tbuckley/cabot-search huggingface dataset:
P14.84 Intraarterial chemotherapy and osmotic blood-brain barrier modification in the treatment of primary CNS lymphoma
Authors: D Fortin, G Gahide, C Iorio-Morin
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Primary central nervous system lymphomas (PCNSL) are considered a rare and aggressive form of central nervous system (CNS) tumors. High-dose methotrexate has become the backbone of PCNSL treatment, and is recommended by the EANO guidelines. In most recent protocols, investigators tend to postpone or even avoid the use of radiotherapy; indeed, its use has become controversial with findings of associated severe neuro-toxicity, especially in elderly patients. To maximize delivery across the BBB, we use cerebral intra-arterial chemotherapy (CIAC) coupled with osmotic blood-brain barrier disruption (OBBBD). We hereby report our single-center experience over 18 years with the CIAC + BBBD technique using 2 different HD-MTX protocols. MATERIAL AND METHODS This phase II study was conducted at the Centre hospitalier Universitaire de Sherbrooke (CHUS) from November 1999 to May 2018. The protocol was approved by the institutional review board, and informed consent was obtained in accordance to institutional regulation in every patient After enrollment and initial evaluation, patients were treated every four weeks (1 cycle) for 12 cycles, unless progression. After general anesthesia, a transfemoral approach was used to catheterize either the right or left internal carotid artery or the dominant vertebral artery, depending on tumor(s) location. OBBBD was performed by infusing 20% mannitol in the selected vascular distribution for 30 seconds at a rate that fills the vascular distribution so as to maximize the contact of the mannitol with the endothelial cells.Two different chemotherapy regimens were sequentially used in this study. High-dose MTX (5 g IV) was the cornerstone of both regimens: the first regimen (1999 to 2007) also included etoposide phosphate IV (400 mg/m²) and cyclophosphamide IV (660 mg/m²), whereas the 2nd regimen (1998 to 2018) also included carboplatin IA (400 mg/m²). RESULTS The present analysis therefore concerns a cohort of 44 naive patients recruited over 18 years in a single center. Median follow-up was 38 months. Overall, a CR was induced in 34 patients (79%). Themedian time to CR was 7.3 months (IQR: 7.8). Of these 34 patients, 11 (25.6%) are still alive, and 9 of these are disease-free after treatment discontinuation. The actuarial median survival (MS) was 46.5 months (95% CI: 30.9–62.2) for the cohort. Survival was 88%, 64%, 54%, 39% and 18% at 1, 2, 3,5 and 10 years (Figure 1 and Table 2).The progression-free survival was 43.4 months (95% CI: 17.9–68.9). Five occurrences of vascular complications related to the treatment were observed (11.6%). Conclusion: CIAC HD-MTX-based protocols with OBBBD is a safe and well-tolerated procedure for the management of primary CNS lymphoma. Our single center data suggests better PFS and survival outcomes compared to IV protocols with less hematologic toxicity and good tolerability, especially in the elderly.
HLA Class I-Specific Effects in AML with Mutated Nucleophosmin
Authors: Kateřina Kuželová, Christoph Röllig, Zdenek Racil, Juliane S. Stickel, Barbora Brodská, Johannes Schetelig, Christian Thiede, Gerhard Ehninger, Grzegorz Helbig, Slawomira Kyrcz-Krzemien, Jiri Mayer, Petr Cetkovsky
Journal: Blood (2016)
Efficacy of an oncology palliative care clinic for improving symptom management and patient satisfaction
Authors: M. Follwell, D. Burman, K. Wakimoto, D. Seccareccia, J. Bryson, G. Sirianni, L. Le, G. Rodin, C. Zimmermann
Journal: Journal of Clinical Oncology (2007)

19552 Background: Previous studies to assess symptom control in a palliative care clinic setting have largely been retrospective. This study prospectively assesses the efficacy of an Oncology Palliative Care Clinic (OPCC) for improving symptom management and satisfaction with cancer care. Methods: All consenting patients newly referred to the OPCC completed the Edmonton Symptom Assessment System (ESAS) and the FAMCARE Scale (modified for patient use) at baseline, one week, and one month. The primary outcomes were the ESAS distress and FAMCARE total scores, for which one-week analyses are presented (paired t-test). Individual ESAS symptom scores were also assessed in an exploratory analysis, with the p-value set at 0.01 to provide some protection from multiple comparisons. Results: 118 patients, all with metastatic cancer, have completed the one-week assessment. The mean ESAS symptom distress score at baseline was 38.31±18.34. One week after the initial OPCC assessment there was a mean decrease in the distress score of 7.94 units (95%CI 5.11–10.76, p&lt;0.0001). The mean baseline score for patient satisfaction was 66.31±13.23, with a mean increase of 7.22 points at one week (95%CI 4.51–9.94, p&lt;0.0001). Individual symptom scores that showed the greatest improvement were anxiety (improved 1.40 units; p&lt;0.0001), nausea (1.16 units, p = 0.0001), dyspnea (1.08 units; p = 0.0003), insomnia (0.97 units, p = 0.0003), pain (1.01 units, p = 0.0018), drowsiness (0.93 units, p = 0.0083), appetite (0.86 units, p = 0.0023) and fatigue (0.77 units p = 0.0039). The only symptoms that did not reach statistical significance were constipation (improved by 0.71, p = 0.053) and depression (0.6 units, p = 0.018). Conclusions: One week after assessment in an OPCC, there were significant improvements in symptom distress and satisfaction with care. It remains to be determined whether or not these results will be sustained at one month. Randomized controlled trials of the effectiveness of an OPCC are needed. No significant financial relationships to disclose.
Targeting innate immunity for tuberculosis vaccination
Authors: Shabaana A. Khader, Maziar Divangahi, Willem Hanekom, Philip C. Hill, Markus Maeurer, Karen W. Makar, Katrin D. Mayer-Barber, Musa M. Mhlanga, Elisa Nemes, Larry S. Schlesinger, Reinout van Crevel, Ramakrishna Vankalayapati, Ramnik J. Xavier, Mihai G. Netea
Journal: Journal of Clinical Investigation (2019)

Vaccine development against tuberculosis (TB) is based on the induction of adaptive immune responses endowed with long-term memory against mycobacterial antigens. Memory B and T cells initiate a rapid and robust immune response upon encounter with Mycobacterium tuberculosis, thus achieving long-lasting protection against infection. Recent studies have shown, however, that innate immune cell populations such as myeloid cells and NK cells also undergo functional adaptation after infection or vaccination, a de facto innate immune memory that is also termed trained immunity. Experimental and epidemiological data have shown that induction of trained immunity contributes to the beneficial heterologous effects of vaccines such as bacille Calmette-Guérin (BCG), the licensed TB vaccine. Moreover, increasing evidence argues that trained immunity also contributes to the anti-TB effects of BCG vaccination. An interaction among immunological signals, metabolic rewiring, and epigenetic reprogramming underlies the molecular mechanisms mediating trained immunity in myeloid cells and their bone marrow progenitors. Future studies are warranted to explore the untapped potential of trained immunity to develop a future generation of TB vaccines that would combine innate and adaptive immune memory induction.
Functional extracellular vesicles engineered with lipid-grafted hyaluronic acid effectively reverse cancer drug resistance
Authors: Jia Liu, Zhilan Ye, Mengxi Xiang, Bingcheng Chang, Jinyuan Cui, Tiantian Ji, Lei Zhao, Qilin Li, Yan Deng, Luming Xu, Guobin Wang, Lin Wang, Zheng Wang
Journal: Biomaterials (2019)
Automated tracking of level of consciousness and delirium in critical illness using deep learning
Authors: Haoqi Sun, Eyal Kimchi, Oluwaseun Akeju, Sunil B. Nagaraj, Lauren M. McClain, David W. Zhou, Emily Boyle, Wei-Long Zheng, Wendong Ge, M. Brandon Westover
Journal: npj Digital Medicine (2019)

Over- and under-sedation are common in the ICU, and contribute to poor ICU outcomes including delirium. Behavioral assessments, such as Richmond Agitation-Sedation Scale (RASS) for monitoring levels of sedation and Confusion Assessment Method for the ICU (CAM-ICU) for detecting signs of delirium, are often used. As an alternative, brain monitoring with electroencephalography (EEG) has been proposed in the operating room, but is challenging to implement in ICU due to the differences between critical illness and elective surgery, as well as the duration of sedation. Here we present a deep learning model based on a combination of convolutional and recurrent neural networks that automatically tracks both the level of consciousness and delirium using frontal EEG signals in the ICU. For level of consciousness, the system achieves a median accuracy of 70% when allowing prediction to be within one RASS level difference across all patients, which is comparable or higher than the median technician-nurse agreement at 59%. For delirium, the system achieves an AUC of 0.80 with 69% sensitivity and 83% specificity at the optimal operating point. The results show it is feasible to continuously track level of consciousness and delirium in the ICU.
P11.09 Pan-RTK inhibition of sLRIG1 mediates AXL downregulation in Glioblastoma
Authors: V Neirinckx, A Hau, A Schuster, S Fritah, A Chevigné, M H H Schmidt, S P Niclou
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Aberrant regulation of receptor tyrosine kinase (RTK) activity is characteristic of Glioblastoma (GBM). However, RTK-based targeted therapies have been largely unsuccessful in GBM patients, partially due to the complexity and redundance of RTK signaling. LRIG1 (Leucine-rich Repeats and ImmunoGlobulindomains protein 1) is known as an endogenous inhibitor of epidermal growth factor receptor (EGFR) during health and disease, however its mechanism of action is poorly understood. We previously showed that the soluble form of LRIG1 potently inhibits of GBM growth in vivo, irrespective of EGFR expression level and status, suggesting the involvement of other RTKs. Here, we aimed to shed light on the molecular mechanisms underlying its anti-cancer activity. MATERIAL AND METHODS We generated a recombinant human soluble LRIG1 protein by expressing LRIG1 ectodomain in insect cells via baculovirus infection and subsequent His-tag purification. rh-sLRIG1 was applied in the medium of classical GBM cell lines, patient-derived GBM stem-like cells and patient-derived 3D tumor organoids. Using different cell-based assays, cell proliferation, invasion, cell morphology, as well as protein expression and protein-protein interactions were investigated. RESULTS We find that recombinant sLRIG1 efficiently reduces proliferation, invasion and viability of GBM cells and patient-derived organoids, and modulates cytoskeleton proteins and cell shape. In line with previous data, the effect of recombinant sLRIG1 is independent of EGFR expression. Interestingly sLRIG1 regulates several RTKs by direct protein downregulation, including AXL, while EGFR expression is not affected. At the molecular level, we find that sLRIG1 interferes with AXL dimerization, while no protein interaction with EGFR is detected. CONCLUSION We identify AXL as a novel LRIG1 target and provide evidence that sLRIG1-mediated RTK downregulation requires direct protein-protein interaction. These data pave the way for a potential therapeutic application of recombinant sLRIG1 in the inhibition of growth factor signaling in GBM.
The Chemotherapy-Free Combination of Vemurafenib and Rituximab Produces Deep and Durable Responses in Relapsed or Refractory Hairy Cell Leukemia (HCL) Patients
Authors: Enrico Tiacci, Luca De Carolis, Francesco Zaja, Monia Capponi, Achille Ambrosetti, Eugenio Lucia, Agostino Antolino, Alessandro Pulsoni, Samantha Ferrari, Pier Luigi Zinzani, Luigi Rigacci, Gianluca Gaidano, Roberta Della Seta, Natalia Frattarelli, Paolo Falcucci, Giuseppe Visani, Robin Foà, Brunangelo Falini
Journal: Blood (2017)
P14.34 Priority of comet tail sign in the planning of stereotactic irradiation for the treatment of brain metastases
Authors: K Mitsuya
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND A highly enhanced cap attached to the surface of metastatic tumours in the brain parenchyma is occasionally encountered on magnetic resonance (MR) images. This atypical cap termed “comet tail sign (CTS)” is attributed to leakage of contrast medium from the tumour body into the oedema surrounding it and is containing no neoplastic tissue (Mitsuya, et al. 2016. J Neurooncol). The purpose of this study was to demonstrate our clinical results of excluding CTS in the planning of stereotactic irradiation (STI) for brain metastases to avoid radiation necrosis. METHODS We selected 16 consecutive cases of newly diagnosed brain metastases with CTS treated with STI between May 2007 and January 2019. Patients underwent STI with target fields including CTS until December 2014 (Group A, n=4), while STI with fields excluding CTS from January 2015 (Group B, n=12). CTS was carefully diagnosed using contrasted T1-weighted images and T2-weighted images by radiation oncologists and neurosurgeons. Treatment outcome and toxicity were compared among two groups. RESULTS Primary cancers were lung in 13 and colon in 3 patients. Ten (63%) were male, and the median age was 68 years (range, 47 to 78). The median follow-up time was 13.5 months from STI. There was no significant difference of the mean tumour volume between two groups (4.28ml vs. 4.68ml). Disease control rates were 25% in Group A and 92% in Group B. Symptomatic radiation necrosis was observed in two (50%) patients of Group A but none (0%) of Group B. CONCLUSION CTS could be excluded from STI target planning to increase local control and to decrease radiation toxicity. Prospective study is needed to clarify optimal STI planning for patients with brain metastasis accompanied CTS in the future.
P11.27 Drug screening of available anti-cancer drugs on patient-derived GBM cultures identifies candidate treatments for a subpopulation of GBM patients
Authors: I Ntafoulis, T Kers, M van der Kaaij, R Balvers, J Hayes, J van Rij, R Tching, A Lindner, J Prehn, A Kremer, C Dirven, S Leenstra, M Lamfers
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The development of new therapeutic agents generally takes many years to translate to clinically-effective new treatments. Among the strategies to reduce this time frame, efforts are now being undertaken to investigate drug repurposing. With this approach, compounds available for a specific disease are evaluated for their therapeutic efficacy in other diseases. We have set up a patient-derived cell culture model to apply this strategy for glioblastoma (GBM). MATERIAL AND METHODS Fresh patient-derived tumour tissue was dissociated and cultured in serum-free medium supplemented with EGF and bFGF. MGMT status was determined by methylation-specific PCR.Drug screening was performed using the NIH anti-cancer collection containing 114 approved oncology drugs. Compounds include chemotherapeutic agents as well as small molecule targeted agents. Readout for drug effects is based on ATP-based viability assay. Using systems modelling approaches, integrated analysis of both mutational and expression data of each tumour is applied to identify key pathways involved in response to specific compounds. RESULTS Molecular analysis demonstrated that copy number variations are preserved under serum-free culture conditions and that the MGMT methylation status is retained in over 75% of cases. Screening of the NIH anti-cancer collection on 55 GBM cell cultures revealed high intertumoral variation in response to most drugs. This included subsets of GBM revealing exceptionally high sensitivity to specific agents at clinically-feasible concentrations. Further ranking of the compounds was made based on the therapeutic index (IC50 tumour versus normal human astrocytes) and predicted blood-brain-barrier crossing capability. Currently, integrated analysis of molecular profiles of the tumour in relation to the drug response data is ongoing with the aim of identifying response predictors to these clinically-approved anti-cancer agents. CONCLUSION Our patient-derived in vitro drug screening assay may offer a tool to identify available anti-cancer agents that are effective in a subpopulation of GBM patients and that may be implemented in future stratified clinical trials for this patient group.
Mutual access and mutual dependence of conceptual components
Authors: Friedemann Pulvermüller
Journal: Behavioral and Brain Sciences (2001)

The HIT model comes close to a view suggested by Donald Hebb, that cognitive representations are organized as distributed neuron webs, cell assemblies, whose components are mutually connected and whose internal connections provide continuous information exchange among sub-components of the representation. Two questions are asked related to (1) the organization of internal connections of a concept representation and (2) the conditions under which information exchange between components are assumed in the HIT model.
P11.55 Thymoquinone enhances the sensitivity of B16-F10 melanoma cell line to Gamma Knife radiosurgery
Authors: M A Hatiboglu, A Kocyigit, E M Guler, K Akdur, I Khan, A Nalli, E Karatas, S Tuzgen
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Melanoma patients with brain metastasis have poor prognosis. Gamma Knife radiosurgery (GKR) is an effective treatment to control brain metastasis from melanoma. Thymoquinone (TQ) has gained attention as a potential therapeutic option due to its anti-tumor effects on various cancers. The aim of the study was to invetsigate the effect of GKR in B16-F10 melanoma cells in vitro and in established intracerebral melanoma model in mice in vivo, and the sensitizing efficacy of TQ towards GKR. MATERIAL AND METHODS Effects of GKR and combination treatment of GKR and TQ were studied on B16-F10 melanoma cells via analyzing cytotoxicty by adenosine triphosphate (ATP) assay; apoptosis induction by acridine orange staining and genotoxicity by comet assay. Expression of STAT3, p-STAT3 (Tyr705) and apoptotic pathway proteins was investigated by western blot analysis. Enzyme Linked Immunosorbent Assay (ELISA) was performed to assess the expression of inflammatory cytokines. Also survival was evaluated in mice with brain tumor after GKR and its combination treatment with TQ. RESULTS The effects of GKR on cytotoxicity, apoptosis and genotxicity were significantly enhanced by TQ on B16-F10 melanoma cells. GKR induced apoptosis through inhibition of p-STAT3 expression, which subsequently regulated pro- and anti-apoptotic proteins such as caspase-3, Bax, Bcl-2, survivin. Combination TQ with GKR irradiation enhanced the apoptotic effect of GKR irradiation. Furthermore, GKR decreased the levels of tumor-related inflammatory cytokines on B16-F10 melanoma cells. This effect was more pronounced when TQ was added to GKR irradiation. GKR with 15 Gy improved the survival of mice with intracerebral melanoma compared to untreated mice. Although, the additive effect of TQ in combination with GKR irradiation on B16-F10 melanoma cells in vitro, TQ did not add any significant survival benefit to GKR treatment in mice with intracerebral melanoma. CONCLUSION Our findings indicate that TQ would be a potential therapeutic and sensitizing agent in addition to GKR to enhance the anti-tumor effect of irradiation. Further studies are required to support our findings.
TOAST: improving reference-free cell composition estimation by cross-cell type differential analysis
Authors: Ziyi Li, Hao Wu
Journal: Genome biology (2019)

In the analysis of high-throughput data from complex samples, cell composition is an important factor that needs to be accounted for. Except for a limited number of tissues with known pure cell type profiles, a majority of genomics and epigenetics data relies on the "reference-free deconvolution" methods to estimate cell composition. We develop a novel computational method to improve reference-free deconvolution, which iteratively searches for cell type-specific features and performs composition estimation. Simulation studies and applications to six real datasets including both DNA methylation and gene expression data demonstrate favorable performance of the proposed method. TOAST is available at https://bioconductor.org/packages/TOAST .
P09.06 Risk factors associated with Meningioma in a Cohort of 2 Million Israeli Adolescents
Authors: S Yust-Katz, E Derzane, L Keinan, A Amiel, A Honig, Y Laviv, A Kanner, G Twig, T Siegal
Journal: Neuro-Oncology (2019)

Abstract Background: Meningiomas are the most common primary central nervous system tumors. Risk factors including- obesity, height, history of allergy/atopy or autoimmune diseases, have been assessed with conflicting results. In this study, we reviewed the database of a large cohort of Israeli adolescents in order to assess potential risk factors for the development of meningiomas. Methods: This study analyzed a cohort of 2,035,915 Jewish men and women who underwent compulsory physical examination as part of screening for army drafting between the age of 16 to 19 from 1948 to 1991. Meningioma incidence was identified by linkage to the national cancer registry. Cox proportional hazard models were used to estimate the hazard ratios for meningioma according the several risk factors including sex, BMI, height, history of allergic and autoimmune disease. Results: Linkage of the adolescent military database with the Israeli cancer registry revealed 480 cases of meningioma. The median age at diagnosis of meningioma was 42.1 ± 9.4 (range 17.4–62.6). On univariate analysis, only gender (female) and height were significantly associated with the risk of meningioma for the whole study population (p&lt;0.01 for both variables). When analyzed separately for gender- height was significant only for men. Spline analysis in the men group showed the minimum risk at a height of 1.62 meters and a statistically significant increase in the risk for meningioma at heights taller than 1.85 meters. BMI was not associated with an elevated risk of meningioma even when analyzed separately for gender. Past medical history including asthma, diabetes, and other atopic and autoimmune diseases were not found to be associated with the risk of meningioma. Conclusion: In this large population study, we found that sex and taller height in adolescent males was associated with an increased risk of meningioma.
Unified Approach Needed to Implement Nutrition Support Services—Reply
Authors: Seth A. Berkowitz, Jean Terranova, John Hsu
Journal: JAMA Internal Medicine (2019)

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