tbuckley/cabot-search huggingface dataset:
DIPG-68. ONCOGENIC MECHANISMS OF H3.3 K27M IN A SPONTANEOUS DIPG MOUSE MODEL
Authors: Jon Larson, Lawryn Kasper, Barbara Paugh, Gang Wu, Hongjian Jin, Yiping Fan, Chang-Hyuk Kwon, David Finkelstein, Andre Silveira, Raymond Xu, Xiaoyan Zhu, Junyuan Zhang, Beisi Xu, Helen Russell, Peter McKinnon, David Ellison, Jinghui Zhang, Suzanne Baker
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine gliomas (DIPG) are deadly childhood brainstem tumors that comprise approximately half of all pediatric high-grade gliomas (HGG). Recurrent, clonal somatic mutations in histone H3 are a molecular hallmark that distinguish genetic mechanisms underlying pediatric and adult HGG, and indicate a strong link between epigenetic dysfunction and pediatric brain tumorigenesis. H3K27M mutations found in nearly 80 percent of DIPGs and over half of non-brainstem HGGs occurring in thalamus or other midline structures, induce a dominant loss of genome-wide H3K27me3. To study this mutation in the developing mammalian brain and investigate how it contributes to gliomagenesis, we generated conditionally activated, epitope-tagged knock-in mice to express K27M or non-mutated H3.3 proteins from the endogenous H3f3a locus. Untransformed embryonic neural precursor cells expressing H3.3K27M demonstrated H3K27me3 loss and a significant growth advantage in vitro with brain region-specific, stage-dependent expression and epigenetic signatures. DIPGs frequently harbor genetic alterations in TP53 and PDGFRA in addition to H3.3K27M, and mice with induced brain-specific Trp53 deletion plus mutated PDGFRAV544ins expression developed spontaneous HGG in vivo. Induction of H3.3K27M significantly accelerated PDGFRAV544ins;Trp53 knockout HGG formation involving the brainstem. Importantly, non-mutated H3.3 epitope-tagged protein did not affect tumor burden or latency. H3.3K27M tumors recapitulate characteristics observed in human DIPG including histopathological features, strong nuclear K27M expression and robust loss of H3K27me3 throughout the tumors. Using RNA-seq and ChIP-seq, we relate the genetic, epigenetic and transcriptional landscapes of these models to primary pediatric DIPG to help identify their developmental origins and oncogenic mechanisms downstream of histone H3.3K27M.
Dementia: assessment, management and support: summary of updated NICE guidance
Authors: Joshua Pink, John O’Brien, Louise Robinson, Damien Longson
Journal: BMJ (2018)

### What you need to know

Dementia describes a range of cognitive, behavioural, and psychological symptoms that can include memory loss, problems with reasoning and communication, and change in personality which impair a person’s ability to carry out daily activities.

A report published by the Alzheimer’s Society in 2013 found there were about 815 000 people living with dementia in the UK (corresponding to a prevalence of 1 in 14 in people over 65 years old), and this number is expected to increase to 1 143 000 by 2025.1 In November 2017, there were 456 739 people on general practice registers with a formal diagnosis of dementia, up from approximately 290 000 people in 2009-10,2 with most of this difference accounted for by an increase in diagnosis rates. Despite this improvement in diagnosis, around 1 in 3 people with established dementia remain unrecognised, and around half of people living with dementia in England do not feel they are getting sufficient post-diagnostic support.3

This article summarises the most recent recommendations from the National Institute for …
Phase 1b open-label study evaluating the safety, pharmacokinetics, and preliminary efficacy of ABT-165 plus FOLFIRI in patients with second-line (2L) colorectal cancer (CRC)
Authors: Z. Wainberg, J. Strickler, M. Gordon, M. Barve, L. Wang, H. Yue, M. Motwani, S. Kasichayanula, L. Naumovski, E. Hamilton
Journal: Annals of Oncology (2018)

Introduction: ABT-165 is a first-in-class dual-variable domain immunoglobulin with specificity for both vascular endothelial growth factor and delta-like ligand 4 (DLL4) that has demonstrated encouraging preliminary clinical antitumor activity as monotherapy. As part of a phase 1 trial, we evaluated an expansion cohort of ABT-165 plus FOLFIRI in patients with 2L CRC previously treated with a fluoropyrimidine/oxaliplatin regimen with or without bevacizumab. Methods: Patients with 2L CRC (≥18 years; Eastern Cooperative Oncology Group performance status 0–2) eligible to receive FOLFIRI were included (NCT01946074). Patients received ABT-165 (2.5 mg/kg) plus FOLFIRI (irinotecan: 180 mg/m 2; leucovorin: dl-400 (or l-200) mg/m 2; fluorouracil bolus: 400 mg/m 2, infusion: 2400 mg/m 2) intravenously on days 1 and 15 in 28-day cycles until disease progression or intolerable toxicity. Assessments (tumor and cardiac imaging) were performed every 2 cycles. Primary objectives were to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the ABT-165 plus FOLFIRI combination therapy. Results: As of 05 Jan 2018, 16 patients with 2L CRC (KRAS mutation status: 4 wildtype, 9 mutated, 3 unknown) have been enrolled (median age [range]: 64 years [42–81]). Pharmacokinetic data illustrated that the overall exposure, as demonstrated by maximum plasma concentration and area under the curve of ABT-165, were not altered by FOLFIRI administration. All patients with 2L CRC experienced a treatment-related adverse event (TRAE). The most common TRAEs (≥50%) were fatigue (81%), diarrhea, nausea (each 63%), anemia (56%), dehydration, and neutropenia (each 50%). Pulmonary hypertension (19%) and gastrointestinal perforation (6%) were also noted. Anemia, neutropenia, and hypertension (each 25%) were the most common grade ≥3 TRAEs. Three of 16 2L CRC patients (19%) had a partial response, 1 of whom was on treatment for 10 cycles with progression-free survival of 8.2 months. Median time on treatment was 16.0 weeks (range: 0.1–40.1). Treatment is ongoing in 2 patients. Evaluation of DLL4 expression, angiogenesis signatures, and molecular profile in archival tissue is in progress, and correlations with outcomes will be presented. Conclusion: Combination therapy with ABT-165 2.5 mg/kg and FOLFIRI was well tolerated and demonstrated encouraging preliminary clinical efficacy in patients with 2L CRC. Further clinical studies are ongoing in this patient population with significant unmet need (NCT03368859).
DIPG-01. TARGETING THE POLYAMINE PATHWAY AS A NOVEL THERAPEUTIC TREATMENT AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Aaminah Khan, Laura Gamble, Denise Yu, Swapna Joshi, Laura Franshaw, Mark Burns, Murray Norris, Michelle Haber, Maria Tsoli, David Ziegler
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is an aggressive paediatric brainstem tumour, with a median survival below 1 year. Polyamines, frequently upregulated in cancer, are small intracellular polycations that control key biological processes including cell replication, translation and differentiation. The aim of this study was to investigate the efficacy of polyamine pathway inhibitors as a therapeutic strategy against DIPG. Difluoromethylornithine (DFMO) is an FDA-approved inhibitor of the enzyme ornithine decarboxylase (ODC1), a key driver of polyamine synthesis. By qPCR and western blotting, high expression levels of key players of the polyamine pathway were observed in a panel of DIPG samples. Using cytotoxicity and soft-agar clonogenic assays, we found that DFMO inhibited the proliferation of DIPG neurospheres. Treatment with the novel polyamine transport inhibitor, AMXT-1501 led to reduced uptake of the radiolabelled polyamine, spermidine, confirming polyamine transport inhibition in DIPG cells. Addition of AMXT-1501 to DFMO showed a potent and synergistic inhibition of DIPG neurosphere proliferation. Western blotting and flow cytometry analysis of Annexin V-stained cells showed that treatment with DFMO or AMXT-1501, alone or in combination, led to apoptotic induction. Consistent with the in vitro results, the combination of DFMO and AMXT-1501 significantly prolonged the survival of all mice bearing DIPG orthografts with 6/9 mice surviving until the humane endpoint of 160 days, representing the most effective combination treatment we have tested to date in our highly aggressive DIPG animal model. AMXT-1501 is currently in clinical development and following completion of adult Phase 1 studies, a clinical trial for DIPG patients is planned.
Long term efficacy results from the phase II CRAB trial: Neoadjuvant bevacizumab, capecitabine and radiotherapy in locally advanced rectal cancer
Authors: V. Velenik, M. Omejc, J. Ocvirk, I. Edhemović, F. Anderluh, I. Oblak, J. But-Hadzic
Journal: Annals of Oncology (2018)

Introduction: Neoadjuvant capecitabine based chemoradiotherapy and radical surgery are considered to be optimal treatment approach to locally-advanced rectal cancer This prospective, nonrandomised, open -label phase II study investigated the efficacy and safety of bevacizumab (Bev) in combination with capecitabine and concurrent radiotherapy (CRT) for the treatment of locally advanced resectable rectal cancer (LARC). The pathological complete response (pCR) was assessed as primary endpoint and local control and survival parameters as secondary endpoints. Methods: Enrolled patients (pts) with MRI-confirmed stage II/III rectal cancer were treated with an infusion of Bev (5 mg/kg) 2 weeks prior to neoadjuvant CRT, followed by Bev 5mg/m2 on week 3, 5, 7 and capecitabine 825 mg/m2 bid including weekends during RT. RT was administered at 50.4 Gy (25 × 1.8 Gy with boost 3 × 1.8 Gy, 3D conformal technique), starting on week 3. Total mesorectal excision was scheduled 6-8 weeks after completion of CRT. Four to six cycles of adjuvant capecitabine chemotherapy were recommended. Results: Sixty-one patients were treated according to protocol: median age was 60 years (range 31-80), 64% of pts were male. Twelve pts (19.7%) presented with stage II and all other with stage III of disease. In 28 patients (45.9%) the tumour invaded the mesorectal fascia. Radical resection was achieved in 57 pts (95%). Sixty patients were eligible for efficacy analysis. TRG 4 (pCR) was recorded in 8 pts (13.3%) and TRG 3 in 9 pts (15%). Fifty-one pts (83.6%) received capecitabine postoperatively. In median follow-up of 60 months (7-60) we recorded four local relapses. The 5-y overall survival, recurrence-free survival, disease-free survival and local control rates were 72.2%, 75.6%, 70% and 92.4%, respectively. Conclusion: In LARC preoperative treatment intensification with bevacizumab concurrently with capecitabine based radiotherapy is well tolerated, with a high compliance rate and acceptable toxicity, as previously reported. Although the investigated treatment does not improve the local effect (pCR), updated long term efficacy results indicate that it achieves high LC rate, DFS, RFS and OS.
RONC-19. LATE NEUROPSYCHOLOGICAL OUTCOMES WITH PROTON RADIATION IN CHILDREN WITH BRAIN TUMOR
Authors: Domitilla Elena Secco, Antonella Cacchione, Francesca Del Bufalo, Sabina Vennarini, Giovanna Stefania Colafati, Ioan Paul Pietro Voicu, Simonetta Gentile, Francesca Santato, Sofia Anzeneder, Andrea Carai, Angela Mastronuzzi
Journal: Neuro-Oncology (2018)

Proton Beam therapy (PBT) is known for determining a lower iexposure of normal tissues to the radiation, therefore leading to lower long-term neuro-cognitive impairment. The present study is aimed at evaluating whether PBT in pediatric patients with brain tumors may lower or counteract the negative neurocognitive outcomes usually associated with photon radiation (XRT). We considered not only general neurocognitive abilities, but also differentiated sub-cortical functions. Seven of 14 hospitalized oncologic patients aged 4-12 years (3medulloblastomas, 3 germ cell tumors, 1 pineoblastoma), treated with PBT after surgical resection and chemotherapy, completed neuropsychological tests assessing both general intelligence quotient(IQ) and sectoral cognitive functions (freedom from distractibility, processing speed, language skills, memory, visual perception, neuro-motor associations, attention, higher executive functions). Assessments were performed prior to surgical resection and one year after the end of the PBT. Non-parametric tests for paired samples (Wilcoxon test) were used to assess pre-to-post differences. IQ scores (total, verbal and performance) remained stable with a statistically nonsignificant and clinically non meaningful decline trend. Sectoral cognitive functions showed in contrast incremental changes over time, which reached significance only for visual accuracy(Z=-2.366; p=.018; pre:-3.39 ± 1.62; post:-1.53 ± 1.91)and visual speed(Z=-2.197; p=.028; pre:-2.19 ± 0.58; post:-1.53 ± 0.83).In sum, PBT may result in cognitive sparing that exceeds that of XRT protocols observed in the literature. Although preliminary, our results also suggest that after PBT, there may be recovery in sectoral cognitive, especially particularly visual functions. Additional long-term data with larger cohort of patients are needed to fully understand the neurocognitive impact of PBT in survivors of pediatric brain tumors.
Dynamic intercellular redistribution of HIT antigen modulates heparin-induced thrombocytopenia
Authors: Jing Dai, Daria Madeeva, Vincent Hayes, Hyun Sook Ahn, Valerie Tutwiler, Gowthami M. Arepally, Douglas B. Cines, Mortimer Poncz, Lubica Rauova
Journal: Blood (2018)
The correlation between RhoA, CDH1 expression and clinicopathological characteristics in Chinese gastric cancer patients
Authors: Q. Wei, Q. He, Q. Xu, J. Li, L. Chen, C. Luo, J. Ying
Journal: Annals of Oncology (2018)

Introduction: The expression of RhoA and CDH1, are reported to be involved in cell adhesiveness. However, their clinicopathological characteristics in Chinese gastric cancer patients are controversial. Methods: Between December 2007 and January 2014, a total of 108 gastric cancer patients receiving surgery were enrolled in this study. Immunohistochemical (IHC) staining of the RhoA and CDH1 protein was performed. The results of IHC staining were classified as low expression group and high expression group. Clinicopathological characteristics and survival data were compared between groups with different expression levels. Results: There is no significant difference between the clinicopathological characteristics and RhoA expression. However, with regard to CDH1 expression, signet-ring cell component was significantly associated with low CDH1 expression(P < 0.001). TTF (medial time to treatment failure)(P = 0.042) and OS(medial overall survival)(P = 0.024) were longer in patients with low RhoA expression compared to those with high RhoA expression, which was not observed in CDH1 group. On multivariate analysis of patients, RhoA expression was an independent negative prognostic factor for overall survival whereas high CDH1 expression was not associated with a favorable prognosis. Conclusion: Taken together, our findings show that high CDH1 expression are associated with specific clinicopathologic characteristics. RhoA expression is an independent negative prognostic factor for gastric cancer.
Chemotherapy Sensitizes Therapy-Resistant Cells to Mild Hyperthermia by Suppressing Heat Shock Protein 27 Expression in Triple-Negative Breast Cancer
Authors: Chaofeng Mu, Xiaoyan Wu, Xinyu Zhou, Joy Wolfram, Jianliang Shen, Dechen Zhang, Junhua Mai, Xiaojun Xia, Ashley M. Holder, Mauro Ferrari, Xuewu Liu, Haifa Shen
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Triple-negative breast cancer (TNBC) is a clinically aggressive disease with poor prognosis. Conventional chemotherapeutics are generally able to shrink the tumor mass, but often fail to completely eradicate cancer stem–like cells (CSCs) that are responsible for high risk of relapse and frequent metastases. In this study, we examined thermal sensibility of CSCs, developed an approach that enabled concurrent elimination of both the bulk of cancer cells and CSCs, and investigated the underlying mechanism. Experimental Design: We designed a platform consisting of gold nanoparticle-coated porous silicon microparticle (AuPSM) that was also loaded with docetaxel micelles (mDTXs) to enable concurrent killing of the bulk of cancer cells by released mDTX and CSCs by mild hyperthermia upon stimulation of AuPSM with near infrared. In addition, we examined the role of heat shock proteins in sensitizing CSC killing. Finally, we applied mDTX-loaded AuPSM to treat mice with SUM159 and 4T1 orthotopic tumors and evaluated tumor growth and tumor metastasis. Results: MDA-MB-231 and SUM159 TNBC cells treated with mDTX-loaded AuPSM and mild hyperthermia displayed significantly reduced efficiencies in mammosphere formation than those treated with mDTX alone or mild hyperthermia alone. Combination treatment also completely inhibited SUM159 orthotopic tumor growth and 4T1 tumor metastasis. Mechanistically, DTX treatment suppressed expression of heat shock protein 27 in cancer cells including the CSCs, rendering cells sensitive to mild hyperthermia. Conclusions: Our results indicate that chemotherapy sensitizes CSC to mild hyperthermia. We have developed an effective therapeutic approach to eliminate therapy-resistant cells in TNBC. Clin Cancer Res; 24(19); 4900–12. ©2018 AACR.
QOL-55. HOME PHYSICAL ACTIVITY INTERVENTION TO IMPROVE COGNITIVE LATE EFFECTS IN CHILDREN TREATED WITH RADIATION FOR BRAIN TUMORS: DESCRIPTIVE FEASIBILITY DATA FROM A PILOT RANDOMIZED CONTROLLED TRIAL (RCT)
Authors: Pamela Wolters, Cristina Abel, Staci Martin, Kevin Smith, Mary Anne Toledo-Tamula, Marie Claire Roderick, Bart Drinkard, Kong Chen, Arthur Kramer, Adrian Schembri, Joan Han, John Glod, Katherine Warren
Journal: Neuro-Oncology (2018)

Cranial radiation therapy (CRT) contributes to cognitive late effects that require rehabilitative interventions. Physical activity (PA) targets CRT-damaged brain mechanisms and cognitive functions. We conducted a pilot RCT to evaluate the feasibility of an innovative home PA intervention program for children treated with CRT for brain tumors. Eligible children 8-17 years, >two years post-CRT, with cognitive late effects were randomized to the Intervention Group (IG), which followed a 12-week home program to increase PA then maintained PA for 12 weeks, or the Control Group (CG), which monitored usual PA for 12 weeks followed by the 12-week program. Psychologists taught Acceptance and Commitment Therapy (ACT) techniques to facilitate PA engagement. Participants used Zamzee accelerometers/website to track moderate-to-vigorous PA (MVPA). Evaluations included plasma/serum circulating growth factors, cardiovascular fitness, cognitive function pre/post the first 12 weeks, and child/parent feasibility questionnaires (1-5 ratings, categories, open-ended questions). Six children (mean age=13.8 years, 10-17; IG=3; CG=3) enrolled and completed the study. Participants enjoyed the activity tracker (mean=3.8) and wore it 3-4 times/week to daily, but it broke easily; most liked the website’s activity graphs, rewards, and challenges (mean=3.3; uploaded data/viewed <1 to 4 times/week). Children rated the ACT sessions/emails lower (mean=2.6) although goal-setting was used consistently. Most frequent self-selected PAs were running, walking, and basketball. Participants liked the program (mean=4.1) and found it helpful (mean=4.0); 6/6 increased their weekly MVPA (total means 41 to 130 minutes). These pilot data suggest good feasibility but indicate aspects of the home PA intervention to revise for the full RCT.
HGG-07. THE DIVERSITY OF MOLECULAR CHARACTERISTICS IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Akihide Kondo, Junya Fujimura, Osamu Akiyama, Mario Suzuki, Hiroyuki Tamaichi, Hajime Arai
Journal: Neuro-Oncology (2018)

High-grade gliomas are challenging tumor to treat in both adult and pediatric patients. Although the incidence of high-grade glioma in the pediatric population is less than that in the adult population, the prognosis of this tumor seems to be better in pediatric patients than in adult patients. Especially in neonatal patients, even a case of spontaneous resolution of tumor was reported, while the patients over 10 years old are difficult to control the progression of tumors. Then, we examine molecular characteristics of high-grade gliomas in 6 pediatric patients according to patients’ ages, those are from 24 days old to 13 years old. Our analysis showed the status of molecular was inconsistent by ages. Based on these observations, we think that high-grade gliomas in pediatric patients may have a diversity of molecular characteristics depending on the age of onset of tumors.
DIPG-50. CHROMATIN IMMUNOPRECIPITATION OF DIFFUSE INTRINSIC PONTINE GLIOMA TUMOR TISSUE IS FEASIBLE AND SHOW DIFFERENT ENRICHMENT COMPARED TO PRIMARY CELL LINE
Authors: Yong Yean Kim, Jaclyn Andricovich, Sridevi Yadavilli, Madhuri Kambhampati, Alexandros Tzatsos, Javad Nazarian
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is the leading cause of mortality in pediatric central nervous system cancers. Histone mutations are found in >80% of DIPG cases. The most common mutation is histone 3.3 at position 27 resulting in lysine to methionine(H3.3K27M). This mutation results in epigenetic changes in methylation and acetylation of histones leading to aberrant change in transcription globally. Analysis of epigenetic changes via chromatin immunoprecipitation followed by sequencing (ChIP-Seq) has been performed in DIPG cell lines but not in tumor tissue. Culture conditions may not accurately reflect the epigenome of the tumor, thus we performed ChIP on three H3.3K27M mutant DIPG tumors (PID675, PID693, PID874). Checking enrichment by PCR revealed that the HOXA gene was enriched by tri-methylation at K27 (K27me3) and TOP3A was enriched by acetylation at K27 (K27ac), as expected. There was enrichment in both K27me3 and K27ac for GLI2. CDKN2A was enriched in K27me3 indicating down regulation in tumor tissue. However, in the DIPG primary cell line derived from PID675, CDKN2A was not enriched in K27me3 or K27ac and GLI2 was only enriched in K27ac. Given the difference seen between tumor tissue and cell line, our findings highlight the crucial importance of profiling the actual tumor tissue in DIPG.