bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-75. APPLICATION OF TUMOR TREATING FIELDS (TTFIELDS) TO THE HEAD AND TORSO OF MICE WITH THE DEDICATED INOVIVO SYSTEM
Authors: Davidi Shiri , Blatt Roni , Munster Mijal , Shteingauz Anna , Porat Yaara , Zeidan Adel , Marciano Tal , Bomzon Zeev , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: November 2021

Abstract

INTRODUCTION
Tumor Treating Fields (TTFields) therapy is an approved anti-cancer treatment for glioblastoma and mesothelioma. TTFields are delivered to patients continuously by two sets of arrays placed on opposite sides of the body at the tumor region to generate two perpendicular electric fields. Previously, in vivo studies of TTFields were limited due to the lack of a dedicated system that could maintain continuous and adequate contact of the arrays with the animal’s skin as well as the stress imposed on the animals by individual housing and the motility limitations they experience during treatment.

METHODS
Different electrode layouts were explored to optimize the intensity of the electric fields delivered to the target locations (therapeutic threshold &gt;1 V/cm). The ability of various adhesive materials and wire coiling prevention strategies to increase TTFields device usage was examined. Stress reduction with different housing methods was evaluated via clinical examination of the animals.

RESULTS
Optimal array layouts were identified based on simulation data for TTFields delivery to the torso or the head of the mouse. Compacting conductors into a single printed circuit cable connected to a novel electric swivel machine resulted in fewer wire entanglements, and the improved adhesives resulted in fewer array replacements, overall elevating device usage. Improved cage design permitted pairs of mice to maintain social interactions while individually housed. Less weight loss was seen for animals housed in the dyadic relative to the standard solitary cages, indicating reduced stress.

CONCLUSIONS
The inovivo system provides means for continuous delivery of therapeutic levels of TTFields to the head and torso of mice while minimizing animal stress and increasing device usage. The new head arrays enable application of TTFields to the head of mice for the first time, allowing expansion of glioblastoma treatment research.
EXTH-77. POLIO VIROTHERAPY OF MURINE BRAIN TUMORS INDUCES MICROGLIA PROLIFERATION AND INFLAMMATION THAT IS POTENTIATED BY IMMUNE CHECKPOINT BLOCKADE
Authors: Yang Yuanfan , Brown Michael , Stevenson Kevin , lopez Giselle , Kornahrens Reb , Zhang Gao , Gromeier Matthias 
Published: November 2021

Abstract
Immunotherapy with polio:rhinovirus recombinant (PVSRIPO) has shown evidence of efficacy in a phase I clinical trial for recurrent GBM, resulting in durable radiographic responses and 21% long-term survival at 36 months. Ongoing research aims to enhance the clinical response rate by resolving the mechanisms of action and therapy resistance in vivo, thereby devising more effective therapies. Mouse glioma (CT2A) cells were intracranially implanted (day 0) in transgenic mice carrying poliovirus receptor CD155, and treated with intratumor PVSRIPO (5×105 pfu; day 6) to dissect early and late events following therapy. A blinded pathological review of 45 post-treatment tumors was performed. On day 8, a histological response, featured by tumor dissociation and shrinkage, with inflammation and microglia enrichment in the treated hemisphere, was common in PVSRIPO group (6/7) compared to controls (0/4). However, the response rate fell over time (7/12 on day 12; 1/7 on day 15) and the therapy was overcome by aggressive tumor regrowth. RNAseq was performed and Gene Set Enrichment Analysis of the tumor microenvironment revealed an acute type-I interferon (IFN)-related inflammation, correlating with the histological findings of profound proinflammatory engagement of microglia (Iba1+) widespread in the treated hemisphere. Microglia proliferation (Ki67+) was observed in the treated hemisphere, likely resulting from PVSRIPO infection, in CT2A and B16 intracranial models. This suggests an association of adaptive antitumor immunity—elicited by immediate intratumor type-I IFN-dominant inflammation—with tumor regression. Thus, buttressing type-I IFN directed antitumor CD8+T cell immunity, e.g. with blockade of the PD1:PD-L1 immune checkpoint, might contribute to tumor remission. Indeed, combination therapy with αPD-L1 antibody in the CT2A model showed longer median survival and higher long-term remission rate compared to monotherapy alone; CD8 T cell depletion can completely abrogate this efficacy with this therapy combination, confirming the role of anti-tumor immunity in this approach.
EXTH-81. STING ACTIVATION PROMOTES ROBUST IMMUNE RESPONSE AND TUMOR REGRESSION IN GLIOBLASTOMA MODELS
Authors: Berger Gilles , Knelson Erik , Nowicki Michal , Mooney David , Chiocca E Antonio , Barbie David , Lawler Sean 
Published: November 2021

Abstract
The immunosuppressive tumor microenvironment in glioblastoma presents a major barrier to effective application of immunotherapeutic approaches in this disease. Although immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease glioblastoma remains largely refractory to current immunotherapeutic approaches. The cGAS-STING cytoplasmic double stranded DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties, but has not been well investigated in glioblastoma to date. Here we investigated the presence of STING pathway components in glioblastoma patient specimens and cell lines by Western blotting and immunostaining. The functionality of the pathway was determined by ELISA, and immune infiltrates, and animal survival were investigated in mouse glioblastoma models after treatment with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature, and appears to be activated as evidenced by elevated phosphoTBK1 staining. We show that human GBM cells do not respond agonists, but that GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils and NK populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants the further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, CAR T cells, or immune checkpoint blockade.
QOLP-02. HEALTH-RELATED QUALITY OF LIFE (HRQOL) AMONG PEDIATRIC PATIENTS WITH NEUROFIBROMATOSIS TYPE 1 (NF1) AND PLEXIFORM NEUROFIBROMA (PN) IN THE UNITED STATES: PERSPECTIVES OF THE PATIENTS AND CAREGIVERS
Authors: Yang Xiaoqin , Yoo Hyun Kyoo , Amin Suvina , Cheng Wendy , Sipsma Heather , Sundaresan Sanjana , Zhang Lujia , Duh Mei Sheng 
Published: November 2021

Abstract

BACKGROUND
PNs occur in 30-50% of pediatric patients with NF1, often resulting in debilitating pain, mobility limitations, significant disfigurement, and may be life-threatening. Real-world evidence on the HRQoL of pediatric NF1 PN patients is limited.

METHODS
Patients ages 8-18 years with NF1 PN (treatment-naïve/new on selumetinib [≤ 1 month of use]) and their caregivers were recruited through Children’s Tumor Foundation to participate in an online cross-sectional survey (12/2020-1/2021). HRQoL measures included Pediatric Quality of Life Inventory (PedsQL; Acute version), Pain Interference Index (PII), and Patient-Reported Outcomes Measurement Information System (PROMIS) mobility and upper extremity functioning subscales. Patients provided self-reported responses; caregivers provided proxy responses and patient characteristics. Agreement between patient-reports and caregiver proxies was assessed using intra-class correlation coefficients (ICCs).

RESULTS
61 patient-caregiver dyads participated in the survey. Patients were mostly white/Caucasian (90.2%), 50.8% female, with a median (range) age of 13.0 (11-16) years. Most were treatment-naïve (96.7%), with NF1 and PN diagnosis for &gt; 5 years (91.8%, 82.0%). On the PedsQL (range: 0-100; higher=better; healthy patient mean scores typically &gt; 80), patient-reported mean scores were 50.3, 56.1, 60.7, and 63.7 for school, emotional, social, and physical functioning; mean total score= 58.5. Caregiver-proxy mean scores ranged from 49.9-61.5 across subscales; mean total score= 55.4. Among patients reporting pain in the last 7 days, PII mean scores (range: 0-6; higher=more interference) were 3.0 (patient-reports) and 2.9 (caregiver proxies). Among patients with movement difficulty in the past 7 days, mean PROMIS scales t-scores (distribution mean= 50; higher=better) were 40.2 and 39.5 (patient-reports), and 35.6 and 30.1 (caregiver proxies), for mobility and upper extremity functioning. ICCs were very good, ranging from 0.85-0.93 across HRQoL measures.

CONCLUSION
NF1 PN can have substantial negative impact on pediatric patients, as demonstrated across various HRQoL domains, highlighting the importance of collecting patient-centered outcomes to guide treatment decisions.
QOLP-10. A LONGITUDINAL OBSERVATIONAL STUDY OF EXERCISE BEHAVIOR IN GLIOBLASTOMA PATIENTS TREATED WITH TUMOR-TREATING FIELDS
Authors: Peters Katherine , Affronti Mary , Kim Jung-Young , Patel Mallika , Johnson Margaret , Bartlett David , Cort Nicole , Lipp Eric , Iden Deborah , Broadwater Gloria , Herndon James , Landi Daniel , Khasraw Mustafa , Desjardins Annick , Friedman Henry , Ashley David M 
Published: November 2021

Abstract
Glioblastoma (GBM) patients can use tumor-treating fields (TTFs) with adjuvant temozolomide (TMZ) to treat their disease. TTFs involve wearing transfixed transducers to the shaved scalp, and the transducers are wired to a battery pack that is either fixed or carried (weighing 2.7 pounds). EF-14 clinical trial did evaluate health-related quality of life with standardized patient-report outcome measures but did not measure exercise behavior. We sought to evaluate the exercise behavior of GBM patients using TTFs. We consented GBM patients who intended to use TTFs with adjuvant TMZ after completion of chemoradiation. After informed consent and before starting TTFs, patients completed a self-administered questionnaire, Godin Leisure-Time Exercise Questionnaire, to assess exercise behavior/physical function. To calculate our primary outcome of total exercise behavior, the frequency of exercise sessions per week within each intensity category was multiplied by the average reported duration, weighted by an estimate of the MET, summed across all intensities, and expressed as average MET-hr/wk. Prior work has defined that physical function can be compared as &lt; 9 MET-h/wk vs. ≥ 9 MET-h/wk. We evaluated at baseline and up to 24-week exercise behavior in patients with TTFs vs. historical controls not using TTFs. We enrolled 19 total GBM patients, with 14 proceeding to use TTFs. Of the 14 patients on TTFs, seven patients (50%) completed ≥ 9 MET-h/wk of exercise, and this level was maintained 8, 16, and 24 weeks after starting TTFs. Six months after the completion of chemoradiation, mean MET-h/wk was decreased in the TTFs group (n=6) (10.71 sd=7.06) vs. historical controls (n=38) (27.35 sd=46.94). TTFs did not interfere with exercise behavior in our GBM cohort, but when compared to GBM patients not utilizing TTFs, there could be a long-term impact on exercise behavior. More research is needed to evaluate exercise behavior in GBM patients using TTFs.
QOLP-15. FEASIBILITY OF AN ELECTRONIC PATIENT REPORTED STEROID TOXICITY MONITORING PROGRAM IN PATIENTS WITH MALIGNANT GLIOMAS
Authors: Macher Jared , Wasilewski Andrea 
Published: November 2021

Abstract

OBJECTIVE
To determine the feasibility of a longitudinal, electronic, patient-reported survey of steroid toxicity in patients with malignant glioma (MG).

BACKGROUND
Corticosteroids are frequently used for management of cerebral edema in MG, with side effects resulting from prolonged use or high dosage. Corticosteroid use is common and may negatively impact quality of life (QOL) and survival in MG.

DESIGN/METHODS
We prospectively enrolled patients with MG receiving neuro-oncologic care at the University of Rochester with or without their caregivers on an IRB-approved study. Subjects received 12 weekly electronic questionnaires through a secure health portal focused on symptoms of corticosteroid toxicities, dosing and functional status. Weekly toxicity scores were calculated based on the number of reported toxicities (0-17). Completed questionnaires were reviewed by a care team member to inform clinical management. Corticosteroid dosing adjustments were documented in the medical record. Feasibility was defined as an overall questionnaire completion rate of 70%.

RESULTS
11 patient/caregiver pairs were enrolled (11 patients, including 9 with caregivers). Median patient age was 58. Patient tumors were glioblastoma (82%), anaplastic astrocytoma (9%) and anaplastic oligodendroglioma (9%). Phase of treatment was concurrent (55%), adjuvant (36%) and recurrence (9%). Median dexamethasone does at study start and conclusion were 4mg/day and 3mg/day. Median weekly toxicity score was 5/17 (range: 0-14). The most common toxicities were muscle weakness, sleep disturbance and weight gain and were reported by 82% of participants. Overall questionnaire completion rate was 81%. Ten percent of questionnaires resulted in clinically significant symptoms requiring follow-up from a provider.

CONCLUSION
Patients with MG experience frequent corticosteroid toxicities. Electronic corticosteroid toxicity monitoring is feasible in patients with MG and may lead to changes in management. Future studies are needed to assess utility of this tool and impact on QOL and survival.
QOLP-33. EVIDENCE OF FINANCIAL TOXICITY IN PRIMARY CENTRAL NERVOUS SYSTEM TUMOR PATIENTS: CORRELATIONS BETWEEN EMPLOYMENT STATUS, SYMPTOM BURDEN AND HEALTH-RELATED QUALITY OF LIFE
Authors: Christ Alexa , Vera Elizabeth , Acquaye Alvina , Briceno Nicole , Choi Anna , Grajkowska Ewa , Jammula Varna , Levine Jason , Lindsley Matthew , Reyes Jennifer , Roche Kayla , Rogers James , Timmer Michael , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Penas-Prado Marta , Pillai Valentina , Polskin Lily , Theeler Brett , Wu Jing , Gilbert Mark , Armstrong Terri , Leeper Heather 
Published: November 2021

Abstract

SIGNIFICANCE AND AIMS
Financial toxicity (FT) after a cancer diagnosis is the consequence of decreased earnings and increased spending. In patients with primary central nervous system (PCNS) tumors, the correlation between FT and factors such as symptom burden, psychological distress, and health-related quality of life has not been extensively studied. We assessed employment status and several patient illness factors in a PCNS tumor cohort.

METHODS
Patient and disease characteristics and patient-reported outcomes (PROs) were collected from adults diagnosed with PCNS tumors between 9/2016-12/2019. Descriptive statistics and regression analyses were used to describe PROs.

RESULTS
Of 277 patients, 77 (28%) reported being unemployed due to tumor diagnosis. They reported difficulty walking (64%) and performing usual activities (64%). This group had lower general health status (p&lt; 0.001) and higher tumor-related symptom severity (p=0.004) than employed patients. Unemployed patients reported high symptom burden with an average of 6 moderate-severe symptoms for those with brain tumors and 10 for those with spine tumors. Both brain and spine tumor patients who were unemployed reported increased mood-related interference (p=0.020), as well as moderate-severe anxiety (30%) and depression (25%) compared to employed patients (15% vs 8%, respectively). Unemployed brain tumor patients reported worse scores in cognitive and neurologic symptom subscales (p&lt; 0.001).

CONCLUSIONS AND IMPLICATIONS
These data provide indirect evidence that financial toxicity that correlates with high symptom burden across several domains and lower health-related quality of life. Future research work will include the COST questionnaire to further evaluate the implications of FT in the PCNS tumor patient population.
RBIO-05. THE IMPACT OF STEREOTATIC RADIOSURGERY (SRS) FOR THE RESIDUAL LESIONS OF PINEAL NON-GERMINOMATOUS GERM CELL TUMORS (NGGCTS) FOLLOWING CONVENTIONAL RADIOTHERAPY: A RETROSPECTIVE STUDY
Authors: Lai Mingyao , Li Juan , Hu Qingjun , Li Shaoqun , Cai Linbo 
Published: November 2021

Abstract

OBJECTIVE
To evaluate the safety and efficacy of stereotatic radiosurgery (SRS) in treating residual lesions of pineal non-germinomatous germ cell tumors (NGGCTs) after conventional radiotherapy.

METHODS
The patients admitted to Guangdong Sanjiu Brain Hospital from 1 January 2008 to 31 December 2018 who diagnosed with pineal NGGCTs pathologically or clinically were retrospectively analyzed. Among those, the patients received conventional radiotherapy with or without SRS were included. The residual lesions after radiotherapy were defined with a maximum diameter &gt; 10mm. Prognosis related parameters such as local control rate, progress-free survival, overall survival and treatment-related toxicity were determined.

RESULTS
The median follow-up time was 34 months (range 8-142 months). The objective response rate and disease control rate were 71.4% and 95.2%, respectively. Three-year progression-free survival rate was 85.2% and 3-year total survival rate was 88.0%. The univariate analysis revealed that both age and concurrent chemotherapy were not correlated with the prognosis (P=0.286, 0.824). Partial tumor resection before radiotherapy and chemotherapy, AFP &gt;500ng/ml, and no more than 4 cycles of adjuvant chemotherapy were poor prognostic factors (P=0.037, 0.010, 0.006). Moreover, no acute radiation response was observed after treatment with SRS. Only 1 out of 27 patients (3.7%) had brain neurotoxicity related to a prolonged course of radiochemotherapy.

CONCLUSION
SRS for residual lesions of NGGCTs following conventional radiotherapy appears to be well tolerant and improved local control. However, the therapeutic efficacy of conventional radiotherapy combined with SRS warrants further investigations in a large-scale randomized controlled clinical trials.
RBIO-06. MECHANISM OF ACTION AND ASSOCIATED EFFECTS OF TUMOR TREATING FIELDS (TTFIELDS) ON LIVING CELLS USING SIMULATIONS
Authors: Marciano Tal , Levi Shay , Fedorov Eduard 
Published: November 2021

Abstract
Following FDA approval, TTFields treatment has become a commonly used modality for treating patients with Glioblastoma (GBM) and Mesothelioma. From the early 2000’s, extensive research has been performed in in-vitro systems for studying the effects of TTFields on living cells. These studies have shown that multiple cellular functions are affected by TTFields. However, the physical mechanism by which the fields exert effects on cells are not well understood. We propose an analytical model for predicting the geometric and electrical parameters enabling amplification of the electric field in the living cells. This amplification favors the emergence of local heating, dielectrophoretic (DEP) force, or electrostatic pressure at TTFields frequencies. This model is supported by simulations of cells in different configurations. Computational studies were performed with Comsol Multiphysics software. Cell models were constituted of cytoplasm, membrane and extracellular matrix. A field of 1V/cm was generated at different frequencies between 10kHz and 1GHz. Maximal field amplification of X20 of the applied field (@200 kHz) was observed in a model of confluent cells with 5nm intercellular distance. Such field amplification could create electrostatic pressure on the membrane potentially leading to its deformation and to stress on the cytoskeleton. Analytical calculations show the field gradient could result in DEP forces of ~10pN on the membrane. Such force could potentially disrupt the membrane or junctions. Results show that a 10nm pore in membrane would lead to a 450 times amplification in the pore’s vicinity, potentially resulting in forces of between 0.1pN and 100pN on intracellular structures. Those forces are sufficient for disrupting microtubules. Specific Absorption Rates of up to 106 W/kg were observed in the vicinity of the pore, suggesting that strong thermal effects may also explain the effect of TTFields on cells. Our generic analytical model predicts the conditions for field amplification at TTFields frequencies.
RTID-08. MACHINE LEARNING TO UNCOVER SIGNATURES OF VULNERABILITY IN GLIOBLASTOMA UMBRELLA SIGNATURE TRIAL (GUST)
Authors: Peng Sen , Lee Matthew , Tang Nanyun , Ahluwalia Manmeet , Fonkem Ekokobe , Fink Karen , Raizer Jeffrey , Walker Christopher , Dhruv Harshil , Berens Michael 
Published: November 2021

Abstract
Glioblastoma is characterized by intra- and inter-tumoral heterogeneity. A glioblastoma umbrella signature trial (GUST) posits multiple investigational treatment arms based on corresponding biomarker signatures. A contingency of an efficient umbrella trial is a suite of orthogonal signatures to classify patients into the likely-most-beneficial arm. Assigning optimal thresholds of vulnerability signatures to classify patients as “most-likely responders” for each specific treatment arm is a crucial task. We utilized semi-supervised machine learning, Entropy-Regularized Logistic Regression, to predict vulnerability classification. By applying semi-supervised algorithms to the TCGA GBM cohort, we were able to transform the samples with the highest certainty of predicted response into a self-labeled dataset and thus augment the training data. In this case, we developed a predictive model with a larger sample size and potential better performance. Our GUST design currently includes four treatment arms for GBM patients: Arsenic Trioxide, Methoxyamine, Selinexor and Pevonedistat. Each treatment arm manifests its own signature developed by the customized machine learning pipelines based on selected gene mutation status and whole transcriptome data. In order to increase the robustness and scalability, we also developed a multi-class/label classification ensemble model that’s capable of predicting a probability of “fitness” of each novel therapeutic agent for each patient. Such a multi-class model would also enable us to rank each arm and provide sequential treatment planning. By expansion to four independent treatment arms within a single umbrella trial, a “mock” stratification of TCGA GBM patients labeled 56% of all cases into at least one “high likelihood of response” arm. Predicted vulnerability using genomic data from preclinical PDX models correctly placed 4 out of 6 models into the “responder” group. Our utilization of multiple vulnerability signatures in a GUST trial demonstrates how a precision medicine model can support an efficient clinical trial for heterogeneous diseases such as GBM.
Surgical Therapies