tbuckley/cabot-search huggingface dataset:
COMP-16. CORRELATING MGMT PROTEIN LEVEL WITH TEMOZOLOMIDE RESPONSE IN GLIOBLASTOMA PATIENTS USING MASS SPECTROMETRY
Authors: Dongyao Yan, Lauren Schaff, Fabiola Cecchi, Steve Benz, Marc Rosenblum, Todd Hembrough, Andrew Lin
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is an aggressive primary brain tumor with median progression-free survival (PFS) of 7 months and median overall survival (OS) of 15 months. Standard treatment at diagnosis consists of surgery, radiation and temozolomide (TMZ). O-6-methylguanine DNA methyltransferase (MGMT) modulates TMZ effect and MGMT promoter methylation status is used to predict outcomes and guide treatment decisions. However, standard testing is limited by poor inter-assay reproducibility and a weak correlation between methylation status and MGMT expression. We quantitated MGMT protein by mass spectrometry in 32 GBM patients to assess its relationship to PFS and OS after upfront TMZ treatment. We obtained archived tumor samples from newly diagnosed GBM patients prior to treatment with surgery, radiation and TMZ. Tumor cells were microdissected and solubilized, and MGMT protein was quantitated using mass spectrometry. PFS (determined by RANO) and OS were assessed using the Kaplan-Meier method and log-rank test. Of the 32 patients (66% male; median age: 63 years),15 expressed MGMT protein. While methylation status agreed with absence of MGMT protein in 8/9 cases, 9/23 samples with unmethylated MGMT had undetectable MGMT protein, indicating poor agreement between methylation status and protein expression. Patients with MGMT levels below 150 amol/ug of total protein had longer PFS than those with higher MGMT levels (HR: 0.51; p=0.0399; median PFS: 303 vs. 260 days). Similarly, MGMT level below 150 amol/ug was associated with longer OS (HR: 0.49; p=0.0311; median OS: 659 vs. 534 days). Discordance between MGMT methylation status and protein expression was found in 31% of GBM samples. MGMT protein expression below 150 amol/ug correlated with longer PFS and OS in TMZ-treated patients. Mass spectrometry-based MGMT quantitation provides a direct readout of protein expression and may be more reliable than methylation testing.
TMIC-47. GLIOMA STEM CELL-VASCULAR INTERFACE IN GLIOBLASTOMA PROGRESSION
Authors: Sree Deepthi Muthukrishnan, Michael Condro, Kaleab Tessema, Maverick Johnson, Harley Kornblum
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is a highly vascularized, invasive and therapy-resistant brain tumor driven by glioma stem-like cells (GSCs). GSCs reside in three specialized niches or microenvironments: the perivascular, hypoxic and invasive niches. The perivascular and hypoxic niches support the maintenance of GSCs within the tumor bulk, whereas the invasive niche consists of GSCs associated with the pre-existing blood vessels that they co-opt to migrate and invade into other brain regions. Recent findings indicate a bidirectional conversion between the perivascular maintenance and invasive niche propelled by the enormous plasticity of GSCs to transdifferentiate into endothelial-like cells (ECs) and pericytes (PCs). Importantly, these GSC-derived EC-like cells are predominantly found in recurrent tumors than matched primary tumors indicating that therapy may promote GSC plasticity and transdifferentiation into vascular elements. The standard treatment for most GBM patients is maximal surgical resection, fractionated radiation and adjuvant chemotherapy with the drug temozolomide. Prior studies demonstrated that radiation therapy (RT) can induce reprogramming and de-differentiation of tumor cells into a GSC-like state. Based on these findings, we tested the effects of RT in promoting the transdifferentiation potential of GSCs into vascular elements. Our in vitro findings show that RT induces EC gene signature and promotes angiogenic activity in GSCs. We also see that radiated GSCs from tumor core and margins embedded in 3D-hydrogel system with varying stiffness that mimics the tumor ECM and microenvironment exhibit differential capacity to form the vascular elements. Xenografted GBM tumors exposed to RT showed enhanced GSC conversion to vascular cells indicating that RT indeed promotes GSC transdifferentiation into vascular elements in vivo. Ongoing experiments are aimed at determining the molecular mechanism, and functional consequences of ablating the RT-induced GSC-vascular interface on tumor growth and recurrence.
EXTH-09. DIANHYDROGALACTITOL (VAL-083) HAS THE POTENTIAL TO OVERCOME MAJOR CHALLENGES IN THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Anne Steino, BeiBei Zhai, Xiaodong Yang, Cassie Kline, Jeffrey Bacha, Dennis Brown, Mads Daugaard, Sabine Mueller
Journal: Neuro-Oncology (2018)

VAL-083 is a structurally unique bi-functional DNA targeting agent that readily crosses the blood-brain barrier and accumulates in brain tumor tissue. Herein we assess the activity of VAL-083 as single agent as well as in combination regimens including Wee1 Kinase inhibitor AZD1775 and radiation therapy in patient derived model systems of DIPG. DIPG derived cell lines SF8628 and NEM157 (H3.3K27) as well as SF10693 (H3.1K27M) and pediatric glioblastoma cell lines SF188 (H3.3K27 wildtype) were treated with increasing concentrations of single agent VAL-083 as well as in combination with AZD1775 and radiation therapy. To determine potential synergistic activity, we applied the Chou-Talalay method, which allows the quantitative determination of drug interactions by calculating a combination index (CI). In vivo activity of VAL-083 as single agent as well as in combination with AZD1775 was assessed in an orthotopic engraftment model of pediatric DIPG (SF8628). The IC50 of VAL-083 ranged from 2.1uM to 19.7uM. The combination of VAL-083 and AZD1775 showed synergistic activity in all tested cell lines with CI ranging from 0.405 to 2.066 with < 1 indicating synergy whereas VAL-083 combined with radiation therapy led to only additive effects. Initial in vivo study showed that combined treatment with VAL-083 and AZD1775 conferred greater survival benefit to mice with engrafted DIPG tumors compared to control as well as single agent treatment. Day 49 after therapy initiation shows: Control: 2/10; AZD1775: 4/10; VAL083 7/10 and VAL-083+AZD1775: 11/11 mice alive. Our present study highlights that the combination of VAL-083 and AZD1775 might be a promising new therapeutic strategy for children with DIPG. Ongoing studies will continue to assess the in vivo activity as well explore the underlying mechanism of action of the combination strategy.
HOUT-28. CLINICAL EXPERIENCE WITH TUMOR TREATING FIELDS (TTFIELDS, OPTUNE®) IN ISRAEL - PATIENT ACCEPTANCE AND SAFETY
Authors: Tali Siegal, Felix Bokstein, Deborah T Blumenthal, Leor Zach, Anca Leibovici, Shlomit Yust-Katz, Alexander Lossos, Tzahala Tzuk-Shina, Alejandro Lokiec, Rachel Grossman, Itay Forschner, Alisa Taliansky, Zvi Ram
Journal: Neuro-Oncology (2018)

TTFields are low intensity, intermediate frequency alternating electric fields, delivered through a portable, non-invasive device (Optune, NovocureTM). The EF-14 phase III trial showed significant prolongation of both progression-free and overall survival in newly diagnosed glioblastoma (GBM) patients. This is the first report on clinical experience with 110 patients treated with TTFields in Israel, focusing on safety and patient acceptance in our country. Patients received Optune-prescription in 6 neuro-oncology centers in Israel and used the device for at least one month. The cohort included both newly diagnosed (n=53) and recurrent GBM (rGBM, n=57) patients. The male/female ratio was 74/36 with a median age of 58.0 (18–82) years at start of treatment. Of patients with rGBM, 51% were treated at first progression. Our data shows a high acceptance, with a compliance rate (monthly usage of the device) within the first 3 months of 80% for newly diagnosed GBM and 66% for rGBM. Median treatment compliance was independent of age, sex and stage of disease. In addition, our data indicates that the compliance is not negatively correlated with time on treatment, as the median compliance for newly diagnosed GBM patients was still at 79% within the first 6 months. With regards to device-related side effects, data shows that in total 30 patients (27%) experienced mild-moderate skin irritations that were usually manageable with local steroid creams and did not cause significant treatment breaks despite the warm climate in Israel. Other side effects related to the device were heat sensation in 10 patients (9%) and electric sensation in 9 patients (8%) that did not cause significant treatment interruption. The accumulating clinical experience shows that TTFields are well-tolerated by patients in Israel without any major deviation from reported treatment-related side effects. Treatment compliance remains stable during a 6-month period.
INNV-48. TUMOR TREATING FIELDS UTILIZATION IN A GLIOBLASTOMA PATIENT WITH A PREEXISTING CARDIAC PACEMAKER: THE FIRST REPORTED CASE
Authors: Shearwood McClelland, Charles Henrikson, Jeremy Ciporen, Jerry Jaboin, Timur Mitin
Journal: Neuro-Oncology (2018)

Tumor treating fields (TTF) have become an important, evidence-based modality in the treatment of glioblastoma (GBM). In patients requiring cardiac pacemakers, TTF therapy is complicated by theoretical concerns regarding a possible electrical interaction between the devices. The authors report a GBM patient with an indwelling cardiac pacemaker who underwent successful TTF application. A 57-year-old man with past medical history of sick sinus syndrome requiring cardiac pacemaker implantation suffered an acute neurologic change and was found on imaging to have a left parieto-occipital lesion, which following his second surgery was found to be GBM. After completion of guideline-concordant chemoradiation, he chose to undergo TTF therapy. Because of the absence of cardiac symptoms and the theoretical risk of far-field sensing by the pacemaker of the TTF device, potentially resulting in pacemaker inhibition, the pacemaker was turned off prior to receiving TTF. Following TTF implementation, the patient responded well; he remains alive more than 25 months following his GBM diagnosis, exceeding the median 20.9 month survival of the recently completed phase III TTF randomized clinical trial for newly diagnosed GBM. Furthermore, he has exhibited neither cardiac morbidity nor adverse scalp reactions to TTF therapy. The first reported case of successful TTF administration in a GBM patient with a previously implanted cardiac pacemaker may allay the concerns of neuro-oncologists, cardiologists, radiation oncologists, and all certified TTF prescribers regarding the applicability of TTF in suitable candidates with preexisting cardiac pacemakers. This case indicates that TTF therapy is efficacious in patients with indwelling MRI-conditional cardiac pacemakers turned to the off position, and that physical removal of the pacemaker is not necessary prior to starting TTF.
STEM-14. GROWTH FACTOR RECEPTOR CO-INHERITANCE DURING ASYMMETRIC CELL DIVISION DRIVES THE CANCER STEM CELL PHENOTYPE
Authors: Masahiro Hitomi, Anastasia Chumakova, Stephanie Jarvis, Neha Anand, Daniel Silver, Arnon Knudsen, Bridget Corrigan, Peter Yoo, Upashruti Agrawal, Kayla Pfaff, Vid Yogeswaran, Malini Kaminen, Masahiko Sato, Sachiko Sato, Bjarne W. Kristensen, Justin Lathia
Journal: Neuro-Oncology (2018)

An asymmetric cell division (ACD) produces a stem cell and a differentiating progeny. Thus ACD ensures the generation of organs with heterogeneous cell populations without depleting pools of stem cells with regenerative capacity. Cancer stem cells (CSCs), which are similar to normal stem cells, can self-renew and regenerate tumors with cellular heterogeneity. CSCs are resistant to therapy and play a critical role in tumor recurrence. ACD has been detected in CSCs from many types of tumors, but its role in CSC fate decision has yet to be fully elucidated. A remaining technical limitation is that ACD is often defined retrospectively based on the observation of an asymmetric fate choice by CSC progeny. We previously demonstrated asymmetric inheritance of a surrogate CSC marker, CD133, during mitosis. To prospectively analyze the biological role of this inheritance asymmetry, we have developed a GFP reporter system capable of monitoring the degree of asymmetry of the CSC marker during mitosis. This reporter also revealed the asymmetric co-inheritance of growth factor receptors, the activation of which overrode the effect of a differentiation-inducing condition that suppresses self-renewal capacity and therapeutic resistance of CSCs. Preliminary time lapse-based lineage tracing detected that daughter cells that inherited higher levels of growth factor receptors based on GFP-reporter signal intensity express higher levels of a core stem cell transcription factor compared to their sister cells that inherited lower levels of growth factor receptors. These data suggest that asymmetrically co-inherited growth factor receptors promote the stem cell state in one of the progeny of a CSC undergoing ACD, ensuring the persistence of a therapeutically resistant population.
MNGI-12. EXPRESSION OF PROGRAMMED CELL DEATH LIGAND-1 (PD-L1) IN MENINGIOMA: CLINICAL UTILITY FOR PREDICTION OF TUMOR RECURRENCE AND ASSOCIATION WITH HYPOXIC RESPONSE AND NFKB2 ACTIVATION
Authors: Shirin Karimi, Suganth Suppiah, Sheila Mansouri, Farshad Nassiri, Yasin Mamatjan, Jeff Liu, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2018)

Tumor recurrence is one of the most important clinical challenges in the management of meningioma patients. Prognostic significance of PD-L1 as a driver for immunosuppressive response and predictor for tumor growth has been demonstrated in several malignancies. We studied the prognostic role of PD-L1 expression for tumor recurrence in meningioma and explored underlying activation mechanisms. We analyzed a total of 93 meningioma cases diagnosed between 1998 and 2016 at University Health Network: F/M ratio 58/35; WHO grades I (43), II (42), III (9) with 47% recurrence rate and median follow up 6.97 years. Immunohistochemical (IHC) analysis on tumor sections showed PD-L1 expression in 33 (35%) cases with distinctive patchy distribution. Univariate and multivariate analyses confirmed that PD-L1 expression is an independent prognostic marker for recurrence free survival(RFS) in meningioma patients after adjusting for extent of resection, WHO grade, and maximum tumor diameter (p<0.0001). Additionally, we performed Gen Set Enriched Analysis (GSEA) on RNA seq data from 88 meningiomas using HUVEC hypoxia Dataset GSE89831 as reference to calculate hypoxia levels. Our results indicated that hypoxic meningiomas have significantly elevated PD-L1 expression. Furthermore, we investigated expression of PD-L1 in 3 different meningioma cell lines under normoxic and hypoxic conditions by real-time PCR. We found that in addition to the expected HIF1a target genes, PD-L1 mRNA level increased when exposed to hypoxic condition. Analysis of RNAseq data from two GEO meningioma studies demonstrated prominent NFKB2 activation associated with PD-L1 mRNA expression. IHC analysis confirmed expression of NFKB2 protein in 26 (30%) cases, which correlated with PD-L1 expression. Our data strongly suggest the clinical utility of PD-L1 expression for prediction of tumor recurrence and a potential link between hypoxia and anti-cancer immunity in meningioma patients. These results also provide a rationale for a potential therapeutic role for PD-L1 inhibitors in clinically aggressive meningioma.
ACTR-30. PHASE 1B/2 STUDY TO ASSESS THE CLINICAL EFFECTS OF PAMIPARIB (BGB-290) IN COMBINATION WITH RADIATION THERAPY (RT) AND/OR TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED OR RECURRENT/REFRACTORY GLIOBLASTOMA (GBM)
Authors: Kent Shih, David Schiff, Lyndon Kim, James Battiste, Jian Campian, Vinay Puduvalli, Patrick Wen, Timothy Cloughesy, Martin van den Bent, Andrea Pirzkall, Katie Wood, Rachel Wei, Bing Du, Song Mu, Vanitha Ramakrishnan, Tobias Walbert
Journal: Neuro-Oncology (2018)

DNA damage caused by TMZ or RT sensitizes tumors to PARP inhibitors, especially in highly replicating tumors (eg, GBM). Pamiparib is a selective PARP1/2 inhibitor with potent PARP trapping that can cross the blood-brain barrier and has shown synergistic cytotoxicity with TMZ in nonclinical experiments. At 60mg BID, the human-equivalent dose-to-trough brain concentrations above the nonclinical efficacy threshold, pamiparib was generally well tolerated and showed antitumor activity in early clinical studies (NCT02361723; NCT03333915). This ongoing dose-escalation/expansion study (NCT03150862) will determine the safety/tolerability and antitumor effects of pamiparib (60mg BID)+RT and/or TMZ. The dose-escalation component consists of three arms. Arm A will establish tolerable duration of pamiparib (2, 4, 6 weeks)+RT in newly diagnosed GBM patients with unmethylated MGMT promoter (unmethyl-GBM). In Arm B, newly diagnosed patients with unmethyl-GBM will receive pamiparib+RT with increasing TMZ doses. Enrollment in Arm B will commence once RP2D for pamiparib+RT is established. In Arm C, patients with recurrent/refractory methylated- or unmethyl-GBM receive pamiparib with increasing TMZ doses. As of 28 March 2018, 15 patients were enrolled (A: 2-wk, n=3; 4-wk, n=6; C: TMZ [40mg], n=6). One DLT (grade 3 nausea) was reported in Arm C. Across arms, pamiparib-related AEs occurring in >3 patients were nausea (n=6) and fatigue (n=5). Two patients experienced three pamiparib-related AEs grade 3 (diarrhea [A: 4-wk, n=1]; fatigue and nausea [C: n=1]). All three resolved with concomitant medication and treatment interruption (A) or discontinuation (C). Of the seven patients with 1 tumor assessment, one (A: 4-wk) achieved an unconfirmed PR; four (A: 2-wk, n=2; 4-wk, n=2) had SD, and two (A: 2-wk, n=1; C: n=1) had PD. Preliminary data suggests pamiparib at 60mg BID is generally well tolerated by patients when administered 4 weeks concurrently with RT for newly diagnosed unmethyl-GBM and when combined with 40 mg TMZ for recurrent/refractory GBM.
MNGI-10. PREDICTORS OF EARLY PROGRESSION OF SURGICALLY TREATED ATYPICAL MENINGIOMAS
Authors: Karol Budohoski, James Clerkin, Christopher Millward, Philip O’Halloran, Mueez Waqar, Seamus Looby, Adam Young, Mathew Guilfoyle, Diana Fitzroll, Abel Devadass, Kieren Allinson, Michael Farrell, Mohsen Javadpour, Michael Jenkinson, Thomas Santarius, Ramez Kirollos
Journal: Neuro-Oncology (2018)

Clinical behaviour of atypical meningiomas is not uniform. While, as a group, they exhibit a high recurrence rate, some pursue a more benign course, whereas others progress early. We aim to investigate the imaging and pathological factors that predict risk of early tumour progression and to determine whether early progression is related to outcome. Adult patients with WHO grade II meningioma treated in 3 regional referral centres between 2007 and 2014 were included. MRI and pathology characteristics were assessed. Gross total resection (GTR) was defined as Simpson 1–3. Recurrence was classified into early and late (≤ 24 months vs. > 24 months). Among the 220 cases thirty-seven (16.8%) patients progressed within 24 months of operation. Independent predictors of early progression were subtotal resection (STR) (p=0.005), parafalcine/parasagittal location (p=0.015), peritumoural oedema (p=0.027) and mitotic index (MI) > 7 (p=0.007). Adjuvant radiotherapy was negatively associated with early recurrence (p=0.046). Thirty-two per cent of patients with residual tumour and 26% after GTR received adjuvant radiotherapy. There was a significantly lower proportion of favourable outcomes at last follow-up (mRS 0–1) in patients with early recurrence (p=0.001). Atypical meningiomas are a heterogeneous group of tumours with 16.8% patients having recurrence within 24 months of surgery. Residual tumour, parafalcine/parasagittal location, peritumoural oedema and a MI > 7 were all independently associated with early recurrence. As administration of adjuvant radiotherapy was not protocolised in this cohort any conclusions about benefits of irradiation of WHO grade II meningiomas should be viewed with caution. Patients with early recurrence had worse neurological outcome. While histological and imaging characteristics provide some prognostic value further molecular characterisation of atypical meningiomas is warranted to aid clinical decision making.
THU0329 An italian observational prospective study on predictors of clinical response to golimumab at 6 months in patients with active psoriatic arthritis
Authors: R. Scrivo, A. Giardino, C. Salvarani, R. Foti, A. Afeltra, O. Viapiana, F. Salaffi, F. Iannone
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The identification of markers of response to biologic agents in the treatment of active psoriatic arthritis (PsA) may help in predicting the outcome and hence in optimising therapy. <h3>Objectives</h3> To evaluate the ability of a panel of candidate factors to predict the clinical response, defined as the achievement of minimal disease activity (MDA) following 6 month therapy with golimumab. <h3>Methods</h3> This Italian 6 month observational study included 149 PsA patients (53.7% males, mean age 49 years (SD 11) inadequate responders to conventional therapies who started the anti-tumour necrosis factor-α golimumab. Estimated factors included demographic data and baseline characteristics of the disease, measures of disease activity and functional disability, and biomarkers. <h3>Results</h3> At 6 months, a high rate of treatment persistency (80%) was observed. MDA was achieved in 44.3% of patients. Multivariate analysis showed Disease Activity in Psoriatic Arthritis (DAPSA) score, high-sensitivity C-reactive protein (hs-CRP), age, and disease duration as baseline factors correlating with MDA achievement at 6 months (table 1). A higher hs-CRP value and the absence of comorbidities were predictive factors for MDA at 6 months in biomarker-enhanced prediction models. Golimumab was effective in improving disease and functional parameters and was well tolerated. <h3>Conclusions</h3> The availability of predictive factors of treatment response identified in this study may be helpful in driving the selection of PsA patients that are most likely to benefit of the therapy with golimumab. <h3>Disclosure of Interest</h3> R. Scrivo Consultant for: Abbvie, MSD, Celgene, Janssen, A. Giardino Employee of: MSD, C. Salvarani: None declared, R. Foti: None declared, A. Afeltra: None declared, O. Viapiana Consultant for: Novartis, Ely Lilly, Sanofi Genzyme, F. Salaffi: None declared, F. Iannone Speakers bureau: Abbvie, Actelion, BMS, Lilly, Novartis, MSD, Pfizer, UCB, Janssen, Celgene, Roche, Sanofi