tbuckley/cabot-search huggingface dataset:
QOL-33. FERTILITY PRESERVATION IN GIRLS WITH BRAIN TUMORS: A SINGLE CENTER EXPERIENCE
Authors: Rina Dvir, Foad Azem, Michal Manistersky, Ilana Berkley, Ronit Elhasid
Journal: Neuro-Oncology (2018)

Premature ovarian dysfunction is increasingly documented in survivors of brain tumors particularly in girls who received high doses of radiotherapy and alkylating agents. Fertility preservation in girls is an important procedure which should be offered to patients with increased risk of gonadal failure. Risk groups for ovarian dysfunction have been previously documented (i.e. Edinburgh criteria). Our center provides a fertility counsel for all girls with pediatric cancer, and patients at increased risk are offered ovarian cryopreservation. PATIENTS AND A retrospective analysis of girls treated with brain tumors between 2010-2016 was performed. We documented age, disease type, treatment protocols, preservation treatment details, treatment delay and complications. 41 girls with brain tumors were assessed. Eight underwent laparoscopic ovarian cryopreservation (6 medulloblastoma, 2 pineal tumors, age range 8-18 years, median 10.4 years). Five had insertion of portacath in the same operative session. Two girls had a prior V-P shunt. Fertility preservation was not performed in: 11 girls with high grade glioma, 4 metastatic tumors, 7 low grade glioma, 4 craniopharyngioma, 3 younger than 3 years and parental refusal in 4. Cryopreservation caused no complications or delays in treatment. Ovarian cryopreservation is recommended when there is a high risk of gonadal failure from oncologic treatment. Fertility counseling by a specialized clinic provides individualized recommendations. Ovarian cryopreservation can be safely performed in selected cases without complications even concurrently with central line insertion, or after V-P shunting. Current knowledge regarding future uses of cryopreserved tissue shall be discussed.
Quality improvement in the management of rectal cancer in a large healthcare system in the United States
Authors: W. Sause
Journal: Annals of Oncology (2018)

Introduction: Intermountain Healthcare is a twenty-three hospital care delivery system located in the State of Utah. The system represents large referral hospitals and smaller community facilities. Approximately sixty percent of patients who reside in the State of Utah receive their care at an Intermountain facility. Intermountain Healthcare has a long history of quality improvement. In order to facilitate quality improvement Intermountain has developed clinical programs for a variety of disciplines. Oncology represents a focused area of interest. These clinical programs have dedicated infrastructure and leadership in place to evaluate care and initiate improvement in a variety of disease sites. Methods: Colorectal cancers represents one of the more common malignancies in the system. System initiatives to eliminate variations in care delivery for colorectal cancer have been continuous for 15 years. Most recently we analyzed care for primary rectal cancer. The analysis substantiated variation in care delivery and variation from standard of care across the system. From 2012 to 2015 224 cases of rectal cancer had primary surgery in the system. Forty patients received care which would be outside the standard of care either by omission of preoperative staging or treatment. Eight of the forty were deemed to be emergent by the provider and received emergent surgical resection. Analysis of outcomes revealed improved local control in those patients deemed appropriate. Results: Analysis of baseline data suggested variation in care delivery. The goal of our quality improvement initiative is to change behavior and improve care. In order to address these treatment inadequacies we initiated a statewide improvement process. This included a continual timely monitoring process. Individual provider score cards comparing their results to their peers. Infrastructure improvement relating to tumor conference presentation and timely pathology review. The resulting behavioral change and outcomes will be presented. Conclusion: Same as above.
Perioperative treatment of gastric cancer: FLOT or not
Authors: F. Djuraev, A. Abdujapparov, N. Atakhanova
Journal: Annals of Oncology (2018)

Introduction: Gastric cancer is one of the most common cases among oncological diseases especially in developing countries of Asia. The same picture nowadays can be observed in Uzbekistan. Despite of breakthrough developments in chemotherapy, gastric cancer is still one of the most leading causes of cancer deaths. Up to day accepted standard of perioperative treatment of patients with operable gastric cancer includes ECF, however survival is still very poor. The aim of this study was to compare docetaxel based triplet FLOT with anthracycline based triplet ECF. Methods: The study enrolled 294 patients with gastric cancer treated in department of Oncology of Tashkent Medical Academy between 2011-2013yy. Eligibility criteria consisted of : stage ≥cT2 and/or cN+ M0, no distant metastatic lesion, absence of severe comorbidities (renal failure, liver failure etc.), no previous chemotherapy. Patients were randomized into 2 arms: 1st arm - 197 patients who received 3 cycles of preoperative and 3 cycles of ECF after radical gastrectomy D2 (cycles repeated every 3 weeks). 2nd arm - 97 patients received 4 preoperative cycles and after surgery 4 postoperative cycles of FLOT regimen (cycle every 2 weeks). Baseline characteristics across 2 arms were similar with respect to age – median age constituted 61; cT3/T4 - 86%, cN+ 83%, disease stage and histological type of cancer. Results: Planned pre- and postoperative cycles in 1st group of ECF were completed in 85,7% and 30,9% correspondingly. However the same indexes in 2nd arm constituted: preoperative 4 cycles were completed in 88,6% and postoperative in 46,3% of cases. Median follow up was 44 months.156 patients died, of them 113 (57,3%) patients form ECF arm, and 43 (44,3%) from FLOT arm. FLOT also improved OS rate 32 months with ECF and 48 months with FLOT (HR 0,72 [CI 0,57-0,89]; p=0.010). 3 year overall survival rate was 43% with ECF and 56% with FLOT. In addition to that FLOT also improved PFS: median PFS made up with ECF 16 months versus 28 months with FLOT, HR 0.72 [0.59 - 0.88]; p = 0.004). However complications rate was slightly higher in group of patients who received FLOT especially diarrhea 2-3 grade, nevertheless these complications were did not impact on the course of chemotherapy and were immediately eliminated. Conclusion: Nevertheless of breakthroughs in targeted and immune therapy, the issue of preoperative and postoperative chemotherapy of gastric cancer is still very important in developing countries, as the choices of immune therapy are very limited due to high financial toxicity in these states. FLOT showed improved outcomes in patients with resectable tumors of stomach in comparison with ECF. The promising results of FLOT let us step forward in fighting gastric cancer.
Reward Processing in Depression: A Conceptual and Meta-Analytic Review Across fMRI and EEG Studies
Authors: Hanna Keren, Georgia O’Callaghan, Pablo Vidal-Ribas, George A. Buzzell, Melissa A. Brotman, Ellen Leibenluft, Pedro M. Pan, Liana Meffert, Ariela Kaiser, Selina Wolke, Daniel S. Pine, Argyris Stringaris
Journal: American Journal of Psychiatry (2018)

A role for aberrant reward processing in the pathogenesis of depression has long been proposed. However, no review has yet examined its role in depression by integrating conceptual and quantitative findings across functional MRI (fMRI) and EEG methodologies. The authors quantified these effects, with an emphasis on development.A total of 38 fMRI and 12 EEG studies were entered into fMRI and EEG meta-analyses. fMRI studies primarily examined reward anticipation and reward feedback. These were analyzed using the activation likelihood estimation method. EEG studies involved mainly the feedback-related negativity (FRN) event-related potential, and these studies were analyzed using random-effects meta-analysis of the association between FRN and depression.Analysis of fMRI studies revealed significantly reduced striatal activation in depressed compared with healthy individuals during reward feedback. When region-of-interest analyses were included, reduced activation was also observed in reward anticipation, an effect that was stronger in individuals under age 18. FRN was also significantly reduced in depression, with pronounced effects in individuals under age 18. In longitudinal studies, reduced striatal activation in fMRI and blunted FRN in EEG were found to precede the onset of depression in adolescents.Taken together, the findings show consistent neural aberrations during reward processing in depression, namely, reduced striatal signal during feedback and blunted FRN. These aberrations may underlie the pathogenesis of depression and have important implications for development of new treatments.
Inhibition of WEE1 kinase and cell cycle checkpoint activation sensitizes head and neck cancers to natural killer cell therapies
Authors: Jay Friedman, Megan Morisada, Lillian Sun, Ellen C. Moore, Michelle Padget, James W. Hodge, Jeffrey Schlom, Sofia R. Gameiro, Clint T. Allen
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Natural killer (NK) cells recognize and lyse target tumor cells in an MHC-unrestricted fashion and complement antigen- and MHC-restricted killing by T-lymphocytes. NK cells and T-lymphocytes mediate early killing of targets through a common granzyme B-dependent mechanism. Tumor cell resistance to granzyme B and how this alters NK cell killing is not clearly defined. <h3>Methods</h3> Tumor cell sensitivity to cultured murine KIL and human high affinity NK (haNK) cells in the presence or absence of AZD1775, a small molecule inhibitor of WEE1 kinase, was assessed via real time impedance analysis. Mechanisms of enhanced sensitivity to NK lysis were determined and in vivo validation via adoptive transfer of KIL cells into syngeneic mice was performed. <h3>Results</h3> Cultured murine KIL cells lyse murine oral cancer 2 (MOC2) cell targets more efficiently than freshly isolated peripheral murine NK cells. MOC2 sensitivity to granzyme B-dependent KIL cell lysis was enhanced by inhibition of WEE1 kinase, reversing G2/M cell cycle checkpoint activation and resulting in enhanced DNA damage and apoptosis. Treatment of MOC2 tumor-bearing wild-type C57BL/6 mice with AZD1775 and adoptively transferred KIL cells resulted in enhanced tumor growth control and survival over controls or either treatment alone. Validating these findings in human models, WEE1 kinase inhibition sensitized two human head and neck cancer cell lines to direct lysis by haNK cells. Further, WEE1 kinase inhibition sensitized these cell lines to antibody-dependent cell-mediated cytotoxicity when combined with the anti-PD-L1 IgG1 mAb Avelumab. <h3>Conclusions</h3> Tumor cell resistance to granzyme B-induced cell death can be reversed through inhibition of WEE1 kinase as AZD1775 sensitized both murine and human head and neck cancer cells to NK lysis. These data provide the pre-clinical rationale for the combination of small molecules that reverse cell cycle checkpoint activation and NK cellular therapies.
LGG-52. DUAL INHIBITION OF mTORC1/C2 AND MEK PATHWAY IS SYNERGISTIC IN MULTIPLE HUMAN MODELS OF PEDIATRIC LOW-GRADE GLIOMA INCLUDING A NOVEL PATIENT-DERIVED NF1 PILOCYTIC ASTROCYTOMA CELL LINE
Authors: Antje Arnold, Ming Yuan, Fausto Rodriguez, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2018)

Pediatric low-grade glioma (PLGG) is the most common brain tumor of childhood. We and others have identified mTORC and MEK-activation in PLGG. The dual mTORC1/2-inhibitor, TAK228, and the FDA approved MEK-inhibitor, trametinib, are promising candidates for targeted PLGG therapy. We treated five different patient-derived PLGG cell models with TAK228 and/or trametinib: JHH_NF1_PA1 (NF1 mutation), BT66_SV40/hTERT (BRAF:KIAA1549 fusion), BT40 (BRAFV600E) Res186 (PTEN deletion) and Res259 (PDGFRα amplification and CDKN2A deletion). In vitro, treatment with TAK228 or trametinib reduces cell proliferation in a dose and time depended manner investigated via MTS-assay. Both drugs exert a synergistic effect at 5-20nM in JHH_NF1_PA1, Res186, and Res259 cells. BT66_SV40/hTERT cells have a 70% reduction in cell growth with 10nM TAK228 (p<0.001 by ANOVA) but not in combination with trametinib. In all cell lines trametinib treatment leads to a pERK inactivation at low nM levels. TAK228 treatment leads to an inactivation of mTORC1 and mTORC2. Apoptosis induction was verified through cleaved PARP via western blot and CC-3 via immunocytochemistry. The combination of TAK228 and trametinib increased apoptosis by up to 127% (p<0.001) in Res186, Res259, and JHH_NF1_PA1 cells. In vivo, BT40 tumor cells were investigated with both agents in immunodeficient mice. In combination TAK228 and trametinib decreased significantly BT40 PLGG xenograft tumor growth compared to vehicle or either agent alone, (p<0.01 by ANOVA). Our results show that PLGG-derived cell lines are sensitive to TAK228 and trametinib treatment. The ongoing in vivo experimentation will provide a pre-clinical rationale for combination therapy of these agents in aggressive PLGG.
CanStem111P trial: A Phase 3 Study of napabucasin (NAPA) plus nab-paclitaxel (nPTX) with gemcitabine (Gem) in adult patients with metastatic pancreatic adenocarcinoma (mPDAC) - Trial in progress
Authors: T. Bekaii-Saab, T. Okusaka, D. Goldstein, B. O’Neill, J. Tabernero, C. Li, M. Reni, B. Jin, C. Oh, L. Borodyansky, E. Van Cutsem
Journal: Annals of Oncology (2018)

Introduction: NAPA is an oral investigational agent, which has been hypothesized to inhibit cancer stemness pathways, including STAT3 pathway implicated in cancer stem-cell viability. Preclinical studies suggest that NAPA may sensitize heterogeneous cancer cells to chemotherapeutic agents, including nPTX and Gem. Encouraging anticancer activity in mPDAC was observed in a phase 1b study (NCT02231723) of 59 patients (pts), reporting 92% (46/50) disease control rate (DCR) and 56% (28/50) overall response rate (ORR), with 2 complete and 26 partial responses in pts who had a RECIST evaluation. Maturing median progression-free survival (mPFS) and median overall survival (mOS) were 7.06 and 9.59 mo, respectively. On the basis of these data, a phase 3 trial is being conducted in North America, Europe, Australia and Asia. Methods: This randomized, open-label, multicenter study (NCT02993731) will assess the efficacy of NAPA + nPTX + Gem vs nPTX + Gem in pts with mPDAC (n = 1132). Pts must not have received systemic treatment for mPDAC. Pts will be randomized in a 1:1 ratio to receive NAPA 240mg PO twice daily continuously plus IV nPTX 125mg/m 2 + Gem 1000mg/m 2 weekly for 3 of every 4 weeks or nPTX + Gem weekly for 3 of every 4 weeks. Pts will be stratified by geography, Eastern Cooperative Oncology Group performance status, and presence of liver metastases. Treatment will continue until disease progression or another discontinuation criterion. The primary endpoint is OS in the general study population (HR 0.80 for OS improvement from 8.5 to 10.63 months); secondary endpoints include ORR, DCR, and PFS. In addition, OS, PFS, ORR, and DCR will be evaluated in the biomarker positive sub-population. Study enrollment is ongoing with >30% of patients enrolled to date.
LGG-05. OPTIC PATHWAY GLIOMA VOLUME PREDICTS VISUAL ACUITY LOSS AND AXONAL LOSS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1
Authors: Robert Avery, Awais Mansoor, Grant Liu, Carmelina Trimboli-Heidler, Gui-Shuang Ying, Nadine Eltoukhy, Roger Packer, Michael Fisher, Marius Linguraru
Journal: Neuro-Oncology (2018)
PFI: Treasury must spell out how schemes benefit public purse, says MPs’ report
Authors: Jonathan Owen
Journal: BMJ (2018)

Private finance initiative (PFI) schemes that are used to fund the building of hospitals and other infrastructure are not in the taxpayer’s interest, and the Treasury is unable to show that they provide value for money, a committee of MPs has said.

The House of Commons Public Accounts Committee said in its report,1 “It is unacceptable that after more than 25 years the Treasury still has no data on benefits to show whether the PFI model provides value for money.”

PFI is a way of getting infrastructure built by getting commercial companies to pay the costs up front. It results in repayments and associated charges for things such as maintenance, in contracts that typically run for decades and have proved to be an increasing burden on the NHS. …
Drug Delivery: A Magnetically Responsive Biomaterial System for Flexibly Regulating the Duration between Pro‐ and Anti‐Inflammatory Cytokine Deliveries (Adv. Healthcare Mater. 12/2018)
Authors: Anita E. Tolouei, Nihan Dülger, Rosa Ghatee, Stephen Kennedy
Journal: Advanced Healthcare Materials (2018)

In article 1800227, Stephen Kennedy and co-workers develop a two-compartment system, an en face SEM image of which is shown. The top of the iron-oxide-laden, magnetically compressible region can be seen as a relatively flat surface on the bottom right portion of the image. The highly porous outer region that is designed to recruit macrophages can be seen surrounding the iron-oxide-laden region. Image credit, James C. Weaver.
EPEN-05. CXorf67 EXPRESSION IS A PUTATIVE DRIVER OF PFA EPENDYMOMA
Authors: Jens-Martin Hübner, Konstantin Okonechnikov, Ji Wen, Wilda Orisme, Bo Tang, Sujuan Jia, Ruth Tatevossian, Jinghui Zhang, Stefan M Pfister, Kristian W Pajtler, David W Ellison, Marcel Kool
Journal: Neuro-Oncology (2018)

Ependymal tumors are brain neoplasms arising throughout all compartments of the central nervous system, with 10-year overall survival rates as low as 60% for pediatric patients. Molecular classification has identified nine molecular groups of ependymal tumors. Among those, the PFA group is associated with an especially dismal outcome and a clear driver for these tumors is yet to be identified. Strikingly, PFA tumors lack the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark but, in contrast to pediatric high-grade gliomas, only a small fraction (~4%) of tumors harbor H3K27M mutations suggesting a different mechanism responsible for histone hypomethylation. Our studies have recently identified aberrant expression and mutations of CXorf67 as a hallmark of PFA ependymoma. Intriguingly, Co-Immunoprecipitation (Co-IP) experiments using a PFA cell line have shown an interaction of CXorf67 with EZH2 and SUZ12. Both of these proteins are core components of the polycomb repressive complex 2 (PRC2) that catalyzes trimethylation of H3K27. Further, knockdown experiments have shown that expression of CXorf67 inversely correlates with H3K27me3 levels strongly indicating a crucial role of CXorf67 in mediating PRC2 activity. Based on our results, we are proposing a model in which expression of CXorf67 leads to histone hypomethylation followed by a derepression of oncogenes which ultimately leads to tumor formation. To test this hypothesis, we performed ChIP-seq analyses for histone marks, EZH2, and CXorf67 in PFA ependymoma and other molecular groups and functional experiments in PFA cell lines to see how CXorf67 may regulate histone hypomethylation and tumorigenesis of PFA ependymoma.
EPEN-28. HETEROGENEITY WITHIN THE PFB EPENDYMOMA SUBGROUP
Authors: Florence Cavalli, Jens-Martin Hübner, Tanvi Sharma, Martin Sill, Betty Luu, Michal Zapotocky, Andrey Korshunov, Stefan Pfister, Kristian Pajtler, Michael Taylor, Kenneth Aldape, Marcel Kool, Vijay Ramaswamy
Journal: Neuro-Oncology (2018)

Posterior fossa ependymoma comprise two distinct molecular groups, termed EPN_PFA and EPN_PFB. Clinically they are very disparate and EPN_PFB are currently being explored for de-escalation of therapy. However, to move forward, a risk stratification within EPN_PFB would be highly desirable. To discern the molecular heterogeneity within EPN_PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy number profiling and clinical correlation across a cohort of 217 primary EPN_PFB. DNA methylation data were analyzed using various methods including spectral clustering, unsupervised consensus clustering and t-distributed stochastic neighbor embedding analysis. The integrated analyses revealed four distinct subgroups with distinct age distributions, copy number alterations, and survival rates. 1q gain was strongly enriched for one of the subgroups and is associated with a worse progression free survival. A univariable analysis revealed that 1q gain, incomplete resection and no upfront radiation were significant predictors of poor progression free survival, and in a multivariable cox regression model, 1q gain was a highly predictive marker of 5 and 10 year progression free survival (HR 3.534 95% CI 1.59–7.87). There is significant intertumoral heterogeneity within EPN_PFB, revealing at least four distinct molecular subgroups. Identification of these subgroups may lead to a better understanding what is driving these tumors. The biological heterogeneity must be accounted for in future pre-clinical modeling and personalized therapies. 1q gain is a significant risk factor of poor progression free survival in EPN_PFB and may represent a prognostic marker in future trials of de-escalation of therapy for EPN_PFB.
Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial
Authors: Kees Okkersen, Cecilia Jimenez-Moreno, Stephan Wenninger, Ferroudja Daidj, Jeffrey Glennon, Sarah Cumming, Roberta Littleford, Darren G Monckton, Hanns Lochmüller, Michael Catt, Catharina G Faber, Adrian Hapca, Peter T Donnan, Gráinne Gorman, Guillaume Bassez, Benedikt Schoser, Hans Knoop, Shaun Treweek, Baziel G M van Engelen, Marie Kierkegaard, Kees Okkersen, Cecilia Jimenez-Moreno, Stephan Wenninger, Ferroudja Daidj, Jeffrey Glennon, Sarah Cumming, Roberta Littleford, Darren Monckton, Hanns Lochmüller, Michael Catt, Catharina Faber, Adrian Hapca, Peter Donnan, Gráinne Gorman, Guillaume Bassez, Benedikt Schoser, Hans Knoop, Shaun Treweek, Baziel van Engelen, Daphne Maas, Stephanie Nikolaus, Yvonne Cornelissen, Marlies van Nimwegen, Ellen Klerks, Sacha Bouman, Linda Heskamp, Arend Heerschap, Ridho Rahmadi, Perry Groot, Tom Heskes, Katarzyna Kapusta, Shaghayegh Abghari, Armaz Aschrafi, Geert Poelmans, Joost Raaphorst, Michael Trenell, Sandra van Laar, Libby Wood, Sophie Cassidy, Jane Newman, Sarah Charman, Renae Steffaneti, Louise Taylor, Allan Brownrigg, Sharon Day, Antonio Atalaya, Fiona Hogarth, Angela Schüller, Kristina Stahl, Heike Künzel, Martin Wolf, Anna Jelinek, Baptiste Lignier, Florence Couppey, Stéphanie Delmas, Jean-François Deux, Karolina Hankiewicz, Celine Dogan, Lisa Minier, Pascale Chevalier, Amira Hamadouche, Berit Adam, Michael Hannah, Emma McKenzie, Petra Rauchhaus, Vincent Van Hees, Sharon Catt, Ameli Schwalber, Ingemar Merkies, Juliane Dittrich
Journal: The Lancet Neurology (2018)