier and log-rank test. Results: Class 1, 2 and 3 included 92, 12 and 13 patients respectively. BRAF wild-type patients were 540. No clinico-pathological differences were observed comparing class 1 to class 2 BRAF mutated. Conversely, BRAF class 3 mutated were more frequently left sided (p = 0.0028), well differentiated (p = 0.0120), pN0 (p = 0.0159), and with no peritoneal metastases (p = 0.0176) compared to class 1. With regard to CMS, class 2 and 3 tumors were all assigned to CMS2-3. Class 1 tumors were assigned to CMS1, 2-3 and 4 in 39%, 44% and 17% of cases. Median OS for BRAF wt, BRAF mutant class1, 2 and 3 were 42.2, 21, 23.4 and 44.5 months respectively. HR for OS was 2.38 (95% CI 1.61-3.54) for class 1, 1.90 (95% CI 0.85-4.26) for class 2 and 0.93 (95% CI 0.51-1.69) for class 3, compared to BRAF wt (p < 0.0001). Median PFS for BRAF wt, BRAF mutant class1, 2 and 3 were 10.1, 7.3, 7.0 and 13.8 months respectively. HR for PFS was 2.02 (95% CI 1.39-2.94) for class 1, 2.49 (95% CI 0.92-6.74) for class 2 and 0.85 (95% CI 0.47-1.54) for class 3, compared to BRAF wt (p < 0.0001). Conclusion: Our data confirm previous findings describing specific features associated with BRAF rare mutations. For the first time clinico-pathological characteristics and outcome data are reported according to the 3 classes categorization of BRAF mutations. In particular, class 1 and 2 share similar features and worse outcome compared to class 3 and wild type patients
TBIO-08. TUMOR MUTATIONAL BURDEN AND DRIVER MUTATIONS: FURTHER INSIGHT INTO THE GENOMIC LANDSCAPE OF PEDIATRIC BRAIN TUMORS
Authors: Roshal Patel, Katharine Halligan, Shakti Ramkissoon, Jeffrey Ross, Lauren Weintraub
Journal: Neuro-Oncology (2018)

Tumor mutational burden (TMB) and driver mutations are potential biomarkers to predict efficacy of immune checkpoint inhibitors (ICPI). Studies demonstrated malignant gliomas with high TMB in children and adults may preferentially benefit from treatment with ICPI. To characterize the association between TMB and known drivers in pediatric brain tumors, comprehensive genomic profiling (CGP) was performed on 723 pediatric (≤18 years) glioma samples using DNA extracted from 40 microns of formalin-fixed paraffin-embedded tissue. CGP utilized hybridization-captured, adaptor ligation based libraries sequenced to a mean coverage depth of >500X for up to 315 cancer-related genes. TMB was calculated as mutations per megabase and categorized as low (0-6), intermediate (6-20), or high (20+). Analysis included 80 clinically relevant driver mutations; genomic alterations known to confer a selective growth advantage. Of 723 brain tumors, TMB was low in 91.8%, intermediate in 6.1%, and high in 2.1%. When excluding tumor suppressor genes (TSGs), there was a trend toward decreased incidence of driver mutations in tumors with high TMB. Additionally, we determined that BRAF alterations were not identified in high TMB tumors, but were enriched in low TMB tumors. However, when including TSGs, 93% of tumors in the high TMB cohort harbored a driver mutation; 63% and 70% in the low and intermediate TMB cohorts, respectively. There is an association between high TMB and incidence of TSGs. In contrast, there is an association between low TMB and BRAF mutations. These represent populations in which ICPI may be more or less effective and further studies are needed.
EAPH-06. HYPERMUTANT PEDIATRIC HIGH GRADE GLIOMAS ARE DRIVEN BY RAS/MAPK MUTATIONS AND RESPOND TO MEK INHIBITION
Authors: Brittany B Campbell, Daniel A Morgenstern, Tatiana Lipman, David Fabrizio, Adam Shlien, Eric Bouffet, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2018)

Hypermutant pediatric high grade gliomas (pHGG) constitute 5–10% of PHGG and are almost invariantly caused by replication repair deficiency (RRD). Constitutive activation of the RAS/MAPK pathway via oncogenic mutations can be targeted with MEK inhibitors (MEKi). We hypothesized that hypermutant RRD PHGG would harbor mutations in NF1 and other MAPK pathway regulators, making their tumors susceptible to MEKi. Tumor sequencing data from >1200 pediatric tumors was extracted from our foundation-medicine cohort. Exome and RNA-seq was performed on tumors from our international RRD consortium. Xenografts from patient derived pHGG were established in NOD-SCID mice and treated with Trametinib and Selumetinib. Functional experiments were performed to demonstrate deregulation of the MAPK pathway in the tumors. Screening of 1215 cancers revealed that RAS/MAPK mutations are the second most common mutation in pediatric tumors. Exome data from patients revealed 95% of PHGG were found to harbor mutations in key RAS/MAPK pathway regulators. Subclonal analysis reveals mutations in the pathway in each subclone and enrichment of these mutations over time. In-vitro and in-vivo treatment of patient derived RRD hypermutant PHGG with MEKi revealed significant tumor suppression with a 50% decrease in tumor volume and improved survival (p <0.001). Finally, two patients with progressive/recurrent PHGG treated with Selumetinib and trametinib exhibited >90% objective tumor response and prolonged survival. These preclinical and clinical observations suggest a novel therapeutic option for children with hypermutant RRD PHGG based on possible oncogenic addiction to RAS/MAPK alterations. These observations are the basis of the upcoming SU2C international clinical trial.
QOL-14. IMPACT OF RADIATION DOSE ON PHYSICAL AND EMOTIONAL OUTCOMES IN PEDIATRIC BRAIN TUMOR
Authors: John Bobo, Kaitlin Oswald, Betty Herrington, Maru Barrera, Andrea Patenaude, Mary Kupst, Cynthia Gerhardt, Kathryn Vannatta, Cynthia Karlson
Journal: Neuro-Oncology (2018)

Pediatric patients with brain tumors often experience disease- and treatment-dependent physical and psychosocial concerns following treatment. The present study evaluated the effect of radiation dose on parent-reported symptoms of pain, physical functioning, and depression following treatment. Mothers and fathers of pediatric patients (n=182; M age = 11.33; SD= 2.25; 47.3% females) diagnosed with a primary brain tumor (M age at diagnosis = 7.39; SD=3.08) completed questionnaires at research visits. Caregivers completed the Child Health Questionnaire and Child Behavioral Checklist to assess children’s physical functioning, pain, and depression symptoms. Chart review was conducted to obtain brain tumor diagnosis, radiation type (whole vs. focal) and radiation dose. Controlling for brain tumor diagnosis, age, and gender linear regressions revealed moderate and high doses of whole brain radiation were significantly related to decreased parent-reported physical functioning (β = -0.354, p < .01). Increased dosage of focal radiation was significantly related to decreased physical functioning (β = -0.191, p < .05) and increased withdrawal/depression (β = 0.189, p < .05). Present results suggest increased radiation dosage is related to children’s mental and physical wellbeing three to four years following treatment. This study adds to existent literature documenting detrimental effects of radiation on neurocognitive outcomes in pediatric brain tumor survivors. Future research on treatment factors related to quality of life are warranted, along with continued research on interventions designed to decrease the negative impact of brain tumor treatment on children’s long-term quality of life.
DIPG-47. RE-IRRADIATION FOR RECURRENT DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Yui Kimura, Keita Terashima, Chikako Kiyotani, Tomoo Osumi, Yoko Shioda, Motohiro Kato, Daisuke Tomizawa, Hiroshi Fuji, Kenichi Usami, Hidekazu Aoki, Rie Irie, Hideki Ogiwara, Yoshiyuki Tsutsumi, Takako Yoshioka, Kimikazu Matsumoto
Journal: Neuro-Oncology (2018)

The prognosis of diffuse intrinsic pontine glioma (DIPG) remains dismal. The only effective treatment is radiation therapy so far. Nevertheless, the therapeutic effect of radiation therapy doesn’t last for long and almost all the patients experience relapse after several months. Recently, re-irradiation for relapsed DIPG was attempted and showed some benefit for those patients. We retrospective reviewed the efficacy and safety of re-irradiation therapy for five DIPG cases from April 2013 to December 2017. Five patients include three boys and two girls, their mean age was 7.2 years old (4–12). One case only did biopsy for diagnosis, others diagnosed clinically. One case underwent ventricular Ommaya reservoir insertion due to hydrocephalus. Radiation doses were from 19.8Gy to 50.4Gy(1.8–3.0Gy/Fr). The median duration between diagnosis and recurrence was 7.5 months (4–10 months), and the mean survival after the re-irradiation was 6.3 months (two of them still surviving). All five patients completed the treatment without acute toxicity, and four out of five patients demonstrated some improvement of their symptoms which occurred at the recurrence. It has been suggested that re-irradiation might be an effective and safe treatment for selected patients with recurrent DIPG.
CRAN-24. LANGERHANS CELL HISTIOCYTOSIS OF THE ORBIT AND SKULL BASE IN A 2 YEAR OLD: CASE REPORT
Authors: William Gump
Journal: Neuro-Oncology (2018)

Langerhans cell histiocytosis (LCH) results from clonal proliferation of cells which resemble Langerhans cells found normally in skin and lymph nodes. We present an unusual LCH case with significant bony erosion of the lateral orbit and skull base. CASE A 2 year old girl presented with several weeks of right proptosis. CT and MR imaging showed an enhancing lateral orbital mass eroding the surrounding bony structures and extending into the anterior aspect of the temporal fossa. Surgical approach via orbitozygomatic craniotomy was challenging due to pathologic absence of the zygomatic arch and lateral orbital wall. A near-total resection was achieved based on direct visualization and postoperative MRI. Delayed reconstruction of the lateral orbital wall was planned. Proptosis resolved postoperatively. PET imaging showed residual disease in the middle cranial fossa but no other foci. The patient is currently receiving chemotherapy. Successful treatment of unifocal LCH usually entails complete surgical excision. Disseminated disease is a poor prognostic factor. Chemotherapy and radiation, including stereotactic radiosurgery, can be employed for residual or nonresectable lesions although long term outcomes are not yet well defined. Delayed reconstruction of bone defects is an option particularly if chemotherapy is anticipated. LCH of the skull base may radiographically mimic high grade neoplasm, and can be associated with significant bony erosion. Maximal safe resection is an important first step in treatment. Chemotherapy for residual disease and delayed bony reconstruction are important components of comprehensive treatment.
Large Changes in Brain Volume Observed in an Asymptomatic Young Child With Type 1 Diabetes
Authors: Paul K. Mazaika, Tandy Aye, Allan L. Reiss, Bruce A. Buckingham
Journal: Diabetes Care (2018)

This case was recorded during the Diabetes Research in Children Network (DirecNet) longitudinal study (1), in which children ( N = 214) had MRI scans at three time points over 5 years. During the analyses, we noted that one subject with diabetes had unusually large brain volume changes (13.5% decrease of gray matter volume and 165% increase in ventricular volume) from age 6.5 to age 8.0 years.

The patient was diagnosed with type 1 diabetes at age 5.6 years when he presented without diabetic ketoacidosis. Neuroradiological reviews of the MRI scans at each time point reported no evidence of gross pathological abnormalities or diffusion restrictions. The patient was on multiple daily insulin injections at the time of his first MRI scan and on infusion pump therapy at the later scans. He was healthy besides type 1 diabetes, prepubertal, with full-term birth, normal weight development, normal thyroid function, and no evidence of neurological deficits. Moreover, he had age-appropriate vocabulary and stable cognitive test scores over the 5-year period. His medical …
DIPG-34. A HUMAN NEURAL STEM CELL DIPG MODEL IDENTIFIES THE RELATIVE CONTRIBUTION OF DIFFERENT ONCOGENIC ELEMENTS TO INVASIVE MALIGNANT TRANSFORMATION
Authors: Youngran Park, Ping An, Dacheng Ding, Charles G Eberhart, Eric H Raabe
Journal: Neuro-Oncology (2018)

Nearly 80% of Diffuse Intrinsic Pontine Glioma (DIPG) harbor H3K27M mutation which is inversely correlated with reduced survival, and 60% of H3K27M mutant cells are associated with TP53 mutation. However, it is unclear how those mutations interact to drive DIPG. To address the relative contributions, we added oncogenic elements that are known to present in DIPG in a stepwise fashion to hindbrain-derived hNSCs. These include the stem cell factor BMI1, p53R248W, H3K27M, constitutively active AKT and hTERT. First, we found that the combination of BMI1 along with p53R248W and hTERT could immortalize neural stem cells, but was insufficient to form tumors in vivo. Addition of activated AKT led to aggressive glial phenotype tumors in the pons of immunodeficient mice, but was not invasive as DIPG. Finally, the introduction of H3K27M mutation increases the invasion ability of transformed cells. We also found that H3K27M mutation increases expression of LIN28B, a stem cell factor, which might be implicated in invasion and tumorigenicity, suggesting that H3K27M mutation might facilitate invasiveness of DIPG through LIN28B and its downstream effectors HMGA2, SNAI1, and SLUG. In summary, we have developed a human hindbrain neural stem cell DIPG model which has both accurate cell of origin and genetic alterations. Our models allow for assessment of the relative contribution to transformation of each genetic element in a stepwise fashion in the likely cell of origin of this deadly tumor.