tbuckley/cabot-search huggingface dataset:
MBRS-11. THE EPIGENETIC REGULATOR, SETD8, FACILITATES SELF-RENEWAL AND INVASION IN MYC-DRIVEN MEDULLOBLASTOMA
Authors: Bethany Veo, Sujatha Venkataraman, Angela Pierce, Ismail Sola, Nicholas Foreman, Rajeev Vibhakar
Journal: Neuro-Oncology (2018)

The involvement of altered epigenetic machinery in neoplastic transformation in medulloblastoma has become increasingly evident. However which epigenetic regulators are functionally critical for Myc-driven medulloblastoma is unclear. To address this problem, we performed a functional genomic screen in Myc-driven MB and identified SETD8/PRE-SET7/KMT5a as a critical player in maintaining proliferation and cell survival of MB cells. In medulloblastoma Myc-amplification is commonly associated with a higher rate of metastatic disease. SETD8, a histone methyltransferase responsible for H4K20me1 marks, is reported to promote and repress factors that mediate cell movement. To identify if loss of SETD8 would impair migration and invasion in MB we knocked down SETD8 and monitored for cell migration and invasion. We found that both migration and invasion are clearly suppressed upon depletion of SETD8. We then determined if the level of H4K20me1 at promoters of key EMT regulators was affected by SETD8 loss. Correspondingly, EMT regulators with downregulated gene expression displayed a reduction in H4K20me1 occupancy. In vivo experiments indicated an enhancement of survival with reduced tumor proliferation in xenograft mouse models. Furthermore, chemical inhibition of SETD8 reaffirmed these phenotypes, slowing growth and invasive ability of MB cells. These results link the aggressive and metastatic behavior of Myc-driven medulloblastoma with SETD8 activity. Our results suggest that SETD8 has a critical role in mediating MB tumorigenesis. Establishing a role for SETD8 as a factor in Myc-driven medulloblastoma has not been described, and has potential to lead to a more effective therapy needed to improve outcomes in high-risk patients.
Treatment of Travelers' Diarrhea: Ciprofloxacin plus Loperamide Compared with Ciprofloxacin Alone
Authors: David N. Taylor, Jose L. Sanchez, William Candler, Scott Thornton, Charles McQueen, Peter Echeverria
Journal: Annals of Internal Medicine (2020)

Objective: To compare the safety and efficacy of loperamide used in combination with ciprofloxacin or ciprofloxacin alone for the treatment of travelers' diarrhea. Design: Double-blind, placebo-con...
DIPG-14. INTEGRATED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) NEXT-GENERATION SEQUENCING REVEALS EPIGENETIC DYSREGULATION OF GENE EXPRESSION AND BROMODOMAIN INHIBITION AS A NOVEL THERAPEUTIC TARGET
Authors: Amanda Saratsis, Andrea Piunti, Tina Huang, Elizaeth Bartom, Patrick Ozark, Stacy Marshall, Jin Qi, Rintaro Hashizume, Rishi Lulla, C David James, Ali Shilatifard
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) has the highest mortality of all pediatric solid tumors. Histone H3 mutation (H3K27M) occurs in 80%, altering chromatin structure and function. To characterize the effects of H3K27M as an oncogenic driver, we analyzed the transcriptome and epigenome in DIPG cell lines. Transcriptomes (RNA-Seq) and genomic enrichment of Histone proteins (ChIP-Seq) were characterized in H3K27M DIPG (n=7), wild-type pediatric high-grade glioma (n=3), neural stem cells (n=1) and astrocyte cell lines (n=1). Reads were aligned (UCSC hg19, Tophat), normalized and quantified (HTSeq), and formatted \ for peak calling (SICER) and genomic enrichment mapping (Ensembl). Differential expression and enrichment patterns were identified (edgeR) then analyzed for biological relevance (TopGO, IPA). Epigenetic therapeutic targets were studied in vitro and in vivo. Unsupervised clustering revealed two DIPG subgroups, distinct from control and H3 wild-type lines. Increased EZH2 (p<0.05), BRD4 (p<0.05) and pol II activity at proximal promoter and enhancer regions (p<0.01) were identified in H3K27M lines relative to wild-type. H3K27M co-localized with H3K27ac, pol II, BRD2 and BRD4 at actively transcribed genes, with PRC2 excluded from H3K27M occupied regions. Neuronal differentiation was repressed in H3K27M lines (p<0.01), consistent with morphologic changes observed after EZH2 inhibition in vitro. BRD inhibition suppressed tumor growth in vitro and in vivo. We present the largest epigenetic analysis of rare DIPG cell lines, implicating tumorgenetic pathways in H3K27M mutants. Our results indicate that H3K27M alters the balance between H3K27me3 and H3K27ac, creating a pro-oncogenic chromatin state that promotes DIPG, and highlighting novel epigenetic therapeutic targets.
Prognostic impact of C-reactive protein/albumin ratio in locally advanced esophageal cancer
Authors: J. Simões, N. Tavares, M. Ribeiro, C. Borges, D. Almeida, A. Costa, L. Águas, S. Meireles
Journal: Annals of Oncology (2018)

Introduction: Currently, esophageal cancer remains one of the cancers most associated with morbidity and mortality. In recent studies, the C-reactive protein/albumin ratio (CAR) has been described as an important marker of prognosis associated with the inflammatory status that influences the carcinogenic process. Methods: Retrospective analysis of patients diagnosed with locally advanced esophageal cancer undergoing treatment with neoadjuvant chemoradiotherapy (NA CT – RT) followed by surgery, in the period between 2010 and 2017, at our institution. CAR analysis was performed prior to initiation of treatment, and clinical evidence of infection or inflammatory status at that time was excluded. It was considered a cut-off of 0,15. Survival analysis was performed using the Kaplan-Meier method and prognostic factors assessed by univariate analysis and by the Cox regression model. Results: Of the 52 patients included in the sample, the median age at diagnosis was 60 years (36-79) and 89% were men. PS ECOG was 0 in 87% of patients. Regarding the histological type, 81% of the patients had epidermoid carcinoma and 19% adenocarcinoma. Regarding location, 31% of the tumors were of the middle third and 69% of the distal third or gastro-oesophageal junction. Forty percent had lymph node metastasis at diagnosis. About 42% of the patients (n = 22) presented low CAR and 58% (n = 30) high CAR. Patients were submitted to CT with cisplatin and 5-FU (54%) or carboplatin and paclitaxel (40%), concomitant with RT. The majority (67%) underwent Ivor-Lewis total esophagectomy and in 25% it was found irresectability during the surgical procedure. Downstaging was achieved in 38.5% of patients, and pathological complete response (pCR) was achieved in 21%. Overall survival (OS) at 2 years for patients with CAR<0.15 was 65%, whereas for patients with CAR≥0.15 was 46% (p < 0.01). In the univariate analysis, the following were prognostic factors for OS: CAR (p = 0.02), tumor downstaging (p = 0.05) and pCR (p = 0.03). In the multivariate analysis, tumor downstaging (HR 0.23, 95% CI 0.06-0.91, p = 0.04) and low CAR (HR 0.09, 95% CI 0.01-8.8, p = 0.03) maintained a positive impact on OS. Conclusion: According to these data, CAR was an independent prognostic factor for OS. It is a promising and innovative prognostic marker in several pathologies, among them esophageal cancer. However, CAR needs validation in prospective multicentric studies.
DIPG-62. CARBOPLATIN SYNERGIZES WITH BCL-2 INHIBITOR TO POTENTIATE KILLING OF DIPG CELLS
Authors: Smit Shah, Jeffrey Rubens, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2018)

The only proven effective therapy for diffuse intrinsic pontine glioma is radiation, and this modality only extends life. Carboplatin is being explored for convection-enhanced delivery in DIPG patients, with the hypothesis being that high doses of carboplatin can effectively kill DIPG cells. The BH3-mimetic, pro-apoptotic drug Obatoclax has excellent brain penetration, making it an appropriate candidate for DIPG therapy. We hypothesized that Carboplatin and Obatoclax would synergize to increase killing of DIPG cells. Carboplatin causes cell death via DNA interchelation. Obatoclax induces apoptosis by inhibition of BCL-2 family of proteins. We found that each drug was effective at low micro-molar to nano-molar doses in JHH-DIPG1, SF7761, SU-DIPG-13 and JHH-DIPG16A cell lines. SF7761 and JHH-DIPG16A are derived from pre-treatment biopsies while SUDIPG13 and JHH-DIPG1 are derived from autopsy samples. We found IC50 of Carboplatin to be 5uM and Obatoclax to be 1nM respectively in our cell lines. Combination therapy by these two drugs led to: (1) decreased BCL-2 expression in all 4 cell lines; (2) decreased proliferation as measured by BrdU (ANOVA p value: 0.0004); (3) threefold increase in cleaved PARP as measured by western blot within 24 hours of incubation in all cell lines. We used immunofluorescence to measure cleaved caspase 3 and found 50 percent increase in this marker of apoptosis as well (p<0.01) via combination therapy. Due to the promising synergistic effects in multiple DIPG cell lines in vitro, tests of efficacy in vivo using DIPG cell lines are currently underway.
Take a Deep Breath - Monitoring of Inhaled Nanoparticles with Magnetic Particle Imaging
Authors: Franz Wegner, Thorsten M. Buzug, Joerg Barkhausen
Journal: Theranostics (2018)

Magnetic Particle Imaging (MPI) is a new imaging modality based on the visualization of Superparamagnetic Iron Oxide Nanoparticles (SPIONs) using magnetic fields.The potential of MPI was recently evaluated in numerous ex vivo and in vivo studies and the technique can now be considered as an established preclinical imaging modality with a promising perspective of clinical applications.
CRAN-23. QUALITY OF LIFE AND SEXUAL FUNCTIONING IN ADULTHOOD TWO DECADES AFTER PRIMARY GROSS-TOTAL RESECTION FOR CHILDHOOD CRANIOPHARYNGIOMA
Authors: Eveline Teresa Hidalgo, Svetlana Kvint, Cordelia Orillac, Michelle W McQuinn, Jeffrey H Wisoff
Journal: Neuro-Oncology (2018)

Gross-total resection (GTR) of craniopharyngioma is associated with high rates of complications that potentially affect quality of life (QoL). This study investigated the impact of GTR on the long-term QoL and sexual functioning in young adults. 81 pediatric patients treated with primary GTR of craniopharyngioma were included in this retrospective cohort study. The Quality of Life Questionnaire SF36v1 and the Medical Outcomes Study family and sexual functioning scale were used to analyze follow-up data. 22 patients consented and completed the questionnaires. The median time of follow-up was 19 years (range 10–26). 55% of the patients reported to have excellent or very good health in general. The mean SF 36v total score was 51.63 for PCS and 49.26 for MCS. There was no significant difference between the patient cohort and the normal population. Twenty-one out of 22 subjects reported about sexual functioning, of whom 25% of women and 54% of men reported at least ‘a little of a problem’ in one or more areas of sexual functioning. Body mass index (BMI) values were: 14% normal, 41% overweight, 36% obese and 9% morbidly obese. Preoperative hypothalamic involvement and retrochiasmatic location of the tumor was significantly correlated with BMI. Young adults with childhood-onset craniopharyngioma report QoL and sexual functioning similar to that of the normal population. Overweight and obesity are more prevalent in the study population. Retrochiasmatic location of the tumor and hypothalamic involvement on the preoperative imaging correlate with higher BMI in long-term follow-up.
Clinical and ultrasound remission after 6 months of treat-to-target therapy in early rheumatoid arthritis: associations to future good radiographic and physical outcomes
Authors: Nina Paulshus Sundlisæter, Anna-Birgitte Aga, Inge Christoffer Olsen, Hilde Berner Hammer, Till Uhlig, Désirée van der Heijde, Tore K Kvien, Siri Lillegraven, Espen A Haavardsholm
Journal: Annals of the Rheumatic Diseases (2018)

To explore associations between remission, based on clinical and ultrasound definitions, and future good radiographic and physical outcome in early rheumatoid arthritis (RA).Newly diagnosed patients with RA followed a treat-to-target strategy incorporating ultrasound information in the Aiming for Remission in rheumatoid arthritis: a randomised trial examining the benefit of ultrasound in a Clinical TIght Control regimen (ARCTIC) trial. We defined 6-month remission according to Disease Activity Score, Disease Activity Score in 28 joints-erythrocyte sedimentation rate, American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean criteria, Simplified Disease Activity Index, Clinical Disease Activity Index and two ultrasound definitions (no power Doppler signal, grey scale score ≤2). Two outcomes were defined: no radiographic progression and good outcome (no radiographic progression+physical function≥general population median), both sustained 12-24 months. We calculated the ORs of these outcomes for the remission definitions.Of 103 patients, 42%-82% reached remission at 6 months, dependent on definition. Seventy-one per cent of patients had no radiographic progression and 37% had good outcome. An association between 6-month remission and no radiographic progression was observed for ACR/EULAR Boolean remission (44 joints, OR 3.2, 95% CI 1.2 to 8.4), ultrasound power Doppler (OR 3.6, 95% CI 1.3 to 10.0) and grey scale remission (OR 3.2, 95% CI 1.2 to 8.0). All clinical, but not ultrasound remission criteria were associated with achievement of a good outcome.Our data support ACR/EULAR Boolean remission based on 44 joints as the preferred treatment target in early RA. Absence of ultrasound inflammation was associated with no radiographic progression.NCT01205854; Post-results.
MBCL-30. SUBGROUP-DIRECTED CLINICAL AND MOLECULAR STRATIFICATION OF DISEASE RISK IN INFANT MEDULLOBLASTOMA
Authors: Debbie Hicks, Gholamreza Rafiee, Edward C Schwalbe, Janet C Lindsey, Rebecca M Hill, Amanda Smith, Stephen Crosier, Abhijit Joshi, Keith Robson, Stephen Wharton, Thomas Jacques, Daniel Williamson, Simon Bailey, Steven C Clifford
Journal: Neuro-Oncology (2018)

Understanding the specific molecular pathology of infant medulloblastoma (iMB) is urgently required to inform contemporary treatments, risk-stratification and clinical trials. Comprehensive analysis incorporating central clinical/ pathological review and molecular subgroup, copy number aberration and mutational status was performed in 204 iMBs (0-5yrs). iMB represented a three-subgroup disease with MBSHH (n=61, 40%) and MBGrp3 (n=62, 42%) predominant. iMBGrp3 was strongly associated with LCA (23%) and MYC amplification (19%). Presence of either feature defined a very high-risk group (10yr OS, 23%), with common rapid progression on therapy. Remaining MBGrp3 tumours could be further stratified by chr11 status into standard (with chr11 loss, 10yr OS 84%) and high (without chr11 loss, 10yr OS, 65%) risk groups. iMBSHH and DN/MBEN pathology were strongly associated (75%); p<0.0001), but classic (18%) and LCA (7%) tumours were also observed, independent of patient age. Multivariate analysis identified sub-total resection (STR; HR 6.2, p<0.0001) and DN/MBEN (HR 0.2, p=0.001) as the only independent prognostic factors. A novel cross-validated iMBSHH survival model defined classic/LCA and/or STR tumours as very high-risk (10yr OS, 23%), compared to favourable-risk totally-resected DN/MBEN disease (10yr OS, 93%). Only DN/MBEN iMBSHH tumours could be rescued at relapse following initial therapy (56% survival post-relapse). Furthermore, novel molecular subgroups identified within iMBSHH were the only feature to predict relapse (SHH-I 78% vs SHH-II 43% 5yr PFS, p=0.025) in this patient group. Combined diagnostic assessment of iMB subgroup, pathology and molecular biomarkers will be essential to direct improved risk-stratified therapies, and novel approaches for very high-risk patients.
Exposure-Response Association Between Concurrent Opioid and Benzodiazepine Use and Risk of Opioid-Related Overdose in Medicare Part D Beneficiaries
Authors: Inmaculada Hernandez, Meiqi He, Maria M. Brooks, Yuting Zhang
Journal: JAMA Network Open (2018)

Concurrent benzodiazepine use is associated with an increased risk of opioid-related overdose; however, it remains unknown how the overdose risk varies with the days of exposure to both medications.To evaluate the exposure-response association between the days with concurrent prescription opioid and benzodiazepine use and the risk of overdose.Retrospective cohort study of Medicare Part D claims data from January 1, 2013, to December 31, 2014. Analyses were conducted in fall 2017 and spring 2018. Participants were Medicare Part D beneficiaries who filled at least 1 prescription for an opioid in 2014.Patients were divided into 2 groups based on whether they had opioid and benzodiazepine supplies on the day before overdose or censoring. The first group only had a supply of opioids (n = 50 583) and the second group had supplies of opioids and benzodiazepines (n = 20 665). The second group was further categorized into 4 subgroups based on the cumulative number of days with overlapping supplies of opioids and benzodiazepines: 1 to 90 days (n = 3603), 91 to 180 days (n = 2930), 181 to 270 days (n = 4082), and 271 days or more (n = 10 050).Cox proportional hazard models were constructed to compare opioid-related overdose (including fatal and nonfatal overdoses) across time-dependent treatment groups, controlling for demographic characteristics, insurance factors, clinical characteristics, and number of unique opioid and benzodiazepine prescribers.Of 71 248 total participants, 25 600 (35.9%) were male and 59 532 (83.6%) were white. Mean (SD) age was 66.5 (14.8) years. On the day before overdose or censoring event, 20 665 of 71 248 patients with an opioid prescription (29.0%) were concurrently using benzodiazepines and 14 132 of 20 665 concurrent users (68.4%) had more than 180 days of overlapping supplies of both medications. The risk of overdose was highest on the first days of concurrent opioid and benzodiazepine use and decreased over time; compared with opioid use alone, the hazard ratio for overdose was 5.05 (95% CI, 3.68-6.93) during the first 90 days of concurrent opioid and benzodiazepine use and 1.87 (95% CI, 1.25-2.80) for days 91 to 180 among those who did not have an event before 90 days.During the first 90 days, concurrent benzodiazepine use is associated with a 5-fold increase in the risk of opioid-related overdose. The implementation of policies deterring concurrent opioid and benzodiazepine use is warranted. Patients using both medications should be closely monitored, particularly during the first days of concurrent use.
Biosimilar Approved for Anemia
Authors: Rebecca Voelker
Journal: JAMA (2018)

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Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): a multicentre, open-label, randomised controlled, phase 3 trial
Authors: Gianni Bisogno, Meriel Jenney, Christophe Bergeron, Soledad Gallego Melcón, Andrea Ferrari, Odile Oberlin, Modesto Carli, Michael Stevens, Anna Kelsey, Angela De Paoli, Mark N Gaze, Helene Martelli, Christine Devalck, Johannes H Merks, Myriam Ben-Arush, Heidi Glosli, Julia Chisholm, Daniel Orbach, Veronique Minard-Colin, Gian Luca De Salvo, Maja Cesen, Adriana Rose, Sima Ferman, Peter Mudry, Daniela Sejnova, Paola Dal Bianco, Ilaria Zanetti, Felix Niggli, Timothy Rogers, Giovanni Cecchetto, Federica De Corti, Florent Guerin, Sheila Terwisscha, Dominique Ranchere, Rita Alaggio, Janet Shipley, Angelo Rosolen, Henry Mandeville, Giovanni Scarzello, Valerie Bernier, Kieran McHugh
Journal: The Lancet Oncology (2018)
Liquid biopsy allows predicting benefit from rechallenge with cetuximab(cet)+irinotecan(iri) in RAS/BRAF wild-type mCRC patients(pts) with resistance to 1st-line cet+iri: Final results and translational analyses of the CRICKET study by GONO
Authors: D. Rossini, C. Cremolini, E. Conca, M. Del Re, A. Busico, F. Pietrantonio, F. Bergamo, R. Danesi, G. Cardellino, E. Tamburini, E. Dell'Aquila, A. Strippoli, G. Masi, G. Tonini, F. Negri, D. Corsi, N. Pella, R. Intini, A. Falcone, D. Santini
Journal: Annals of Oncology (2018)

Introduction: CRICKET (NCT02296203) was designed to investigate the activity of the rechallenge with cet and iri as 3 rd -line treatment in RAS/BRAF wild-type mCRC pts with acquired resistance to 1st-line cet- and iri-based therapy. The role of liquid biopsies as a tool to identify pts more likely to benefit from this strategy was investigated. Methods: Eligibility criteria included RAS/BRAF wild-type status on tissue samples; prior 1 st -line iri-based, cet-containing regimen with at least RECIST partial response (PR), 1 st -line PFS ≥6 months, and progression within 4 weeks after the last cet; prior 2 nd -line oxaliplatin- and bevacizumab-based treatment. Pts received 3rd-line cet + iri until PD. The primary endpoint was response rate (RR) according to RECIST v1.1. With p0 = 5%, and p1 = 20%, 1-sided-α and β errors of 0.05 and 0.20, 27 pts were required. The null hypothesis can be rejected if responses are observed in ≥ 4 pts. Liquid biopsies were collected at the rechallenge baseline. ctDNA was analyzed with ddPCR for specific RAS/BRAF mutations (mut), and then by ultra-deep NGS with Ion Torrent S5 XL. Results: Between Jan 2015 and Jun 2017, 28 pts were enrolled in 9 centres. The primary endpoint was met. Six PRs (two unconfirmed) and 9 disease stabilizations (RR: 21%, 95%CI: 10-40%, disease control rate: 54%, 95%CI: 36-70%) were reported. RAS mut were found in liquid biopsies collected at the rechallenge baseline in 12 (48%) out of 25 evaluable pts (6 KRAS G12D, 5 KRAS G12V with 1 harboring also Q61H and 1 NRAS Q61L). No RAS mut were detected in samples from pts who achieved a confirmed PR. Pts with RAS wt ctDNA had significantly longer PFS than those with RAS mut ctDNA (mPFS: 3.9 vs 1.9 mos; HR: 0.48 [95%CI 0.20-0.98], p = 0.048). No BRAF or PIK3CA mut were found. Conclusion: This is the first prospective demonstration of the activity of rechallenge with cet + iri in some mCRC pts initially sensitive and then resistant to first-line iri- and cet-based therapy, with no RAS/BRAF mut in pre-treatment liquid biopsies. Partially funded by Merck Serono SpA.