tbuckley/cabot-search huggingface dataset:
Polymer hydrogels as innovative carriers for anticancer therapy
Authors: M. Kędzierska, A. Drabczyk, S. Kudłacik–Kramarczyk, P. Potemski, B. Tyliszczak
Journal: Annals of Oncology (2018)

Introduction: Battle with cancer diseases is currently one of the greatest challenges of medicine. Recently, the number of cancer cases has doubled, that contributed to the fact that scientists are searching for new solutions that will help to deal with these illnesses. In the standard methods of administering cancer drugs, their therapeutic effect is not fully exploited. Traditional methods of treatment often cause undesirable side effects in the body of the patient. Additionally, introduced drug affects negatively not only diseased cells but also healthy ones. Therefore, numerous studies are currently conducted to develop materials used as carriers of such drugs. Such a carrier will enable the delivery of the drug directly to the place affected by the disease and after the completing its function it will biodegrade without affecting negatively the body of the patient. Methods: In the presented research hydrogel polymers have been proposed as drug carriers due to their non-toxicity and biodegradability. Research included the synthesis of hydrogels by means of the photopolymerization process. Hydrogels have been obtained using chitosan - a polysaccharide widely used for biomedical purposes. Moreover, received materials have been modified with selected extracts of natural origin. Then, analyzes were conducted to determine the cytotoxicity of the hydrogels to tumor cells (Jurkat cells - lymphoblastic leukemia). Cytotoxicity was determined using MTT and XTT tests in accordance with the standard: PN-EN ISO 10993-5: 2009. Such a test allowed to determine the proliferation and viability of tumor cells cultured in the presence of the obtained materials. Cells that did not survive under the influence of the tested materials retained their enzymatic activity, which led to the transformation of the selected reagent into a colored form whose concentration could be determined spectrophotometrically. Results: Studies were performed for 7 days, after certain periods of time viability of cells has been defined. In Table 1. results of analysis are presented. Conclusion: Based on the presented research it can be concluded that obtained hydrogels in most cases had a negative impact on the growth of cancer cells. Such a negative impact has been noticed even after 3 days of contact with synthesized hydrogels. Therefore, it can be stated that such materials can be considered as materials interesting from a medical point of view with special emphasis on application in cancer treatment. The authors would like to thank The National Centre for Research and Development (Grant no: LIDER/033/697/L-5/13/NCBR/2014).
ATRT-25. CHECKPOINT MOLECULE B7-H3 IS HIGHLY EXPRESSED ON ATYPICAL RHABDOID TERATOID TUMOR (ATRT) AND IS A PROMISING CANDIDATE FOR CAR T CELL THERAPY
Authors: Johanna Theruvath, Claus-Moritz Graef, Sabine Heitzeneder, Robbie Majzner, Siddhartha Mitra, Samuel H Cheshier, Crystal Mackall
Journal: Neuro-Oncology (2018)

ATRT are highly malignant brain tumors arising in very young children. The prognosis is extremely poor. Hence new treatments are urgently needed. B7-H3 (CD276) is a member of the B7 family of molecules involved in immune regulation and is over-expressed on a wide variety of solid cancers. We recently created a 4-1BB second-generation CAR targeting B7-H3. To date, there is little data on the most efficacious route of administration of CAR T-cells in malignant brain tumors. The goal of this study was to test the anti-tumor activity of the B7-H3 CAR in highly aggressive ATRT xenograft models and compare intracavitary, intraventricular and intravenous administration in terms of efficacy, toxicity and persistence of CAR T-cells. We observed high expression of B7-H3 on primary ATRT patient samples and all tested cell lines. Administration of a single intracavitary or intraventricular infusion of 1x106 B7-H3 CAR T-cells was able to eradicate tumor burden, whereas 1x107 B7-H3 CAR T-cells administered intravenously led to similar results. Intravenous administration led to high levels of circulating inflammatory cytokines, which were undetectable following local administration. Animals from all groups were protected from tumor re-challenge and displayed similar numbers of CAR-T-cells in the brain after re-challenge. In summary, B7-H3 represents a promising target for CAR-T cell therapy in ATRT and administration of B7-H3 CAR T-cells is efficacious in eradicating ATRT. Efficacy and persistence of CAR-T-cells appeared similar regardless of the route of administration, however, the risk of systemic toxicity may be reduced following locoregional treatment compared to systemic administration.
Assessment of Liver Fibrosis With Elastography Point Quantification vs Other Noninvasive Methods
Authors: Fabio Conti, Carla Serra, Ranka Vukotic, Cristina Felicani, Elena Mazzotta, Stefano Gitto, Giovanni Vitale, Antonietta D’Errico, Pietro Andreone
Journal: Clinical Gastroenterology and Hepatology (2018)
Neuroimmune disorders of the central nervous system in children in the molecular era
Authors: Elizabeth Wells, Yael Hacohen, Amy Waldman, Jan M. Tillema, Ariane Soldatos, Beau Ances, Susanne Benseler, Bibi Bielekova, Russel C. Dale, Josep Dalmau, William Gaillard, Mark Gorman, Benjamin Greenberg, Ann Hyslop, Carlos A. Pardo, Robert C. Tasker, E. Ann Yeh, Amit Bar-Or, Sean Pittock, Adeline Vanderver, Brenda Banwell, Jessica Carpenter, Irene Cortese, Nathan Dean, Racquel Farias-Moeller, William Gallentine, Carol Glaser, Raphaela Goldbach-Mansky, Ilana Kahn, Bennett Lavenstein, William McClintock, William McDow, Jennifer Murphy, Avindra Nath, Roger Packer, Tova Ronis, David Schleyer, Stephanie Schleyer, Peter Shibuya, Ursula Utz, Gilbert Vezina, David Wessel
Journal: Nature Reviews Neurology (2018)
NURS-19. NEUROFIBROMATOSIS THERAPEUTICS: PEARLS TO TREAT THE COMPLEX CHILD
Authors: Molly Hemenway, Melissa Waters
Journal: Neuro-Oncology (2018)

Children with Neurofibromatosis (NF) who need treatment for a central nervous system (CNS) tumor and/or plexiform neurofibromas present challenges in treatment decisions, symptom management, and care coordination. NF patients tolerate chemotherapy differently from other children undergoing treatment (without an underlying syndrome) and are at high risk for secondary tumors if treated with radiation therapy. The side effects that NF patients experience require a different approach to adverse effect management, both with standard chemotherapy and targeted agents. Recent research has led to a much larger population of children with plexiform neurofibromas seeking treatment with MEK inhibitors. In contrast to most standard chemotherapy, these agents are dosed daily and given at home, often over a period of 1-2 years. Due to the ease of administration, patients require less clinic and hospital visits, but often more phone triage with families to help manage side effects. Nurses require knowledge of the common adverse effects of these medications to help with ongoing management. Prevention and early management of skin and gastrointestinal toxicities by nurses may support compliance and tolerance of this longer-term therapy. High quality care for children with NF1 and undergoing treatment for a CNS tumor and/or plexiform neurofibromas requires increased coordination and collaboration between multiple disciplines to care for the whole child. We will present treatment considerations and challenges, side effect management protocols developed by multiple disciplines, and share pearls for coordinating care for patients with the complex medical needs that are inherent with NF and CNS tumors and/or plexiform neurofibromas.
MBCL-49. PROGNOSTIC SIGNIFICANCE OF MOLECULAR SUBGROUPS OF MEDULLOBLASTOMA IN CHILDREN RECEIVING IRRADIATION-SPARING REGIMENS
Authors: Kee Kiat Yeo, Ashley Margol, Rebekah Kennedy, Long Hung, Nathan Robison, Girish Dhall, Shahab Asgharzadeh
Journal: Neuro-Oncology (2018)

Radiation therapy, while a mainstay of medulloblastoma treatment, is associated with significant age-dependent neurocognitive morbidity in children. Relatively little is known about the subgroup-specific outcome of infants and young children with medulloblastoma treated with irradiation-sparing regimens. Infants and young children <10 years of age with medulloblastoma treated with irradiation-sparing regimens (Head Start, COG-99703, or others) at Children’s Hospital Los Angeles since 1980 were identified. Molecular subgroup was determined using a 31-gene TaqMan Low Density Array signature. Survival analyses were conducted based on 4 molecular subgroups (WNT, SHH, Group 3, and Group 4). Seventy-six patients with medulloblastoma were identified, with five excluded from survival analysis secondary to non-cancer related deaths. Of these 71 patients, 30 did not receive irradiation as part of their upfront therapy. These patients were divided into SHH (n=17), Group 3 (n=3) and Group 4 subgroups (n=10), with no WNT subgroup identified. Median age at diagnosis was 2.16 (range:0.24-9.80) years. 5-year progression-free survival rates for SHH, Group 3, and Group 4 for this irradiation-sparing cohort were 76.5%±10.3%, 0% and 0%, respectively; 5-year overall survival rates for SHH, Group 3 and Group 4 were 94.0%±5.7%, 0% and 26.7%±15.0%, respectively. There was a marked difference in outcome among infants/young children with SHH medulloblastoma vs Group 3/4 medulloblastoma treated with irradiation-sparing regimens. Most patients <10 years of age with SHH medulloblastoma were treated effectively with irradiation-sparing regimens, with high salvageability among those who progressed. Group 3/4 medulloblastoma patients treated without irradiation had extremely poor outcome.
CRAN-07. SIGNIFICANT RATES OF ACTH SUPPRESSION MISDIAGNOSED AS ACTH DEFICIENCY AFTER PERIOPERATIVE DEXAMETHASONE IN CRANIOPHARYNGIOMA
Authors: Kyriaki Pieri, Maria Michaelidou, Antonia Dastamani, Helen A Spoudeas
Journal: Neuro-Oncology (2018)

ACTH suppression may masquerade as ACTH deficiency in children and young people (CYP) receiving dexamethasone for pituitary tumour surgery. In our experience, GH is always the first, and ACTH the last anterior pituitary deficit, with LH/FSH and TSH intermediate in hierarchical loss. To investigate long term adrenal recovery and true ACTH deficiency rate in patients with craniopharyngioma receiving hydrocortisone replacement, and whether a spontaneous puberty and detectable pre-dose 8am plasma ACTH predict intact ACTH reserve. Longitudinal retrospective record review of 53 cases (29M), diagnosed aged 6.87(1.12–17.18) years and followed for 6.98(1.43–26.73) years. 9 of 53 (16.98%) never required hydrocortisone of whom 8 (88.9%) were GHD, 6 (66.7%) TSHD, 5 (55.6%) LH/FSHD and 1 (11.1%) had DI at last follow-up. A further 6 of 53 (11.3%) had hydrocortisone for presumed ACTHD (peak cortisol <117nmol/l) but “recovered” with intact cortisol reserve and detectable plasma ACTH 36.2ng/L(13.9–52.9) after 3.08(2.38–10.33) years. All were GHD, 5 (83.3%) LH/FSHD, 4 (66.7%) TSHD and 2 (33.3%) had DI. In the last 38 (71.7%) patients, ACTH remains undetectable (<5ng/L); all require cortisol, GH and thyroxine replacement, 31/32 (96.9%) of postpubertal age require sex steroids and 31/38 have DI, after 6.40(1.43–26.73) years. Adrenal suppression can be prolonged. Significant (13.6%) recovery rates at a median 7 years may further increase with time. Overdiagnosis of ACTHD may be misattributed to surgery or radiation. We encourage readdressing the need for hydrocortisone in CYP with detectable pre-dose 8am ACTH >10ng/L and without concurrent TSH and post-pubertal LH/FSH deficiency.
DIPG-72. TARGETING MULTIPLE PATHWAYS AS A TREATMENT STRATEGY IN DIFFUSE MIDLINE GLIOMA
Authors: Michael Salacz, Donna Murray, Richard Kast
Journal: Neuro-Oncology (2018)

Diffuse midline glioma (DMG) is an entity characterized by midline location, treatment refractoriness, short survival, and H3 histone mutation. DMG encompasses pediatric diffuse intrinsic pontine glioma (DIPG), as most (80%) harbor an H3 mutation as well. DMGs require both H3 histone mutation and second mutated pathway for tumorigenesis. Minimally-toxic targeting with valproic acid and metformin (reverse H3 effects), simvastatin and vitamin D to inhibit hedgehog, sertraline for RTK-Ras, and temozolomide for cytotoxicity is proposed in combination with a mitotic inhibitor. Nativis Voyager® system is a non-sterile, non-invasive, non-thermal, portable, investigational medical device that uses a specific, localized ultra-low radio frequency energy (ulRFE®) cognate, based on Lorenz Force, for the treatment of brain cancer. The AIA cognate is hypothesized to stabilize microtubule disassembly by changing the charge dynamics at the tubulin monomer subunit and strengthening the bond between monomers. Early data suggest the repurposed drug cocktail in combination with mitotic inhibition can provide a meaningful therapeutic and minimally toxic benefit in DMG. This type of approach using existing FDA-approved medications would speed protocol development from the bench to the bedside. A compassionate use study will begin enrolling pediatric patients, using the repurposed drug cocktail in combination with a newly developed Nativis Voyager Pediatric system. Clinical trial information: CT02296580
DIPG-58. SUBTYPE-SPECIFIC OVEREXPRESSION OF WILMS’ TUMOR PROTEIN IN PEDIATRIC MIDLINE HIGH GRADE GLIOMAS
Authors: Sulgi Lee, Madhuri Kambhampati, Sridevi Yadavilli, Mariarita Santi, Roger J Packer, Conrad R Cruz, Isabel Almira, Eugene Hwang, Javad Nazarian
Journal: Neuro-Oncology (2018)

Midline pediatric high grade gliomas (HGGs), especially diffuse intrinsic pontine gliomas (DIPGs), are deadly pediatric brain cancer that makes up 10–15% of all central nervous system (CNS) tumors in children; little progress has been made in improving outcomes for these patients. Immunotherapy is a strategy that has shown promise for treatment of malignancy, although identification of tumor associated antigens is critical to an effective immunotherapeutic approach. Wilms’ tumor protein (WT1) has been heavily implicated in cancer development, and it may serve as an attractive immunotherapy target in HGGs. Here, we validated WT1 as a potential tumor associated antigen in pediatric midline gliomas using formalin fixed paraffin embedded (FFPE) tumor, intra-patient healthy tissue controls, fresh frozen post-mortem tissues, and patient-derived DIPG primary cell lines. Immunohistochemical staining of patient FFPE specimens showed strong WT1 immunoreactivity in tumor compared to adjacent healthy tissue controls. Western blot of tumor further validated higher WT1 levels in tumor versus adjacent normal tissues. Tumor showed cytoplasmic expression of WT1, confirmed by immunofluorescent (IF) staining. In addition, a striking dichotomy of expression was noted with absent/weak WT1 immunoreactivity in H3.1K27M subtype gliomas, compared to moderate/strong signal in H3.3K27M subtypes. Western blotting assay and reverse transcription quantitative PCR using DIPG primary cell lines also validated the differential expression of the protein. Our study suggests that WT1 is an attractive potential target protein for pediatric midline glioma immunotherapy and may differentiate between the underlying histone mutations.
Primary gastric diffuse large B cell lymphoma: A single center experience from developing country
Authors: A. Gogia, V. Raina, M. Sharma
Journal: Annals of Oncology (2018)

Introduction: Primary gastric diffuse large B cell lymphoma (PGDLBCL) accounts for 1% of gastric malignancies and 20% of all gastrointestinal lymphoma. There is paucity of data regarding PGDLBCL from developing countries. Methods: In this retrospective study, 70 patients with PGDLBCL from 2006 to 2015 were included at All India Institute of Medical Sciences (AIIMS), New Delhi, India. Their clinical features, pathological characteristics, base line IPI score, stage at presentation, type of treatment and outcome were analyzed. Results: Median age was 41.5 years (range 20-77yrs). B-symptoms were present in 42 (60%) patients and 35 (50%) patients were presented with poor performance status (ECOG 3/4). According to Ann Arbor staging, 49 patients (70%) were in stage I, 14 (20%) stage II, 02 (2.8%) stage III and 05 (7%) in stage IV. IPI risk categorizations, low risk 30%, low intermediate risk 20%, high intermediate risk 20% and high risk 30%. Sixty three cases (90%) were non germinal center/Activated B cell type (ABC). Twenty eight patients were treated with CHOP, 27 patients with R (Rituximab) +CHOP and rest were treated with CVP +/- R. Radiation therapy (RT) was received as consolidative treatment in 50% of cases. Complete remission (CR) was observed in 75% of cases. Median event free (EFS) and overall survival (OS) was 72% and 58% with median follow up period of 42 months. Helicobacter pylori (HP) antibody testing was positive in 14 cases (20%) and all patients received anti-HP treatment. HP associated PGDLBCL were associated with less B symptoms, low IPI, better CR rate (P Conclusion: PGDLBCL consists 60% of all gastric lymphoma at our centre. Around half of them are presented with B symptoms and poor performance status. H. Pylori positivity is seen in 20% of cases and associated with low risk IPI with good survival. Addition of rituximab to CHOP has a statistical significant survival impact in patients with PGDLBCL. RT may be omitted in selective cases of PGDLBCL, where RCHOP/RCVP (rituximab based chemotherapy) is being considered, to avoid radiation induced side effect with same survival. Chemotherapy may be omitted in some selected cases of HP associated PGDLBCL.
Abstract 13894: Dihydrobiopterin Causes Endothelial Nitric Oxide Synthase Dysfunction in Rats in vivo
Authors: Masato Tsutsui, Katsuhiko Noguchi, Toshihiro Matsuzaki, Mayuko Sakanashi, Junko Nakasone, Taro Uchida, Mika Tanada, Haruaki Kubota, Kazuhiro Sugahara, Yusuke Ohya
Journal: Circulation (2012)

Background:   Vascular levels of dihydrobiopterin (BH2), an oxidized form of tetrahydrobiopterin (BH4), have been reported to be elevated in arteriosclerotic lesions where endothelial nitric oxide synthase (eNOS) is dysfunctional. However, no study has ever addressed the potential role of BH2 in the regulation of eNOS activity in vivo. Thus, in this study, we tested our hypothesis that an increasing BH2 concentration causes eNOS dysfunction in rats.     Methods and Results:   Male Wistar rats were treated with either saline, methotrexate (MTX) which is a specific dihydrofolate reductase inhibitor that blocks intracellular conversion of BH2 to BH4, or MTX plus sepiapterin (SEP) which is a BH2 precursor (n=8-10). Treatment with MTX alone did not significantly affect aortic BH4 (59±9 vs. 73±6 pmol/g) or BH2 (80±9 vs. 33±6 pmol/g) levels or basal blood pressure (BP) (137±8 vs. 128±4 mmHg) as compared with saline treatment (control). Treatment with MTX/SEP also did not significantly change aortic BH4 levels (79±20). However, MTX/SEP treatment significantly and markedly increased aortic BH2 levels by 8.7 times (291±29,  P  P  P  P  P     Conclusions :  These results demonstrate, for the first time, that BH2 causes eNOS dysfunction in rats in vivo in the absence of BH4 deficiency, providing a novel insight into the regulatory mechanism of eNOS activity.
Two-step recanalization technique for a pancreatic duct stricture complicated by massive pancreatic stones
Authors: Takeshi Ogura, Atsushi Okuda, Miyuki Imanishi, Rieko Kamiyama, Kazuhide Higuchi
Journal: Endoscopy (2018)

Electrohydraulic lithotripsy (EHL) under endoscopic retrograde cholangiopancreatography (ERCP) guidance has been established as a treatment option for pancreatic duct stones (PDSs) [1] [2] [3]. However, a complicated pancreatic duct stricture or PDS located in the pancreatic head can cause difficulties with pancreatoscope insertion and PDS visualization, thereby rendering EHL challenging. Here, we describe technical tips for the two-step recanalization of a pancreatic duct stricture complicated by massive PDSs.
MBRS-58. VISMODEGIB NANOPARTICLE ENHANCES TUMOR TARGETING IN AN IN VIVO MEDULLOBLASTOMA MODEL
Authors: Hiroto Kiguchi, Yosef Shamay, Janki Shah, Jake Vaynshteyn, Daniel Heller, Praveen Raju
Journal: Neuro-Oncology (2018)

Medulloblastoma, the most common pediatric malignant brain tumor, is divided into at least four molecular subtypes. The Sonic Hedgehog (SHH) subtype, accounts for approximately 30% of all cases and has an intermediate prognosis (5-year overall survival of 60%). Current treatments involve surgery, adjuvant radiotherapy for older children, and chemotherapy, however, lead to devastating morbidity, including decline in cognition and intellect, endocrine deficiencies, and secondary malignancies. More recently, targeted treatment options that inhibit the Hedgehog pathway have demonstrated clinical efficacy, including the Smoothened inhibitor, Vismodegib, however result studies have also shown secondary toxicities including effects on bone development. Here we investigated the efficacy of Vismodegib packaged in a fucoidan-based nanoparticle (Fi-Vis) that targets P-selectin, a protein overexpressed on vascular endothelial cells and is induced by 2Gy ionizing radiation (XRT) in a time- and dose-dependent manner. This p-selectin targeting nanoparticle drug delivery system shows selectivity toward tumor vasculature and not normal brain vasculature in a genetically relevant SHH-driven medulloblastoma mouse model as assessed by ex vivo infrared imaging. Quantitative RT-PCR analysis on SHH medulloblastoma tumor tissue following 2Gy XRT and Fi-Vis single dose treatment (as low as 10mg/kg) showed a synergistic inhibition of Gli1 expression (up to ~90% target inhibition). Furthermore, we demonstrate that lower single fraction XRT doses as low as 1Gy also induce P-selectin expression within medulloblastoma tumor vasculature. These data suggest applicability of combined XRT and tumor vasculature-targeted nanotherapeutic dose de-escalation strategies for medulloblastoma and potentially other pediatric brain tumors.
EPID-06. ESTABLISHING A BASELINE TIME-FRAME FOR SYMPTOM ONSET TO DEFINITIVE DIAGNOSIS OF CHILDREN WITH NEWLY-DIAGNOSED CENTRAL NERVOUS SYSTEM (CNS) TUMORS: A MULTI-INSTITUTIONAL COLLABORATIVE STUDY
Authors: Scott Coven, Vanisha Patel, Joseph Stanek, David Walker, Sarah Rush, Jonathan Finlay
Journal: Neuro-Oncology (2018)

We have previously documented in a single institution study the presence of diagnostic delays in children with central nervous system (CNS) tumors. This cohort study serves to establish an accurate multi-institutional Ohio baseline from symptom onset to definitive diagnosis in children with newly-diagnosed CNS tumors. The medical records of children with newly-diagnosed CNS tumors were retrospectively reviewed from January 2004 to December 2017 at Nationwide Children’s Hospital and Akron Children’s Hospital. Records were reviewed for age, gender, tumor type, presenting symptoms, number of healthcare visits prior to diagnosis, time interval (in months) from onset of symptoms to definitive diagnosis and any associated genetic syndromes. Of the 372 patients with newly-diagnosed CNS tumors, 47 children had known pre-disposition syndromes (neurofibromatosis types 1 and 2, and tuberous sclerosis). Among the remaining 325 children, the median time interval from symptom onset to definitive diagnosis was 42 days while the mean symptom interval was 150 days (range < 1 to 5,475 days). Almost half of all documented health care visits occurred at their primary care provider or emergency department, whereas a smaller proportion of patients were seen in various multiple subspecialty settings, most commonly Neurology and Ophthalmology. This multi-institutional cohort study updates our previously documented single institution time interval and provides a consistent Ohio “benchmark” for our future planned interventions to reduce the time interval from symptom onset to diagnosis through adaptation of the UK ‘HeadSmart’ program throughout the State of Ohio and ultimately throughout the USA.