tbuckley/cabot-search huggingface dataset:
HGG-32. ARG-AUXOTROPHIC PATIENT-DERIVED GLIOBLASTOMA MULTIFORME CELL LINES SHOW INCREASED SENSITIVITY TOWARDS DOXYCYCLINE-INDUCED GROWTH INHIBITION
Authors: Fatemeh Shokraie, Christin Riess, Tomas Fiedler, Björn Schneider, Carl Friedrich Classen, Claudia Maletzki
Journal: Neuro-Oncology (2018)

Arginine auxotrophy constitutes a metabolic defect that renders tumors susceptible towards arginine-depleting substances, such as bacterial arginine deiminase (ADI). In our previous studies, Arg auxotrophy and thus ADI-susceptibility was confirmed on patient-derived GBM models in vitro and in vivo. Functionally, effects were attributable to induction of autophagy, senescence and necrosis. To improve this approach, we here examined whether ADI-treatment may be combined with doxycycline (Dox) - an antibiotic with anti-cancer activities by targeting mitochondria. The effect of doxycycline was first investigated on a panel of patient-derived GBM cell lines to determine general sensitivity (N=8). Analysis revealed higher susceptibility of Arg-auxotrophic compared to Arg-prototrophic cells (N=4 cell lines each). Thereafter, doxycycline (IC20) was combined with ADI (35 mU/mL) in simultaneous and sequential regimens (72h each). Combined application of both agents slightly enhanced antitumoral effects of the monotherapy in selected cell lines. Decreased mitochondria content after Dox treatment was confirmed by immunofluorescence and quantitative PCR. This effect was only partially counteracted after the combination. Instead, necrosis was the dominating mode of cell death, while autophagy was found to play a minor role. No effect on radiosensitivity was seen in either treatment regimen, i.e. simultaneous or sequential. Taken together, our data support the conclusion that ADI can be combined with substances impairing mitochondria function, likely to result in an efficient oncolytic regimen. Ongoing trials focus on improvement of the treatment protocol by implementing this approach into standard clinical drug regimen and in vivo testing.
Multivalent Ligands: Integrin Clustering Matters: A Review of Biomaterials Functionalized with Multivalent Integrin‐Binding Ligands to Improve Cell Adhesion, Migration, Differentiation, Angiogenesis, and Biomedical Device Integration (Adv. Healthcare Mater. 12/2018)
Authors: Fatemeh Karimi, Andrea J. O'Connor, Greg G. Qiao, Daniel E. Heath
Journal: Advanced Healthcare Materials (2018)

Biomaterials functionalized with nano-scale clusters of integrin-binding ligands exhibit enhanced cell-material interactions including higher adhesion rates, greater adhesion strength, increased proliferation, and better biomedical device integration in comparison to materials functionalized with randomly spaced ligands. The review in article 1701324 by Daniel E. Heath, Greg G. Qiao, and co-workers focuses on the methodologies that have been developed in order to generate these materials as well as their improved in vitro and in vivo performance.
The prognostic impact of sidedness in RAS wild-type colorectal cancer
Authors: N. Tavares, A. Costa, D. Almeida, S. Meireles, C. Fernandes, C. Rey, C. Sarmento, M. Damasceno
Journal: Annals of Oncology (2018)

Introduction: Colorectal cancer (CRC) is a heterogeneous disease and sidedness [right colon (RC) vs. left colon (LC)] reflects different clinical, biological and molecular behaviors, which could have a significant prognostic impact. This study tried to evaluate the impact of sidedness on overall survival (OS) and progression-free survival (PFS) in RAS wild-type (RAS-WT) CRC patients treated with anti-EGFR antibodies in first line palliative chemotherapy. Methods: Retrospective cohort of adult patients with CRC RAS-WT treated with anti-EGFR antibodies in first line palliative chemotherapy between 01/01/2012 and 31/12/2016 in a tertiary university hospital. Differences between groups were determined according to chi-square test; OS and PFS were estimated by Kaplan-Meier method and multivariate analysis according to Cox regression; a significant level of 0.05 was chosen to assess the statistical significance. Results: We included 65 patients. Fifteen patients had RC tumors (cecum: 5; ascendant: 1; hepatic flexure: 1; proximal transverse: 6) and 50 had LC tumors (splenic flexure: 3; descending: 3; sigmoid: 33; rectum: 11). The median age at diagnosis of metastatic disease was 63 years-old [28-79]. Thirty eight patients (58.5%) were treated with cetuximab and 27 (41.5%) with panitumumab. Concomitant chemotherapy protocol was FOLFIRI in 41 patients (63.1%), FOLFOX in 19 (29.2%) and irinotecan in 5 (7.7%). There were no statistically significant differences between RC and LC groups. The median OS was 33.8 months (CI 95% 19.4-48.3 months). In univariate analysis, patients with RC cancer had an unfavorable OS (RC 26.8 vs. LC 43.4 months, p = 0.001). An ECOG performance status ≥1 at metastatic diagnosis, presence of bone metastases, hypomagnesemia during anti-EGFR treatment and irinotecan monotherapy had prognostic impact on OS. In multivariate analysis, ECOG ≥1 (HR 0.323, CI 95% 0.149-0.698, p = 0.004), RC (HR 0.322, CI 95% 0.129-0.804, p = 0.015), irinotecan monotherapy (HR 0.319, CI 95% 0.097-0.869 p = 0.027) and bone metastases (HR 0.220, CI 95% 0.058-0.838, p = 0.027) kept their negative prognostic impact in OS. The median PFS was 13.0 months. Patents with RC (RC 7.5 vs. LC 16.3 months, p < 0.001) and those who were treated with Irinotecan monotherapy (irinotecan 8.2 vs. FOLFOX/FOLFIRI 13.9 months, p = 0.003) also had worse PFS, both in univariate and multivariate analysis. Conclusion: In our cohort of CRC RAS-WT patients, right-sided tumors demonstrated worse OS and PFS, thus reflecting the significant prognostic impact of sidedness. Growing evidence on sidedness should alert oncologists to RC cancer patients as a group with a more aggressive disease and for which the optimal treatment strategy is still controversial. Performance status, the presence of bone metastases and treatment with irinotecan monotherapy vs. FOLFOX/FOLFIRI also emerged as prognostic factors.
DIPG-18. IMMUNE RESPONSE GENERATED WITH THE USE OF AUTOLOGOUS DENDRITIC CELLS PULSED WITH AN ALLOGENIC TUMORAL CELL LINES LYSATE IN PATIENTS WITH NEWLY DIAGNOSED DIPG
Authors: Andres Morales La Madrid, Daniel Benitez-Ribas, Raquel Cabezón, Georgina Flórez, Mari Carmen Molero, Patricia Puerta, Antonio Guillen, Sonia Paco, Angel M Carcaboso, Vicente Santa-Maria Lopez, Ofelia Cruz, Carmen De Torres, Noelia Salvador, Manel Juan, Jaume Mora
Journal: Neuro-Oncology (2018)

BACKGROUND AND Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive and lethal brainstem tumor in children. Dendritic cells have T-cell stimulatory capacity and, therefore, potential antitumor activity for disease control. We designed a phase Ib immunotherapy clinical trial with the use of autologous dendritic cells pulsed with an allogenic tumor cell lysate in patients with newly diagnosed DIPG after upfront irradiation (RT). Nine patients with newly diagnosed DIPG were enrolled. Clinical and radiologic response to RT was confirmed and patients were neurologically stable and off-steroids prior to study entry. Autologous dendritic cells vaccines (ADCV) were prepared from monocytes obtained by leukapheresis. Five ADCV doses were administered intradermally during induction phase. In the absence of tumor progression, patients received 3 boosts of tumor lysate every three months. Non-specific and specific antitumor response was generated in 8/9 patients included in the study. Immunological responses were also confirmed in the T lymphocytes from the cerebrospinal fluid (CSF) of 2 patients. These preliminary results demonstrate that ADCV generates a DIPG-specific immune response detected in peripheral blood mononuclear cells and CSF. This strategy shows a promising backbone for future schemas of combination immunotherapy.
MBRS-39. TWIST1 PLAYS A REGULATORY ROLE IN MEDULLOBLASTOMA METASTASIS
Authors: Alice Cardall, Aishah Nasir, Franziska Linke, Anna M Grabowska, Ian D Kerr, Beth Coyle
Journal: Neuro-Oncology (2018)

Paediatric medulloblastoma (MB) are frequently metastatic, resulting in a poor prognosis for the patient. Little is known about the underlying mechanisms; therefore, our ability to develop novel therapeutic approaches is limited. We hypothesise that, despite medulloblastomas being neuro ectodermal in origin, they metastasise via an epithelial-mesenchymal transition (EMT) -like pathway, mediated by the EMT transcription factor TWIST1. TWIST1 protein and gene expression were analysed in patient tissue microarrays by immunohistochemistry and in MB cell lines by qRT-PCR respectively. Bioinformatic analyses using Genomatix and R2: Genomics Analysis and Visualization Platform were used to further investigate the role of TWIST1 and predict candidate target genes. The functional and physical interactions between TWIST1 and the multidrug transporter ABCB1 were investigated using 3D migration and invasion models of metastatic D283MED (TWIST1 positive) and TWIST1-transfected MED6 cells and by chromatin immunoprecipitation (ChIP). High TWIST1 expression was associated with metastatic MB patients (p≤0.05) and group 3 metastatic cell lines. Genomatix analysis predicted a TWIST1 binding site was present in the ABCB1 promoter. This was confirmed by ChIP analysis of D283MED cells (p≤0.05). Overexpression of TWIST1, in TWIST1-transfected MED6 cells, resulted in the formation of large cell aggregates (a metastatic phenotype), which could be inhibited by vardenafil (ABCB1 inhibitor; p≤0.05). Vardenafil was also able to attenuate aggregation of D283MED cells (p≤0.05). Other potential TWIST1-target genes are also currently under investigation. Our data reveals a key regulatory role for TWIST1 during MB metastasis. TWIST1 target genes, including ABCB1, offer potential novel therapeutic targets for metastatic MB.
Self-assembled dual fluorescence nanoparticles for CD44-targeted delivery of anti-miR-27a in liver cancer theranostics
Authors: Xiao Zheng, Fan Zhang, Yawei Zhao, Jing Zhang, Jianati Dawulieti, Yue Pan, Lianzhi Cui, Madi Sun, Dan Shao, Mingqiang Li, Kan He, Ming Zhang, Jing Li, Li Chen
Journal: Theranostics (2018)

Despite the vital role miRNA-27a plays in driving the development and progress of liver cancer, miRNA-based inhibition therapy is hampered due to its undesired degradation and off-target effects. Herein, a multifunctional nanoparticle for noninvasive tracking of targeted delivery of anti-miR-27a oligonucleotides against liver cancer was constructed. Methods: Dual-fluorescent conjugates (QD-HA-PEI) were first fabricated through crosslinking hyaluronic acid (HA), polyethyleneimine (PEI) and near-infrared (NIR) fluorescent quantum dots (QDs) via a facile one-pot approach. Antisense oligonucleotide was then encapsulated by QD-HA-PEI to form anti-miR-27a/QD-HA-PEI via electrostatic interactions. Targeting, biodistribution, bioimaging, in vitro cytotoxicity and in vivo anti-tumor effects were evaluated and the underlying mechanism was studied. Results: The NIR fluorescence of anti-miR-27a/QD-HA-PEI could be employed to monitor CD44 receptor-targeted cellular uptake and tumor accumulation. Importantly, the intrinsic fluorescence of anti-miR-27a/QD-HA-PEI remained in the "ON" state in extracellular or blood environment, but switched to the "OFF" state in the intracellular environment, indicating pH-responsive oligonucleotide release. Furthermore, anti-miR-27a/QD-HA-PEI exhibited effective and selective anti-cancer effects in vitro and in vivo with fewer side effects via the direct down-regulation of oncogenic transcription factors FOXO1 and PPAR-γ. Conclusion: Our findings validate the dual-fluorescent nanoparticles as delivery vectors of therapeutic miRNA, capable of simultaneous tumor imaging and tracking of miRNA-based modulation therapy, thereby providing an efficient and safe approach for liver cancer theranostics.
HGG-17. TUMOR MUTATIONAL BURDEN ANALYSIS OF PEDIATRIC TUMORS PROVIDES A DIAGNOSTIC TOOL FOR GERMLINE REPLICATION REPAIR DEFICIENCY AND PREDICT RESPONSE TO IMMUNE CHECKPOINT INHIBITION
Authors: Brittany B Campbell, Nicholas Light, David Fabrizio, Eric Bouffet, Valerie Larouche, David Samuel, Duncan Stearns, Kristina A Cole, Enrico Opocher, Gregory Thomas, Magnus Sabel, Peter Dirks, Michael Taylor, David Malkin, Steffen Albrecht, Roy Dudley, Nada Jabado, Cynthia Hawkins, Adam Shlien, Uri Tabori
Journal: Neuro-Oncology (2018)

Hypermutation constitute an important subgroup of cancers and confers sensitivity to immune checkpoint inhibition (ICI). Glioblastoma arising in children with Constitutional Mismatch Repair Deficiency Syndrome (CMMRD) are ultrahypermutant. Our objective was to quantify the frequency of hypermutant tumors in children, determine whether mutational signatures can predict germline mutations, and treat hypermutant tumors with ICIs. Deep panel sequencing of 2984 pediatric tumors (585 brain tumors). Tumor mutation burden was correlated to mutation burden from exome and genome sequencing (R2 = 0.94). Mutational signatures were analyzed to predict source of hypermutation. Data on 36 patients with hypermutant tumors identified by sequencing were enrolled on an ICI registry trial. Hypermutant tumors (>10 mut/MB) comprised 5% of all pediatric tumors (n=143). These were highly enriched for replication repair mutations (p<0.0001) and mutation loads correlated with hypermutant adult tumors that have shown demonstrable clinical response to ICI. Hypermutation was found in 5% of childhood and 6% of adult glioblastoma. All glioblastomas with greater than 100 Mut/MB harbored MMR/polymerase mutations suggesting germline bMMRD (p =10-7). Clinical data collected on 19 ultrahypermutant tumors revealed germline mutations in replication repair genes in all patients. Of the 36 patients with hypermutant cancers treated with ICI, 24 had brain tumors, and favorable sustained responses are observed. High mutation burden is a sensitive predictor of germline CMMRD. Hypermutant tumors are more common in the pediatric setting than previously appreciated, opening novel therapeutic avenues. ICI shows promise for hypermutant pediatric cancers including glioblastoma.
Pediatric 131I-MIBG Therapy for Neuroblastoma
Authors: José Willegaignon, Karin Paola Crema, Nathaliê Canhameiro Oliveira, Rogério Alexandre Pelissoni, George Barberio Coura-Filho, Marcelo Tatit Sapienza, Carlos Alberto Buchpiguel
Journal: Clinical Nuclear Medicine (2018)

Purpose 131 I-metaiodobenzylguanidine ( 131 I-MIBG) has been used in the diagnosis and therapy of neuroblastoma in adult and pediatric patients for many years. In this study, we evaluated whole-body 131 I-MIBG clearance and radiation doses received by patients, family caregivers, and medical staff to establish appropriate radiation safety measures to be used in therapy applications. Methods Research was focused on 23 children and adolescents with metastatic neuroblastoma, with ages ranging from 1.8 to 13 years, being treated with 131 I-MIBG. Based on measured external dose rates from patients, dosimetric data to patients, family members, and others were calculated. Results The mean ± SD 131 I-MIBG activity administered was 8.55 ± 1.69 GBq. Percent whole-body retention rates of 131 I-MIBG at 24, 48, and 72 hours after administration were 48% ± 7%, 23% ± 7%, and 12% ± 6%, with a whole-body 131 I-MIBG effective half-life of 23 ± 5 hours for all patients. The mean doses for patients were 0.234 ± 0.096 mGy·MBq −1 to red-marrow and 0.251 ± 0.101 mGy·MBq −1 to whole body. The maximum potential radiation doses transmitted by patients to others at 1.0 m was estimated to be 11.9 ± 3.4 mSv, with 97% of this dose occurring over 120 hours after therapy administration. Measured mean dose received by the 22 family caregivers was 1.88 ± 1.85 mSv, and that received by the 19 pediatric physicians was 43 ± 51 μSv. Conclusion In this study, we evaluated the whole-body clearance of 131 I-MIBG in 23 pediatric patients, and the radiation doses received by family caregivers and medical staff during these therapy procedures, thus facilitating the establishment of radiation safety measures to be applied in pediatric therapy.
Neoadjuvant chemotherapy in gastric cancer
Authors: A. Bounedjar, R. Yaici, M A Melzi, N. Kechad, M. Abada
Journal: Annals of Oncology (2018)

Introduction: Gastric cancer currently ranks second in global cancer mortality. Most patients are diagnosed at an advanced stage when systemic chemotherapy is the only available treatment option, which may improve its prognosis. This study was conducted to evaluate the response to neoadjuvant chemotherapy in patients with advanced gastric cancer, based on the surgical resectability rate. Methods: We carried a retrospective study from January 2015 to December 2017 on patients treated at the medical oncology department of BLIDA University Hospital and other department in Algeria, and received neoadjuvant chemotherapy for their locally advanced gastric cancer (T3-4 / N1-3M0). The objectives of the study are the evaluation of the resectability rate and the R0 resection rate. Results: During this study period, 66 patients were included for neoadjuvant chemotherapy of a locally advanced gastric tumor. The average age of these patients is 64 years [44 years-90 years]. There is a clear male predominance, 21 women (32%) and 45 men (68%). The result of fibroscopy showed: the least frequent localization of gastric tumor was cardia with 13% followed by practically the same rate 45% of antrum and pylore, the macroscopical aspect was dominated by the ulcerative-vegetative form in 57%. In 73% the adenocarcinoma was the most frequent histological type of the gastric tumor. 28 patients (42.4%) underwent surgery, with 23 of them had R0 resection (82.1%). Conclusion(s): Neoadjuvant chemotherapy has improved the surgical resectability rate in patients with locally advanced gastric cancer as well as the quality of surgery.
GERM-15. A PHASE 2 TRIAL OF RESPONSE-BASED RADIATION THERAPY FOR PATIENTS WITH LOCALIZED CENTRAL NERVOUS SYSTEM GERM CELL TUMORS (CNS GCT): A CHILDREN’S ONCOLOGY GROUP (COG) STUDY
Authors: Jason Fangusaro, Shengjie Wu, Shannon MacDonald, Erin Murphy, Dennis Shaw, Ute Bartels, Soumen Khatua, James Boyett, Chris Williams-Hughes, Mark Souweidane, Hsiao-Ming Lu, David Morris, Ashok Panigrahy, Arzu Onar-Thomas, Maryam Fouladi, Amar Gajjar, Girish Dhall
Journal: Neuro-Oncology (2018)

Intracranial germ cell tumors represent 3-5% of pediatric CNS tumors. Non-germinomatous germ cell tumors (NGGCT) have worse outcomes compared to germinomas, however, improved survivals were achieved on COG ACNS0122 utilizing a combination of chemotherapy and craniospinal irradiation (CSI). Since CSI is associated with significant late effects, a Phase 2 study was undertaken to determine whether irradiation could be reduced without impacting survival in a subgroup of NGGCT patients. Patients with localized disease who achieved a complete (CR) or partial response (PR) to chemotherapy were eligible for reduced irradiation to 30.6Gy whole ventricular field (WVI) and 54Gy tumor-bed boost as compared to 36Gy CSI plus tumor-bed boost as used on ACNS0122. Between 5/2012 and 11/2016, 107 eligible patients were accrued. Median age was 11 years (range: 4-22) and 75% were male. Tumor location was pineal in 58, suprasellar in 37, ventricular in 6 and bifocal in 6 patients. Sixty-six patients achieved CR/PR post-induction and received reduced irradiation. The 2-year progression-free survival (PFS) was 89% (95% CI: 81%-97%) and overall survival was 92% (95% CI: 86%- 99%). Eight patients progressed; seven had a distant relapse (outside the irradiation field) and one patient had a local plus distant relapse. Alpha-fetoprotein and beta-human chorionic gonadotropin levels were not associated with PFS. There were no unexpected treatment-related adverse events or deaths. Although these survival data are encouraging, distant relapses noted in all of the patients who progressed are concerning. Longer follow-up of the ACNS1123 cohort may better inform our recommendations in the future.
Interprofessional Evidence-Based Practice Competencies
Authors: Deepa Rani Nandiwada, William Kormos
Journal: JAMA Network Open (2018)

Loai Albarqouni, MD, MSc; Tammy Hoffmann, PhD; Sharon Straus, MD, MSc; Nina Rydland Olsen, PhD; Taryn Young, PhD; Dragan Ilic, PhD; Terrence Shaneyfelt, MD, MPH; R. Brian Haynes, MD, PhD; Gordon Guyatt, MD, MSc; Paul Glasziou, MBBS, PhD
DIPG-74. DNA METHYLATION STOCHASTICITY IN DIPG
Authors: Michael Koldobskiy, Garrett Jenkinson, Elisabet Pujadas, Allison Martin, Charles Eberhart, John Goutsias, Eric Raabe, Andrew Feinberg
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a dismal prognosis and no effective treatment. Recent studies point to a critical role for epigenetic dysregulation in this disease. Nearly 80% of DIPGs harbor mutations in histone H3 encoding replacement of lysine 27 with methionine (K27M), leading to global loss of the repressive histone H3K27 trimethylation mark, global DNA hypomethylation, and a unique gene expression profile. Recent studies across diverse cancers have highlighted the role of epigenetic variability as a driving force in tumor evolution. Epigenetic variability may underlie the heterogeneity and phenotypic plasticity of cancer cells and allow for the selection of cellular traits that promote survival and resistance to therapy. Our group has recently described a novel mathematical framework for analyzing variability of DNA methylation directly from whole-genome bisulfite sequencing data by modeling stochastic Markov processes, allowing rigorous computation of DNA methylation entropy at precise genomic locations. We have carried out genome-wide characterization of DNA methylation at single-base resolution in DIPG in order to generate comprehensive genome-wide maps of DNA methylation entropy. We find a global increase in DNA methylation entropy in DIPG. Dissection of the targets of this perturbation highlights specific genes and regulatory regions under epigenetic control in DIPG cells. We assess the effect of pharmacologic DNA methyltransferase inhibition on the DNA methylation landscape and on gene expression in DIPG patient-derived neurosphere cell lines. We find that DNA methyltransferase inhibition alters expression of genes involved in cell death, differentiation, cellular defense, and immune signaling.
Complaints made to the GMC
Authors: Abi Rimmer
Journal: BMJ (2018)

The number of complaints made about doctors to the General Medical Council has fallen by 17% over past four years, data show Abi RimmerThe BMJ Between 2008 and 2013, the number of complaints made to the GMC increased, from 4340 in 2008 to 9097 in 2013. 1 Since 2013, the number of complaints has been falling.There were 8898 complaints made to the GMC in 2014, 8313 in 2015, 8256 in 2016, and 7577 in 2017.As of 14 June, 3290 complaints had been made in 2018.Of the complaints made in 2017, 5581 (73.7%) were closed at the triage stage, before an investigation was undertaken, and 474 (6.3%) were referred directly to the doctor's employer.Just over 680 (9.0%) investigations were closed during the GMC's investigation.The data also show that, over time, the proportion of complaints that resulted in a sanction has fallen.In 2013, 6% of complaints resulted in a sanction which fell to 5% in 2014, 4% in 2015, 3% in 2016, and 1.4% in 2017.
Brexit—an impartial view?
Authors: David Barlow
Journal: BMJ (2018)

Brexit divides the country, the main political parties, and families. One reason for this polarisation is the triumph of “opinion” over hard data. Remainers and leavers are both guilty of confirmation bias. In 1859 John Stuart Mill wrote that to understand a subject one should hear both sides of an argument.1 What the general public needs now, 160 years later, is a dispassionate, disinterested, objective assessment of whether genuine risks to health exist. The public needs it; we doctors expect it; The BMJ doesn’t …