tbuckley/cabot-search huggingface dataset:
DIPG-61. HISTONE DEACETYLASE INHIBITOR PANOBINOSTAT SYNERGIZES WITH DUAL MTOR INHIBITOR TAK228 TO POTENTIATE KILLING OF DIPG CELLS
Authors: Smit Shah, Jeffrey Rubens, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2018)

We have previously identified activity of the brain-penetrating dual TORC1/2 kinase inhibitor TAK228 (MLN0128) in DIPG. Currently, HDAC inhibitor Panobinostat is in clinical trials in patients with DIPG and is also known to synergize with mTOR inhibition in other cancer types. We hypothesized that TAK228 and Panobinostat would synergize to increase killing of DIPG cells. We found that each drug was effective at low nanomolar doses in JHH-DIPG1, SF7761, SU-DIPG-13 and JHH-DIPG16A. SF7761 and JHH-DIPG16A are derived from pre-treatment biopsies while SUDIPG13 and JHH-DIPG1 are derived from autopsy samples. Panobinostat increased H3KAc27 in all cell lines at low nanomolar doses. TAK228 also inhibited both TORC1 (pS6) and TORC2 (pAKT) at low nanomolar doses. Combination therapy caused a fivefold 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 40 percent increase in this marker of apoptosis as well (p<0.01 by ANOVA). Because both agents have a short half-life in mice, we hypothesize that an altered dosing scheme may be feasible to take advantage of the rapid induction of apoptotic synergy caused by dual treatment. 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.
NSRG-13. INTER-RATER RELIABILITY OF A METHOD FOR DETERMINING THE PRE-OPERATIVE HYPOTHALAMIC INVOLVEMENT OF PEDIATRIC CRANIOPHARYNGIOMA
Authors: Ros Whelan, Eric Prince, David Mirsky, Robert Naftel, Aashim Bhatia, Benedetta Pettorini, Shivram Avula, Susan Staulcup, Matthew Cox-Martin, Todd Hankinson
Journal: Neuro-Oncology (2018)

Pediatric craniopharyngioma confers significant morbidity, with injury to the hypothalamus representing a particular challenge. This insight led to reconsideration of goals of surgery for certain patients. Puget et al (2007), proposed a pre- and post-operative grading system based on the degree of hypothalamic invasion on MRI. Their system defined three grades: 0, 1, and 2 where 0 represents no involvement of the hypothalamus, 2 represents hypothalamic involvement and 1 is defined as tumor abutting the hypothalamus. In a prospective cohort, they found that use of the system decreased morbidity. This system, however, has not been externally validated. We present the results of an inter-rater reliability study to predict the feasibility of this approach in the treatment of pediatric craniopharyngioma. Six experts graded twenty-nine pre- and postoperative MRI scans according to the methods of Puget and colleagues. Inter-rater reliability was calculated using Fleiss K and Krippendorf alpha values. Inter-rater reliability in the pre-operative context was in the range of 0.57-0.58 (K and alpha values respectively), demonstrating only moderate agreement. Inter-rater reliability in the post-operative context was in the range of 0.39 for both methods of statistical evaluation. Inter-rater reliability for the system as defined is moderate. It may be possible that slight refinements of the MRI grading system, such as collapsing the 3 grades into 2, will allow for improvement in reliability.
CRAN-01. QUALITY OF LIFE AND GROWTH AFTER CHILDHOOD CRANIOPHARYNGIOMA: RESULTS OF THE MULTINATIONAL TRIAL KRANIOPHARYNGEOM 2007
Authors: Kerstin Heinks, Svenja Boekhoff, Monika Warmuth-Metz, Maria Eveslage, Junxiang Peng, Gabriele Calaminus, Hermann L Müller
Journal: Neuro-Oncology (2018)

Quality of life (QoL) after childhood-onset craniopharyngioma (CP) is frequently impaired due to tumor and/or treatment-related factors such as endocrine deficits and hypothalamic involvement/lesions. PATIENTS AND In a multinational trial, we prospectively analyzed parental and self-assessment of CP patient QoL at 3 months, one and 3 years after CP diagnosis related to growth hormone (GH) substitution. 47 of 194 CP recruited between 2007 and 2015 in KRANIOPHARYNGEOM 2007 were analyzed for QoL one and 3 years after CP diagnosis. QoL was assessed by Pediatric Quality of Life (PEDQOL) questionnaire and PEDQOL scores of parental and self-assessed QoL during 3 years follow-up after CP diagnosis were analyzed. Parents estimated QoL of their children worse than patients did themselves. GH substitution had no relevant effect on short-term weight and height development. CP patients GH-treated at 3 years follow-up presented at baseline (one year after diagnosis, before GH substitution) with reduced self-assessed QoL when compared with GH non-treated CP. QoL stabilized during 1–3 years of follow-up in GH-treated patients, whereas non GH-treated patients experienced decreases in autonomy (p=0.03), cognition (p=0.01), and physical function (p=0.04). Parents assess QoL in CP survivors worse than their children. GH substitution should be considered as a therapeutic option to ameliorate imminent impairments of QoL after CP.
DIPG-03. EXCITATORY SYNAPSES BETWEEN PRESYNAPTIC NEURONS AND POSTSYNAPTIC GLIOMA CELLS PROMOTE DIPG PROGRESSION
Authors: Humsa Venkatesh, Anna Geraghty, Wade Morishita, Lydia Tam, Itay Tirosh, Aviv Regev, Hannes Vogel, Mario Suva, Robert Malenka, Michelle Monje
Journal: Neuro-Oncology (2018)

High-grade gliomas represent the leading cause of brain tumor-associated death in children. We have recently discovered that active neurons robustly regulate glioma growth through activity-regulated secreted factors that critically include neuroligin-3. Secreted neuroligin-3, in addition to activating multiple oncogenic signaling pathways, induces glioma cell expression of numerous synapse-associated genes. Here, we report that neuron-glioma interactions include bona fide synaptic communication. Glioma cell expression of synapse-related genes was confirmed at the single cell level in primary glioma samples. Structural synapses between presynaptic neurons and post-synaptic glioma cells were identified by high-resolution confocal and electron microscopy. Voltage clamp recordings from patient-derived DIPG cells xenografted to the CA1 region of the hippocampus demonstrates AMPAR-mediated excitatory neurotransmission between presynaptic neurons and post-synaptic glioma cells with local electrode stimulation of inputs to the CA1 region. Millisecond timescale excitatory post-synaptic currents (EPSCs) were observed in approximately 10% of DIPG cells. A subpopulation of glioma cells exhibit a second electrophysiological profile with longer, ~1 sec depolarization in response to neuronal activity. As depolarization of normal neural precursor cells during development affects neural stem cell proliferation, we tested the hypothesis that neuron to glioma synapse-mediated depolarization promotes glioma growth. Using in vivo optogenetic techniques to depolarize patient-derived DIPG cells, we found that DIPG cell depolarization robustly promotes proliferation. These findings define an unexpected integration of glioma cells into neural circuitry, identify excitatory synaptic neurotransmission as a mechanism driving glioma growth and elucidate the previously unexplored potential to target glioma circuit dynamics for therapy of these lethal cancers.
Impact of FOLFOXIRI and bevacizumab (bev) compared to FOLFOX and bev on health related quality of life (HRQOL) in patients with metastatic colorectal cancer (MCRC): Analysis of the CHARTA-AIO 0209 trial.
Authors: Julia Quidde, Hans-Joachim Schmoll, Benjamin Garlipp, Christian Junghanss, Malte Leithaeuser, Arndt Vogel, Michael Schaefers, Ulrich Kaiser, Heinz-Gert Hoeffkes, Axel Florschütz, Jörn Rüssel, Stephan Kanzler, Thomas Edelmann, Helmut Forstbauer, Thomas Goehler, Carla Hannig, Bert Hildebrandt, Carsten Bokemeyer, Jörg Steighardt, Alexander Stein
Journal: Journal of Clinical Oncology (2017)

3544 Background: FOLFOXIRI/bev is a highly efficacious first line regimen in MCRC. Despite higher rates of neutropenia, diarrhea and stomatitis, FOLFOXIRI/bev is tolerable and feasible in MCRC patients. To date nothing is known about the impact of this regimen on HRQOL. Methods: 250 patients were randomized to FOLFOX/bev (arm A) or FOLFOXIRI/bev (arm B). HRQOL were assessed at baseline, every 8 weeks during induction treatment (6 months) and every 12 weeks during maintenance treatment, using the EORTC QLQ-C30, QLQ-CR29 and QLQ-CIPN20. The mean values of every score were calculated as the average of week 8, 16 and 24 assessment. Test concerning mean values were performed as t-test, with global type I error set at 0.05. HRQOL deterioration and improvement rates were analyzed and compared between treatment groups using chi² tests. Results: For HRQOL analysis, 237 patients were eligible (arm A: 118; arm B: 119). Compliance rate with the HRQOL questionnaires was 95.4% at baseline, 72.6% at week 8, 59.5 % at week 16 and 43.5% at week 24. Whereas mean global quality of life score (GHS/QOL) was similar between arm A and B (59.8 vs. 58.8; p = 0.726), mean scores for nausea/vomiting (9.4 vs. 16.0; p = 0.015) and diarrhea (23.7 vs. 32.1; p = 0.051) significantly or borderline significantly favored arm A during induction period. Furthermore, at week 8 scores of nausea/vomiting (9.2 versus 17.3, p = 0.006) appetite loss (19.5 vs. 29.4; p = 0.035) and financial problems (18.3 vs. 29.5; p = 0.021) and at the end of treatment physical functioning (75.0 vs. 65.8; p = 0.048) were significantly better for arm A compared to arm B. No significant differences were observed in the remaining EORTC scores. The rates of deterioration and improvement between baseline and week 8 of at least 10 points in the EORTC scores were similar (e.g. deterioration-rate GHS/QOL score 21.5% vs. 26.5% for arm A vs. B; p = 0.461). Conclusions: Although no remarkable detriment in HRQOL was noted, the better efficacy of FOLFOXIRI/bev compared to FOLFOX/bev is associated with a decrease in mainly gastrointestinal QOL scores. Further subgroup-analyses will be presented at the meeting. Clinical trial information: NCT01321957.
PCLN-09. LEVERAGING CONVOLUTIONAL NEURAL NETWORKS TO PREDICT ADAMANTINOMATOUS CRANIOPHARYNGIOMA DIAGNOSIS FROM PREOPERATIVE PARAMETERS
Authors: Eric Prince, Ros Whelan, Susan Staulcup, Kenneth Jones, Michael Yang, Lindsey Hoffman, Michael Handler, Nicholas Stence, Todd Hankinson
Journal: Neuro-Oncology (2018)

Adamantinomatous craniopharyngioma (ACP) is a rare epithelial tumor that arises in the suprasellar region. The clinical complexity associated with ACP requires unique surgical goals, making preoperative diagnosis highly desirable. Presently, definitive diagnosis of ACP requires operative tissue sampling. ACP harbors unique features on axial imaging, including cystic and calcified components. Convolutional neural networks (CNN) are computational systems that enable machines to learn operations via the assessment of examples that are task-independent, and are applied to various research fields such as computer vision and machine learning. CNNs are particularly useful with image recognition, as this preserves spatial relationships of data. CNNs have been shown to successfully identify images without a priori information of features. Inductive Transfer is a machine learning concept that is concerned with storing knowledge gained from solving a problem and applying that knowledge to a different problem. Using Inductive Transfer to overcome relatively low class populations, we leveraged the knowledge learned from several CNN models, including the Google® Inception-v4 architecture. CNNs were used to classify ACP out of a preoperative medical image dataset that also included other pathologies present in ACP differential diagnoses, such as pituitary adenoma, optic tract glioma, etc. Even baseline performance rivalled that of human performance by clinical experts. Our results suggest that CNNs can be utilized improve the reliability of pre-operative diagnosis of ACP, thereby improving clinical care.
Practical guidelines for the characterization and quality control of pure drug nanoparticles and nano-cocrystals in the pharmaceutical industry
Authors: Leena Peltonen
Journal: Advanced Drug Delivery Reviews (2018)

The number of poorly soluble drug candidates is increasing, and this is also seen in the research interest towards drug nanoparticles and (nano-)cocrystals; improved solubility is the most important application of these nanosystems. In order to confirm the functionality of these nanoparticles throughout their lifecycle, repeatability of the formulation processes, functional performance of the formed systems in pre-determined way and system stability, a thorough physicochemical understanding with the aid of necessary analytical techniques is needed. Even very minor deviations in for example particle size or size deviation in nanoscale can alter the product bioavailability, and the effect is even more dramatic with the smallest particle size fractions. Also, small particle size sets special requirements for the analytical techniques. In this review most important physicochemical properties of drug nanocrystals and nano-cocrystals are presented, suitable analytical techniques, their pros and cons, are described with the extra input on practical point of view.
Amrubicin in patients with platinum-refractory metastatic neuroendocrine carcinoma of the gastrointestinal tract
Authors: H. Osumi, E. Shinozaki, K. Chin, D. Takahari, M. Ogura, T. Ichimura, T. Wakatsuki, Y. Ota, I. Nakayama, M. Suenaga, K. Yamaguchi
Journal: Annals of Oncology (2018)

Introduction: Patients with gastrointestinal neuroendocrine carcinoma (GI-NEC) have a poor prognosis. Platinum-based combination chemotherapy is commonly used as first-line treatment; however, there are a few reports about the role of amrubicin (AMR) and salvage chemotherapy for GI-NEC. This study aimed to analyze the efficacy and safety of AMR monotherapy in patients with platinum-refractory GI-NEC. Methods: We retrospectively analyzed platinum-refractory GI-NEC patients who received AMR monotherapy between April 2012 and September 2017 at the Cancer Institute Hospital. The dose of AMR administered was 30–45 mg/m2 on days 1–3 every 3–4 weeks. We evaluated the overall response rate (ORR) according to the RESICT ver1.1, progression-free survival (PFS), overall survival (OS), and adverse events by CTCAE ver 4.0. OS and PFS were estimated using the Kaplan-Meier method and compared using the log-rank test. All reported P values were the result of two-sided tests; P < 0.05 was considered significant. Results: 14 males and 3 females (median age, 65 years (range, 60–75)) were received platinum-based chemotherapy before AMR monotherapy. (cisplatin plus irinotecan (n = 14, 82.3%), cisplatin plus etoposide (n = 1, 5.9%), and fluoropyrimidine plus platinum (n = 2, 11.8%) Primary sites of NEC included stomach (n = 10, 58.8%), colorectal (n = 3, 17.6%), esophagus (n = 3, 17.6%), and duodenum (n = 1, 5.9%). The median cycles of AMR administration were 3 (range, 1-15). The ORR rate was 5.8%, the median PFS was 2.1 months (1.4–6.9), and the median OS was 13.7 months (6.9–17.2). Grade 3/4 neutropenia occurred in 41.1% of patients and febrile neutropenia occurred in 5.8%. Other non-hematological toxicities were not severe and treatment related deaths were not observed. 11 patients received the subsequent chemotherapy after AMR and they had significantly longer OS than those who couldn't be received the subsequent chemotherapy. (17.2 months (5.9–NA) vs. 8.9 months (1.1–NA), p = 0.0427). Conclusion: AMR showed minimum activity and safety when used for the treatment of platinum-refractory GI-NEC. Neutropenia was encountered as the most serious adverse event. It should be considered to perform the subsequent chemotherapy after AMR if possible.
IMMU-13. A FAILURE TO RESOLVE INFLAMMATION: ROLE OF RESOLVINS IN THE TREATMENT OF PEDIATRIC CNS TUMORS
Authors: Jessica Clymer, Chantal Barksdale, Jaimie Chang, Nicholas Kieran, Megan Sulciner, Romain Colas, Pratiti Bandopadhayay, Sui Huang, Charles Serhan, Dipak Panigrahy, Mark Kieran
Journal: Neuro-Oncology (2018)

Current brain tumor therapies are focused on reducing tumor burden by inducing apoptotic and necrotic tumor cells. However, inflammation in the tumor microenvironment caused by this debris can accelerate tumor progression. Inflammation is endogenously regulated resolvins and protectins, molecules that are biosynthesized and act in the brain and cerebrospinal fluid. They clear cellular debris via local macrophages while reducing localized inflammatory cytokines. We hypothesized that control of inflammation through resolvins and protectins could represent a novel treatment modality by pharmacologically promoting the clearance of tumor cell debris by microglia, thereby depriving the surviving tumor cells of inflammatory stimuli. METHODS AND We show that debris generated by killing of either medulloblastoma or glial tumors (using cisplatin chemotherapy, dabrafenib targeted therapy or the epigenetic inhibitors JQ1) stimulate residual live tumor cells to grow. This effect was inhibited by nanogram levels of resolvins/protectins and without toxicity in a variety of tumor types including orthotopic models. The effect was mediated via enhanced macrophage and microglial phagocytosis of tumor cell debris and counter-regulation the secretion of pro-inflammatory cytokines/chemokines, including CCL5, TNFα, CCL2, CXCL1, and CCL4. We show that resolvins and protectins stimulate the clearance of tumor cell debris by stimulating macrophage and microglial phagocytosis and counter-regulating pro-inflammatory and pro-tumorigenic cytokines. This approach not only has relevance to our current approaches to cancer therapy (focused on maximal tumor cell kill), but may have an impact on the side effects of current immunotherapies where therapy induced inflammation in the tumor results in significant morbidity.
Mast cell activation syndrome: Importance of consensus criteria and call for research
Authors: Peter Valent, Cem Akin, Patrizia Bonadonna, Karin Hartmann, Sigurd Broesby-Olsen, Knut Brockow, Joseph H. Butterfield, Andreas Reiter, Jason Gotlib, Mariana Castells, Joshua D. Milner, Melody C. Carter, Hirsh Komarow, Deepti Radia, Animesh Pardanani, Karl Sotlar, Massimo Triggiani, Hans-Peter Horny, Michel Arock, Lawrence B. Schwartz, Dean D. Metcalfe
Journal: Journal of Allergy and Clinical Immunology (2018)
Th1/Th17 polarization persists following whole-cell pertussis vaccination despite repeated acellular boosters
Authors: Ricardo da Silva Antunes, Mariana Babor, Chelsea Carpenter, Natalie Khalil, Mario Cortese, Alexander J. Mentzer, Grégory Seumois, Christopher D. Petro, Lisa A. Purcell, Pandurangan Vijayanand, Shane Crotty, Bali Pulendran, Bjoern Peters, Alessandro Sette
Journal: Journal of Clinical Investigation (2018)

In the mid-1990s, whole-cell pertussis (wP) vaccines were associated with local and systemic adverse events that prompted their replacement with acellular pertussis (aP) vaccines in many high-income countries. In the past decade, rates of pertussis disease have increased in children receiving only aP vaccines. We compared the immune responses to aP boosters in individuals who received their initial doses with either wP or aP vaccines using activation-induced marker (AIM) assays. Specifically, we examined pertussis-specific memory CD4+ T cell responses ex vivo, highlighting a type 2/Th2 versus type 1/Th1 and Th17 differential polarization as a function of childhood vaccination. Remarkably, after a contemporary aP booster, cells from donors originally primed with aP were (a) associated with increased IL-4, IL-5, IL-13, IL-9, and TGF-β and decreased IFN-γ and IL-17 production, (b) defective in their ex vivo capacity to expand memory cells, and (c) less capable of proliferating in vitro. These differences appeared to be T cell specific, since equivalent increases of antibody titers and plasmablasts after aP boost were seen in both groups. In conclusion, our data suggest that there are long-lasting effects and differences in polarization and proliferation of T cell responses in adults originally vaccinated with aP compared with those that initially received wP, despite repeated acellular boosters.
MBCL-45. ROLE OF IRRADIATION IN RELAPSED MEDULLOBLASTOMA: A REPORT OF THE GERMAN MEDULLOBLASTOMA RELAPSE STUDIES
Authors: Stephan Tippelt, Julia Küter, Ruth Mikasch, Nele Siegler, Monika Warmuth-Metz, Stefan Rutkowski, Martin Mynarek, Katja von Hoff, Torsten Pietsch, Stefan M Pfister, Olaf Witt, Rolf-Dieter Kortmann, Stefan Dietzsch, Robert Kwiecien, Andreas Faldum, Udo Bode, Gudrun Fleischhack
Journal: Neuro-Oncology (2018)

In pediatric patients with medulloblastoma (MB) the 5-year-OS rate dependent on risk group is 35% to 90%. In unresectable or metastatic recurrence longterm prognosis is poor. Aim of this study was to evaluate the role of irradiation in relapsed MB patients registered in the German studies HIT-MED, HIT-REZ-97/-2005 and HIT-REZ-Registry between July 1997 and December 2016. Data analyzed at relapse were age, gender, stage, primary/relapse therapy, and follow-up. Kaplan-Meier analysis and log rank test were used to estimate the PFS/OS after 1st recurrence and (re)irradiation. 257 patients with recurrent/refractory MB [75 female/182 male, median age 11.0 years (0.8-37.9), median PFS after 1st diagnosis 24.8 months (2.6-270.2), 81% metastatic disease at relapse] were included in this analysis. Median PFS and OS after first relapse were 12.3 months (95%CI: 9.4;15.2) and 23.8 months (95%CI: 19.3-28.3), the 5-year-PFS and 5-year-OS rate were 6.8%±1.7% and 19.3%±2.7%, respectively. The PFS and OS differed significantly between 4 different cohorts: patients (A) with 1st irradiation at 1st relapse (n=29), (B) with re-irradiation (n=54), (C) without re-irradiation at 1st relapse (n=164), and (D) without irradiation at any time (10). The best 5-year-PFS and 5-year-OS rate were observed in cohort A with 20.1% ±7.8 and 34.2% ±9.3, respectively. Looking for different strata significant differences were seen in patients with metastatic disease. Radiotherapy at relapse can be used as salvage therapy in patients without primary irradiation. It can lead to prolonged PFS and OS especially in patients with metastatic disease. Supported by German Children’s Cancer Foundation.