tbuckley/cabot-search huggingface dataset:
Abstract 159: Eicosapentaenoic Acid and Docosahexaenoic Acid Have Distinct Membrane Locations and Lipid Interactions as Determined by X-ray Diffraction
Authors: R. P Mason, Samuel C Sherratt
Journal: Circulation Research (2017)

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) differentially influence lipid oxidation, signal transduction, fluidity, and cholesterol domain formation, potentially due to distinct membrane interactions. We used small angle x-ray diffraction to test EPA and DHA effects on model membrane structure. Vesicles were prepared to model human peripheral cell membranes using 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine (POPC) and cholesterol (C) (0.3 C:POPC mole ratio), and treated with vehicle, EPA, or DHA (1:10 mole ratio to POPC). Membrane width ( d- space) was 59.5 Å at 10°C, decreasing to 54.7 Å at 30°C due to increased acyl chain dynamics. EPA or DHA had no effect on membrane d -space (&lt;1 Å change). Electron density profiles from diffraction data were superimposed on corresponding vehicle profiles (Fig. 1). EPA increased membrane hydrocarbon core electron density over a broad area, up to ± 20 Å from the membrane center, indicating an energetically favorable extended membrane orientation for EPA, stabilized by van der Waals interactions. By contrast, DHA increased electron density in the phospholipid head group region starting at ± 12 Å from the membrane center, due to DHA-surface interactions, resulting in a pronounced electron density reduction and increased disorder in the membrane hydrocarbon core centered ± 7-9 Å from the membrane center. DHA disordering effects were less apparent at higher temperatures, likely due to greater rotational dynamics, while EPA effects were stable. The contrasting EPA and DHA effects on membrane structure signify distinct molecular locations/orientations and may contribute to observed differences in biological activity.
Comparison of efficacy and safety between redo-endoscopic treatment and surgery for recurrent gastric neoplasms at the scar of prior endoscopic submucosal dissection
Authors: D. Kim, H. Na, J. Ahn, J. Lee, K. Jung, K. Choi, H. Song, G. Lee, H. Jung
Journal: Annals of Oncology (2018)

Introduction: The clinical outcomes of treatment options for recurrent gastric neoplasms at the scar of prior endoscopic submucosal dissection (ESD) are not well known. Hence, clinicians decide treatment options case-by-case without much evidence. The aim of this study was to compare the efficacy and safety of treatments options for recurred gastric neoplasms at prior ESD scar. Methods: From June 2010 to May 2017, we retrospectively investigated 51 patients who treated with redo-ESD, 23 patients with argon plasma coagulation (APC), and 18 patients with operation. We analyzed short-term and long-term outcomes of each treatment. Clinical outcomes between primary and redo-ESD were also compared. Results: Median intervals between prior ESD and second treatment were 10.9, 13.2, and 9.6 months for redo-ESD, APC, and operation group, respectively (p = 0.088). Hospital duration was significantly different between groups [median (interquartile range), 3 (3-4) vs. 3 (2-3) vs. 8 (7-9), p < 0.001]. Adverse events, such as pneumonia (p = 0.196), gastrointestinal bleeding (p = 0.390), and perforation (p = 1.000), were comparable between the groups. Operation group exhibited significantly higher risk for outlet obstruction (p = 0.037) and mechanical ileus (p = 0.037) than other treatment groups. There was significant difference between groups about overall recurrence rate (19.6% vs. 39.1% vs. 0%) and local recurrence rate (13.7% vs. 30.4% vs. 0%). Kaplan-Meier plot showed local recurrence free survival differences between the groups and it was significantly different between the groups after adjusting overall follow-up duration (log rank test, p = 0.026). Redo-ESD exhibited longer median procedure time (31.0 vs 22.0 min, p = 0.018) and lower en bloc resection rate (68.6% vs. 94.1%, p = 0.004) than prior ESD. Complete resection rate (80.4% vs. 70.6%) and adverse event rate [bleeding (7.8% vs. 5.9%, p = 1.000) and perforation (3.9% vs. 2.0%, p = 1.000)] were comparable between redo-ESD and prior ESD. Recurred neoplasm larger than 15 mm was associated with lower complete resection rate [odds ratio (OR) 7.81, 95% confidence interval (CI) 1.6-57.5, p = 0.018]. And neoplasms located on upper two-thirds exhibited higher local recurrence rate (OR 10.5, 95% CI 1.6-207.8, p = 0.037) with redo-ESD. Conclusion: Argon plasma coagulation exhibited much higher recurrence rate that should not be considered as a first line treatment for recurred gastric neoplasms at prior ESD scar. However, considering higher adverse event rate of outlet obstruction and mechanical ileus with operation, redo-ESD could be an alternative to operation for selected patients.
TBIO-22. A NOVEL PEDIATRIC IDH1 MUTANT GLIOBLASTOMA CELL LINE AND XENOGRAFT MODEL
Authors: Dennis Metselaar, Michaël Meel, Piotr Waranecki, Kenn Zwaan, Pino Poddighe, Dannis van Vuurden, Gertjan Kaspers, Esther Hulleman
Journal: Neuro-Oncology (2018)

The isocitrate dehydrogenase-1 (IDH1) mutation serves as a hallmark for secondary high-grade gliomas, occurring in over 75% of all secondary glioblastomas (GBM) in adults. IDH1 mutations in pediatric high-grade gliomas are much rarer, and its role is still largely unknown. The lack of biologically representative in vitro and in vivo IDH1 mutant models makes it a difficult to study malignancy. Here we describe the establishment of a pediatric endogenous IDH1 mutant GBM primary cell line (VUMC-HGG-09) derived from an 11 year old female patient. We effectively cultured the VUMC-HGG-09 cells both as neurospheres in a serum-free environment, and as an adherent monolayer in serum enriched medium. VUMC-HGG-09 cells were orthotopically injected into brains of athymic nude mice, which caused successful engraftment and aggressively growing tumors in all the animals. Hematoxylin and vimentin staining showed a diffuse GBM like growth pattern through the whole brain. Furthermore, presence of the human R132H IDH1 mutation was confirmed by immunohistochemistry of the resected mouse brains. Shallow sequencing, whole chromosome painting FISH, and SNP-array were used to map chromosomal aberrations. These data revealed a rarely found chromothripsis like pattern within chromosome 7 and several minor deletions and translocations among other chromosomes. The VUMC-HGG-09 is a unique model that to our knowledge represents the first in vitro and in vivo pediatric IDH1 mutant glioma model. Therefore, VUMC-HGG-09 could serve both as a pediatric GBM cell culture model, as well as a novel in vitro and in vivo model to study the mechanistics of IDH1 mutant tumors.
Noninvasive Assay for Donor Fraction of Cell-Free DNA in Pediatric Heart Transplant Recipients
Authors: William S. Ragalie, Karl Stamm, Donna Mahnke, Huan Ling Liang, Pippa Simpson, Ronit Katz, Aoy Tomita-Mitchell, Steven J. Kindel, Steven Zangwill, Michael E. Mitchell
Journal: Journal of the American College of Cardiology (2018)
HGCSG1401: A retrospective cohort study evaluating the safety and efficacy of regorafenib in patients with metastatic colorectal cancer: Analysis of risk factors for liver dysfunction
Authors: A. Ishiguro, S. Yuki, S. Nakano, Y. Kawamoto, K. Sawada, Y. Tsuji, T. Honda, T. Miyagishima, S. Yoshida, K. Hatanaka, T. Sasaki, O. Muto, H. Ohnuma, S. Kato, A. Sato, M. Abe, K. Kato, T. Amano, Y. Sakata, Y. Komatsu
Journal: Annals of Oncology (2018)
GERM-26. LONG-TERM HEALTH-RELATED QUALITY OF LIFE IN ADULT SURVIVORS OF PEDIATRIC INTRACRANIAL GERM CELL TUMOR
Authors: Andrea Lo, Normand Laperriere, David Hodgson, Karen Goddard
Journal: Neuro-Oncology (2018)

To investigate health-related quality of life (HRQOL) in survivors of intracranial germ cell tumors (IGCT). Survivors of IGCT were invited to complete the 36-Item Short Form Survey Instrument (SF-36). The SF-36 is scored from 0-100, with a higher number representing a more favorable HRQOL. The study cohort consisted of 12 survivors of IGCT, 6 males and 6 females. Median age was 13 years at diagnosis, and 26 years at time of study. Median follow-up was 11 years. Five patients had germinomas, and 7 had non-germinomatous germ cell tumors. All 12 patients received radiation therapy (RT), 10 to the craniospinal axis, 1 to the whole ventricles and 1 to the tumor bed alone. Nine patients received chemotherapy. Mean SF-36 scores were 67.9 (standard deviation [SD] 33.2) for physical functioning, 58.3 (SD 37.4) for role limitations due to physical health, 77.8 (SD 32.8) for role limitations due to emotional problems, 43.1 (SD 18.4) for vitality, 74.3 (SD 15.3) for mental health; 62.5 (SD 32.0) for social functioning, 74.2 (SD 33.4) for pain, and 57.1 (SD 24.0) for general health; mean scores were ≥1 SD lower than that of Canadian normative data for vitality, social functioning and general health. Physical component score was 43.6 (SD 13.9) and mental component score was 47.6 (SD 11.2), normalized to a US population with mean of 50 and SD of 10. Long-term HRQOL for survivors of IGCT is lower than that of the overall population, particularly in vitality, social functioning and general health.
Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations
Authors: Adam G. Sowalsky, Huihui Ye, Manoj Bhasin, Eliezer M. Van Allen, Massimo Loda, Rosina T. Lis, Laleh Montaser-Kouhsari, Carla Calagua, Fen Ma, Joshua W. Russo, Rachel J. Schaefer, Olga S. Voznesensky, Zhenwei Zhang, Glenn J. Bubley, Bruce Montgomery, Elahe A. Mostaghel, Peter S. Nelson, Mary-Ellen Taplin, Steven P. Balk
Journal: Cancer Research (2018)

Primary prostate cancer can have extensive microheterogeneity, but its contribution to the later emergence of metastatic castration-resistant prostate cancer (mCRPC) remains unclear. In this study, we microdissected residual prostate cancer foci in radical prostatectomies from 18 men treated with neoadjuvant-intensive androgen deprivation therapy (leuprolide, abiraterone acetate, and prednisone) and analyzed them for resistance mechanisms. Transcriptome profiling showed reduced but persistent androgen receptor (AR) activity in residual tumors, with no increase in neuroendocrine differentiation. Proliferation correlated negatively with AR activity but positively with decreased RB1 expression, and whole-exome sequencing (WES) further showed enrichment for RB1 genomic loss. In 15 cases where 2 or 3 tumor foci were microdissected, WES confirmed a common clonal origin but identified multiple oncogenic alterations unique to each focus. These findings show that subclones with oncogenic alterations found in mCRPC are present in primary prostate cancer and are selected for by neoadjuvant-intense androgen deprivation therapy. In particular, this study indicates that subclonal RB1 loss may be more common than previously appreciated in intermediate- to high-risk primary prostate cancer and may be an early event, independent of neuroendocrine differentiation, in the development of mCRPC. Comprehensive molecular analyses of primary prostate cancer may detect aggressive subclones and possibly inform adjuvant strategies to prevent recurrence.
Chimeric antigen receptor T (CAR T) cells: another cancer therapy with potential applications in kidney disease and transplantation?
Authors: A. Richard Kitching, Juli Jaw
Journal: Kidney International (2018)

The grand challenge in better treating immune conditions in nephrology, including transplantation and autoimmune kidney diseases, is to establish or re-establish tolerance. Such an outcome would cure the condition and obviate the need for ongoing immunosuppression. In addition, tolerogenic regimens might be both more specific and associated with fewer short- and long-term side effects, which are a major cause of morbidity and mortality in these conditions. In the past, the field of immunology has adapted treatment approaches from oncology, from cyclophosphamide in the 1960s to rituximab in the 2000s.
CRAN-18. CASE SERIES OF INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMOR: A SINGLE INSTITUTION EXPERIENCE
Authors: Nidhi Shah, Andrew Walter
Journal: Neuro-Oncology (2018)

Intracranial non-germinomatous germ cell tumors are a rare, heterogenous group of neoplasms, commonly occurring in the pineal and/or suprasellar regions. The subtypes include yolk sac tumor (YST) or endodermal sinus tumor (EST), embryonal carcinoma (EC), choriocarcinoma (CHC), and mixed malignant subtypes. Diagnosis is usually made without a biopsy, through detection of elevated levels of Alpha-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (βHCG) in the serum and/or cerebrospinal fluid. Three patients with intracranial NGGCT were treated at our institution, using a combination of surgery, chemotherapy, and/or radiation therapy. The clinical presentation of all cases included signs and symptoms of obstructive hydrocephalus. Patient #1 was diagnosed with malignant teratoma at birth via neuroimaging; she died from complications due to surgical resection. Patient #2 was diagnosed with choriocarcinoma of the pituitary gland at age 5 years via elevated AFP in serum and CSF; he was treated with alternating cycles of carboplatin/etoposide and ifosfamide/etoposide, followed by whole ventricle radiation therapy. He is now 28 months off-therapy, without evidence of disease. Patient #3 was diagnosed with choriocarcinoma of the pineal and suprasellar regions at the age 7 years, via elevated beta-HCG in serum and CSF, with evidence of bimodal disease. Treatment included 6 cycles of risk-adapted chemotherapy followed by whole ventricle radiation therapy. Neuroimaging continues to show no evidence of disease with normalization of tumor markers, at 24 months off-therapy. Patients #2 and #3 have residual neuroendocrine and neuropsychological deficits, but remain neurodevelopmentally appropriate. Combination of chemotherapy and radiation therapy is required for optimal prognosis.
DEV-16. TREATMENT OF CENTRAL NERVOUS SYSTEM ATYPICAL TERATOID/RHABDOID TUMOR WITH VDC/ICE PROTOCOL, SURGERY AND CRANIOSPINAL IRRADIATION
Authors: Piti Techavichit, Shanop Shuangshote, Kanhatai Chiangthong, Darintr Sosothikul, Panya Seksarn
Journal: Neuro-Oncology (2018)

Central Nervous System Atypical Teratoid/Rhabdoid Tumor (ATRT) is rare and aggressive tumor. Standard treatment for ATRT is not well established. To study characteristics and outcomes of ATRA patients treated with non-CNS malignant rhabdoid tumors (MRT) chemotherapy protocol, surgery and cranio-spinal irradiation (CSI). A retrospective review in patients diagnosed with ATRT at our department from 2007 to 2017. Eight patients were diagnosed with pathological confirmed ATRT (7 males and 1 females). Age ranged from 5 to 136 months (median 23 months). Tumors were infra-tentorial in six patients and spinal metastasis in two patients. Presenting symptoms were consisted of increase ICP in all patients with hemiparesis in three. Total tumor removal was performed in four, partial removal in three and biopsy in one patients. Adjuvant chemotherapy consist of ifosfamide, carboplatin and etoposide alternate with vincristine, doxorubicin and cyclophosphamide, total of eight cycles, was given in seven patients. Craniospinal radiation (CSI) was given in five patients with 54 and 36 Gy at tumor bed and spine respectively. With the median follow up of 28 months, overall survival is 37.5%. All survive patients underwent upfront total tumor removal and received CSI immediately after chemotherapy completion with no spinal metastasis. Five patients died of disease with median survival time of 12 months. One patient, age five months, died one month after diagnosis with no further treatment. Treatment outcome of ATRT is unfavorable with intensive adjuvant chemotherapy protocol. The major prognostic factors for survival is respectability, metastatic disease and CSI.
Predictive factor for early recurrence of resected hepatocellular carcinoma
Authors: T. Kato, H. Noda, A. Yoshizawa, N. Kasahara, F. Watanabe, Y. Endo, Y. Kaneda, T. Rikiyama
Journal: Annals of Oncology (2018)

Introduction: Recurrence rate of hepatocellular carcinoma (HCC) after surgical resection is over 10% per year, and it reaches 70-80% after 5 years. Early recurrence after hepatectomy occurs in some patients, but its risk factors have not been clarified yet. We carried out to clarify the risk factors of early recurrence after hepatectomy for HCC. Methods: We reviewed 107 patients with surgically resected HCC in Saitama Medical Center, Jichi Medical University between January 2008 and February 2018. Two patients who did not underwent enhanced computed tomography (CT) before surgery, 12 patients who developed multiple synchronous HCC, 4 patients who took warfarin, 4 patients who died of other diseases, and 5 patients whose postoperative follow-up was less than 12 months were excluded from this study. We reviewed these 80 patients and compared between 17 patients who developed tumor recurrence within a year after hepatectomy named early recurrence (ER) group, and other 63 patients named non-ER group. Retrospectively, we calculated the tumor volume (TV) by 3DCT and greatest tumor dimension (GTD) on enhanced abdominal CT. Then, we calculated the ratio between preoperative serum AFP and TV (AFP/TV), and GTD (AFP/GTD), and the ratio between preoperative PIVKA-II and TV (PIVKA-II/TV), and GTD (PIVKA-II/GTD). We compared these two groups about the clinicopathological characteristics, including AFP/TV, PIVKA-II/TV, AFP/GTD and PIVKA-II/GTD to investigate the risk factors of ER of HCC after hepatectomy. Results: Among these 80 cases, 36 patients developed tumor recurrence. Of all, 17 patients developed tumor recurrence within a year. In multivariate analysis, large GTD (Odds ratio OR1.59 (1.09-2.32) P = 0.0162) and high values of PIVKA-II/TV (OR 1.01 (1.0-1.01) p = 0.0037) are associated with high risk of developing tumor recurrence within a year after hepatectomy. Conclusion: Large GTD and High PIVKA-II/TV might be a significant new predictive factor for early recurrence after hepatectomy for HCC. We have to do closer follow-up for patients who had large GTD or high PIVKA-II/TV after hepatectomy.
MBRS-14. REGULATION OF MEDULLOBLASTOMA IMMUNOGENICITY BY TP53 AND TNF ALPHA
Authors: Alexandra Garancher, Hiromichi Suzuki, Vijay Ramaswamy, Michael D Taylor, Robert J Wechsler-Reya
Journal: Neuro-Oncology (2018)

Many immunotherapies act by enhancing the ability of T cells to kill tumor cells. But T cell killing depends on recognition of antigens presented by Class I MHC (MHC-I) on the tumor cell surface; if a tumor lacks MHC-I, it cannot be recognized by T cells. To study the efficacy of immunotherapy for Group 3 medulloblastoma, we have used mouse models driven by overexpression of Myc and dominant negative p53 (“MP tumors”), or by overexpression of Myc and Gfi1 (“MG tumors”). While both tumors grow in immunodeficient mice, only MP tumors grow in immunocompetent mice. To understand this difference, we analyzed expression of immunoregulatory molecules, and found that MP tumors completely lack surface MHC-I. Mechanistically, this is because two key proteins required for MHC-I trafficking - TAP1 and ERAP1 - are targets of p53; since MP tumors lack functional p53, they also lack TAP1 and ERAP1, and surface MHC-I. These studies suggest that p53 plays a critical role in determining immunogenicity, and that p53-mutant tumors are resistant to immune attack. To overcome this resistance, we treated tumor cells with agents that regulate MHC-1. We found that low doses of tumor necrosis factor alpha (TNF alpha) can rescue expression of ERAP, TAP and MHC-I on MP tumor cells. In vivo, TNF alpha prolongs survival of tumor-bearing mice, and markedly augments the efficacy of immune checkpoint inhibitors. These results raise the possibility that TNF alpha could be used prior to immunotherapy to render tumors more sensitive to T cell attack.
Phase III randomized study of the proposed adalimumab biosimilar GP2017 in psoriasis: impact of multiple switches
Authors: A. Blauvelt, J.-P. Lacour, J.F. Fowler, J.M. Weinberg, D. Gospodinov, E. Schuck, J. Jauch-Lembach, A. Balfour, C.L. Leonardi
Journal: British Journal of Dermatology (2018)

Adalimumab is used to treat several inflammatory diseases, including plaque psoriasis. GP2017 is a proposed adalimumab biosimilar.To assess the impact of multiple switches between GP2017 and reference adalimumab (ref-ADMB) following the demonstration of equivalent efficacy and similar safety and immunogenicity, in adult patients with active, clinically stable, moderate-to-severe plaque psoriasis.This 51-week double-blinded, phase III study randomly assigned patients to GP2017 (n = 231) or ref-ADMB (n = 234) 80 mg subcutaneously at week 0, then 40 mg biweekly from week 1. At week 17, patients were rerandomized to switch (n = 126) or continue (n = 253) treatment. The primary end point was patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with equivalence confirmed if the 95% confidence interval (CI) for the difference in PASI 75 between treatments was ± 18%. The key secondary end point was the change from baseline to week 16 in continuous PASI. Other end points were PASI over time; PASI 50, 75, 90 and100; pharmacokinetics; safety; tolerability and immunogenicity for the switched and continued treatment groups.Equivalent efficacy between GP2017 and ref-ADMB was confirmed for the primary (66·8% and 65·0%, respectively; 95% CI -7·46 to 11·15) and key secondary end points (-60·7% and -61·5%, respectively; 95% CI -3·15 to 4·84). PASI improved over time and was similar between treatment groups at week 16, and the switched and continued groups from weeks 17 to 51. There were no relevant safety or immunogenicity differences between GP2017 and ref-ADMB at week 16, or the switched and continued groups from weeks 17 to 51. No hypersensitivity to adalimumab was reported upon switching.Following the demonstration of GP2017 biosimilarity to ref-ADMB, switching up to four times between GP2017 and ref-ADMB had no detectable impact on efficacy, safety or immunogenicity.
LGG-08. PILOCYTIC ASTROCYTOMAS, EXHIBIT DIFFERENTIAL AGE-BASED PATTERNS OF BRAFV600E AND BRAF GENE FUSIONS ACROSS DIFFERENT LOCATIONS
Authors: Mukesh Barange, Mamta Gurav, Hetakshi Kurani, Omshree Shetty, Prakash Shetty, Aliasgar Moiyadi, Ayushi Sahay, Jayant Sastri Goda, Rahul Krishnatry, Girish Chinaswamy, Tejpal Gupta, Rakesh Jalali, Sridhar Epari
Journal: Neuro-Oncology (2018)

Pilocytic astrocytomas (PCA) are characterised by BRAF fusions and V600E mutation. MATERIAL and FFPE tissues of PCA diagnosed during 2011-17 were evaluated for BRAFV600E mutation by Sanger sequencing and KIAA1549:BRAF fusion transcripts (KIAA1549:BRAF 16-9, KIAA1549:BRAF 15-9 and KIAA1549:BRAF 16-11) by reverse transcriptase polymerase chain reaction. 272 cases of PCA of age range 1-46 years (≤14 years:176; 15-25 yrs:76, 26-39yrs:19 and >39yrs:1) formed the sample. BRAFV600E and fusions were mutually exclusive. 25 of 234 (10.7%) were BRAFV600E mutated [cerebellum: 9/90(10%), suprasellar: 5/30(17%), CH: 4/27(15%), brain stem: 2/14(14%) and thalamic: 2/13(15%) 4th ventricle: 1/10 (10%) and 3rd ventricle: 2/7 (28.6%). Whereas 75 of 224 (33.5%) were BRAF fusion [KIAA1549-BRAF 16-9 (n: 52), 15-9 (n:15) & 16-11 (n:8)] positive. 40% of cerebellar (36/91), 37% of suprasellar (10/27), 43% of brain stem (6/14), 36% of spinal (5/14), 21% of CH (5/24), 21% of ON (4/19), 27% of thalamic (3/11), 55.6% of 4th ventricle (5/9) and 50% of pineal (1/2) were fusion positive. None of the 19 ON cases showed BRAFV600E. It was also not detected in <3 yrs and >25 yrs age; but was seen in 15.4% (10/65) of cases in 15-25yrs. BRAF fusions were more common in ≤14 yrs (57/145; 39%). Interestingly, none of cases >30 years showed BRAF alterations. Two cases were associated with NF-1 both were negative for BRAF alterations. BRAF fusions are common than BRAFV600E in PCA across all locations and interestingly both are extremely rare >30years.