bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-44. DOSIMETRIC IMPACT OF TUMOR TREATING FIELDS ON CONCURRENT RADIATION THERAPY FOR PEDIATRIC BRAIN TUMORS
Authors: Quan Enzhuo , Han Eun , Chung Christine , Briere Tina , Sadighi Zsila , McGovern Susan 
Published: November 2021

Abstract

INTRODUCTION
Early results suggest that tumor treating fields (TTF) concurrent with radiotherapy (RT) for glioblastoma yields acceptable dosimetry in adults; the impact on RT dose distribution in children is unknown. This study was undertaken to evaluate the dosimetric impact of TTF on concurrent photon RT for children with brain tumors.

METHODS
CT scans of an anthropomorphic pediatric head phantom (approximately 15-year-old) and an infant-head-sized spherical phantom were acquired with and without TTF attached. For each phantom, simulated supratentorial tumor targets were initially contoured on CT datasets acquired without TTF attached. Treatment plans using volumetric modulated arc therapy were created to deliver 60Gy and 50Gy to the gross tumor volume (GTV) and clinical tumor volume (CTV), respectively, in 30 fractions. The dose distributions of the same treatment plans were then re-computed with TTF attached. Target coverage metrics were compared between dose distributions with and without TTF. To measure skin dose, treatment plans were delivered with thermoluminescent dosimeters placed on the phantoms at various locations, with and without TTF attached.

RESULTS
The presence of TTF slightly reduced target coverage. For the two phantoms studied, D95 of the CTV was reduced by 0.65% and 1.03%, and D95 of the GTV was reduced by 0.7% and 1.05%, respectively. Electrodes under the direct beam path increased skin dose by an average of 43.3% (0.3Gy – 20.7Gy), but all skin dose measurements stayed within tolerances. TTF electrodes out of the RT field did not cause an increase in measured dose.

CONCLUSIONS
The dosimetric impact of TTF on pediatric head phantoms receiving concurrent RT resembles that reported in adult studies. Although the tumor dose is not significantly affected, the skin dose notably increases due to the bolus effect from the TTF electrodes, which may be mitigated by skin-sparing planning and shifting of the device during RT.
CTNI-45. RESPONSE EVALUATION OF AR-67 FROM A PHASE-2 RECURRENT GLIOBLASTOMA TRIAL BY ARTIFICIAL INTELLIGENCE ASSISTED TUMOR VOLUMETRIC ESTIMATION: COMPARISON WITH THE SUM OF THE PERPENDICULAR DIAMETERS PRODUCT
Authors: Bisdas Sotirios , Grewal Jai , Stieber Volker , Cavaliere Robert , Devoe Craig , Jensen Randy , Brownell Elise , Runk Tina , Dupont-Roettger Diana 
Published: November 2021

Abstract

BACKGROUND
Modified Radiographic Response Assessment in Neuro-Oncology (“mRANO”) criteria based on SPDP form the basis for assessing treatment response in Glioblastoma but are subject to sampling bias and difficulty in differentiating between pseudo- and true disease progression. Volumetric image analysis using AI may overcome these limitations of standard techniques and improve our ability to detect changes earlier and more accurately.

METHODS
Images from eight reGBM patients enrolled in a Phase-2 reGBM study of Vivacitas Oncology’s drug, AR-67, were re-assessed using IAG’s AI-assisted volumetric measurements. A median of five MRI time points from each patient were included. The mRANO response was determined by central reading and tumor volumetric measurement using IAG’s proprietary platform. Statistical significance was set at p&lt; .0001.

RESULTS
Four patients showed responses, two patients showed stable disease, and two patients showed progressive disease. Tumor volume was correlated (r=0.97) with SPDP, but was driven by high coefficients in large lesions. Standard SPDP overestimated tumor size in larger tumors using the Bland-Altman analysis (mean difference: 829; 95% CI: 704 to -2362) leading to discrepancies in response rates. For example, the mean response rate based on IAG’s volumetric criteria was +22% (1.29) compared with +17% using SPDP (0.81). Eight out of 45 time-points also differed in the directionality of responses (e.g., increase vs. decrease) with SPDP underestimating the positive effects of AR-67 compared to AI analysis.

CONCLUSIONS
IAG’s AI-assisted tumor volumetric analysis is feasible for clinical trials and may be more sensitive for evaluating treatment-related response rates vs. SPDP methodology. This is particularly true for measuring large lesions, and may also allow for more accurately differentiating between pseudo- and true disease progression. The data included eight patients’ MRI images from a Phase-2 reGBM study, showing that five patients achieved the primary end-point of six months Progression-Free Survival, suggesting AR-67’s therapeutic potential.
CTNI-54. A SINGLE ARM PHASE II STUDY OF THE DUAL MTORC1/MTORC2 INHIBITOR VISTUSERTIB PROVIDED FOR SPORADIC PATIENTS WITH GRADE II-III MENINGIOMAS THAT RECUR OR PROGRESS AFTER SURGERY AND RADIATION
Authors: Plotkin Scott , Kumthekar Priya , Wen Patrick , Barker Fred , Beauchamp Roberta , Gerstner Elizabeth , Muzikansky Alona , Smith Miriam , Stemmer-Rachamimov Anat , Jordan Justin , Ramesh Vijaya 
Published: November 2021

Abstract
Grade II/III meningiomas have increased rates of recurrence with no approved medical therapies. The historical progression-free survival at 6 months (PFS-6) is 25% with rates &gt;35% declared of interest for drug development. NF2 gene inactivation occurs in about half of meningiomas. Based on our studies showing mTORC1 and mTORC2/SGK1 pathway activation in NF2-deficient meningiomas and the paradoxical activation of the mTORC2/AKT pathway, we hypothesized that mTORC1/mTORC2 inhibitors would be active in meningiomas. We studied the effect of vistusertib in patients with progressive/recurrent grade II/III meningiomas (NCT03071874). Vistusertib was administered orally at 125mg twice daily on two consecutive days each week. MRIs were obtained every 56 days. Tumor size was defined as the largest cross-sectional area. Progression was defined as ≥ 25% increase in the sum of products of all measurable lesions over smallest sum observed. The primary endpoint was PFS-6. Secondary endpoints included toxicity, radiographic response, and correlative studies including immunohistochemistry for mTORC1/2 pathway activation and genetic biomarkers. Twenty-eight patients (13 female, median age 58 years, median KPS 80%) were enrolled. Median tumor size was 4.4cm; 71% were grade II and 50% harbored pathogenic NF2 variants. Four patients discontinued treatment voluntarily and 1 each withdrew for intercurrent illness and non-compliance. PFS-6 is 47% (CI, 26%-65%) and OS-12 is 72% (95%CI, 48%-86%). PFS but not OS was shorter for patients with grade 3 meningiomas; there was no difference in PFS/OS between genetic groups. Adverse events at least possibly related to vistusertib with frequency &gt;10% include nausea, fatigue, hypophosphatemia, diarrhea, anorexia, dry mouth, hypertriglyceridemia, hypertension, vomiting, increased ALT, constipation, and weight loss. Vistusertib treatment was associated with a PFS-6 rate exceeding the target of 35% for recurrent high-grade meningioma. Adverse events were tolerable in this patient population. These data support the continued development of mTORC1/2 inhibitors in this setting.
CTNI-55. THE CDK4/6 INHIBITOR ABEMACICLIB IN PATIENTS WITH RECURRENT MENINGIOMA AND OTHER PRIMARY CNS TUMORS
Authors: Coffee Elizabeth , Panageas Katherine , Young Robert , Morrison Tara , Daher Ahmad , Grommes Christian , Gavrilovic Igor T , Lin Andrew , Miller Alexandra , Schaff Lauren , Daras Mariza , DeAngelis Lisa , Diamond Eli , Piotrowski Anna , Malani Rachna , Nolan Craig , Pentsova Elena , Santomasso Bianca , Stone Jacqueline , Nair Suresh , Mellinghoff Ingo K , Kaley Thomas 
Published: November 2021

Abstract

BACKGROUND
Medical therapies for recurrent brain tumors are limited. Abemaciclib is a small molecule CDK4/6 inhibitor that has demonstrated antitumor activity in multiple cancer types and crosses the blood-brain barrier.

METHODS
We conducted a phase II trial of single-agent abemaciclib in patients with recurrent primary brain tumors utilizing a novel CNS basket trial design with multiple tumor types accrued to separate cohorts including patients with recurrent IDH-wildtype gliomas (Cohort A), any recurrent gliomas requiring cytoreductive surgery (Cohort B), and any other recurrent primary brain tumors (Cohort C) including IDH-mutant gliomas, meningiomas, and other tumor types. In all patients, abemaciclib was administered orally at 200mg twice daily for each 28-day cycle. In cohort B abemaciclib was administered 4-7 days prior to surgery then resumed after recovery. Neuroimaging disease assessments were performed every two cycles. Cohorts were individually assessed for efficacy, tumoral molecular characteristics, and exploratory biomarker analyses. Next generation sequencing was performed on patients who had prior surgery.

RESULTS
To date, a total of 61 patients have enrolled and initiated treatment with abemaciclib. Cohort A enrolled 9 patients with IDH-wildtype WHO grade II and III astrocytomas. Cohort B enrolled 10 patients with astrocytomas of varying IDH-status. Cohort C is a diverse group of 42 patients including 22 treatment-refractory meningiomas, 10 IDH-mutant gliomas (5 astrocytomas, 5 oligodendrogliomas), 3 ependymomas, 3 primary CNS lymphomas, 2 pituitary tumors, 1 glioneuronal rosette forming tumor, and 1 diffuse midline glioma. A total of 7 grade 3 toxicities occurred in 6 patients: fatigue (3), neutropenia (2), colitis (1) and seizure (1); no grade 4 toxicities occurred.

CONCLUSIONS
We present the results of a novel CNS basket trial looking at the efficacy of abemaciclib across multiple recurrent primary brain tumors. Efficacy results will be presented, highlighting an update on promising results in the 22 patients with recurrent meningiomas.
CTNI-56. EVALUATING DRUG DISTRIBUTION IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) TREATED WITH CONVECTION ENHANCED DRUG DELIVERY
Authors: Szychot Elwira , Bhagawati Dolin , Gill Steven , Walker David , Hyare Harpreet 
Published: November 2021

Abstract

BACKGROUND
There is currently no method for evaluating drug distribution and tumour coverage using the convection-enhanced drug delivery (CED) technique in Diffuse Intrinsic Pontine Glioma (DIPG).

AIMS
To determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED of carboplatin and sodium valproate.

METHODS
12 children with DIPG received between 4–18ml of infusate, through 2 pairs of catheters to encompass tumour volume on 2 days. Volumetric T2W and Diffusion Weighted Imaging (DWI) MRI sequences were performed before and after the first cycle of CED therapy and Apparent Diffusion Coefficient (ADC) maps were calculated. The tumour volume pre and post CED was automatically segmented (ITKSnap) on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were registered and subtracted (FSL) to visualize the infusate distribution.

RESULTS
ADC and T2W demonstrated a significant (&lt; 0.001) change in mean tumour volume post-infusion (mean ADC volume pre: 19.8ml, post 24.4ml; mean T2W volume pre 19.4ml, post 23.4ml). A significant correlation (p&lt; 0.001) was observed for the difference in tumour volume and the actual infused volume (ADC, r=0.76, T2W, r=0.70). There was a significant increase (p&lt; 0.001) in mean ADC and mean T2W signal intensity ratio post-infusion, no significant correlation with infusion volume. Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion visually demonstrated high signal intensity, presumed infusate coverage of the tumour.

CONCLUSIONS
ADC and T2W MR sequences could potentially be used to evaluate the volume of distribution of infusate delivered by CED, paramount to ensure tumour coverage and leading to more effective therapy evaluation. This will facilitate the use of CED in future clinical trials.
CTNI-58. EFFICACY AND SAFETY OF LAROTRECTINIB IN ADULT AND PEDIATRIC PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION-POSITIVE PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Doz François , van Tilburg Cornelis M , Geoerger Birgit , Nysom Karsten , Øra Ingrid , Boni Valentina , Chisholm Julia , Chung Hyun Cheol , DuBois Steven G , Melcón Soledad Gallego , Gerber Nicolas U , Goto Hiroaki , Grilley-Olsen Juneko E , Hansford Jordan R , Hong David S , Italiano Antoine , Kang Hyoung Jin , Capra Michael , Schulte Johannes H , Stefanowicz Joanna , Tahara Makoto , Ziegler David S , Gavrilovic Igor T , Norenberg Ricarda , Dima Laura , De La Cuesta Esther , Laetsch Theodore W , Drilon Alexander , Perreault Sébastien 
Published: November 2021

Abstract

BACKGROUND
NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a first-in-class, highly selective TRK inhibitor approved for patients with TRK fusion cancer, with a 75% objective response rate (ORR) in 206 evaluable patients with various non-CNS cancers (Hong et al, ASCO 2021). We report data on patients with TRK fusion-positive primary CNS tumors.

METHODS
Patients with TRK fusion-positive primary CNS tumors in 2 clinical trials (NCT02637687, NCT02576431) were identified. Objective responses were investigator-assessed.

RESULTS
As of July 2020, 33 patients with TRK fusion-positive primary CNS tumors were identified (19 high-grade gliomas [HGG], 8 low-grade gliomas [LGG], 2 glioneuronal tumors, 2 neuroepithelial tumors, 1 CNS neuroblastoma, 1 small round blue cell tumor). Median age was 8.9 years (range 1.3-79.0). Patients were heavily pre-treated, with 45% having ≥ 2 prior systemic therapies. ORR was 30% (95% CI 16-49): 3 complete responses (all pediatric), 7 partial responses, 20 stable disease, and 3 progressive disease. ORR in patients with HGG and LGG were 26% (95% CI 9-51) and 38% (95% CI 9-76), respectively. Median time to response was 1.9 months. Responses were seen regardless of the number of prior systemic therapies. The 24-week disease control rate was 73% (95% CI 54-87). Median PFS was 18.3 months (95% CI 6.7-not estimable [NE]) and median overall survival (OS) was not reached (95% CI 16.9-NE) at a median follow-up of 16.5 months; 12-month OS rate was 85% (95% CI 71-99). Treatment duration ranged from 1.2 to 31.3+ months. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 3 patients (9%). There were no treatment discontinuations due to TRAEs.

CONCLUSIONS
In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and favorable safety regardless of age or number of prior systemic therapies.
CTNI-59. A MULTICENTER OBSERVATIONAL STUDY OF CS-131 SEEDS EMBEDDED IN A COLLAGEN CARRIER TILE FOR NEWLY DIAGNOSED AND RECURRENT OPERABLE INTRACRANIAL NEOPLASMS – TRIAL IN PROGRESS
Authors: Dunbar Erin , McCracken David , nowlan adam , Chen Clark , Dusenbery Kathryn , Ferreira Clara , Kotecha Rupesh , McDermott Michael , Jaikumar Sivakumar , Shen Colette , Monyak David , Trusheim John , Wanebo John , Day Samuel , Lee Stuart , Wardak Zabi , Patel Toral , Choi Mehee , Misell Lisa , Brachman David 
Published: November 2021

Abstract

BACKGROUND
For patients with operable intracranial neoplasms, there are opportunities to augment local control beyond traditional methods, such as external beam radiation therapy. Brachytherapy, the implantation of radioactive sources into the resection cavity, can be useful in this setting by providing immediate initiation of radiation and limiting the exposure of surrounding normal tissue to radiation. Traditional intracranial brachytherapy has been limited by uneven dose distributions, complicated workflows, extended procedural times, cost of dedicated equipment, and frequent adverse events. To address these issues, a permanently implanted device with Cs-131 radiation seeds embedded in a bioresorbable collagen carrier tile (GammaTile, GT Medical Technologies, Tempe, AZ USA) was developed. Described as surgically targeted radiation therapy (STaRT), it is FDA-cleared for use in newly-diagnosed malignant intracranial neoplasms and recurrent intracranial tumors, and has demonstrated excellent safety and efficacy in early commercial use. The primary objectives of this multicenter, prospective, observational (phase IV) registry study are to evaluate “real-world” clinical outcomes and patient-reported outcomes that measure the safety and efficacy of STaRT using the GammaTile.

METHODS
Patients undergoing resection (R) of brain tumors with intra-operative GammaTile placement are eligible for enrollment. Planned sample size is 600 at up to 50 enrolling sites. First subject was enrolled 10/14/2020. Tumor pathology, overall survival, radiation- and surgery-related adverse events, patient- and provider-reported quality of life, serial MRIs, and timing of surgical bed and/or distant recurrence are collected. Powered primary endpoints for recurrent brain metastases, recurrent glioblastoma, and recurrent meningioma (surgical bed-progression free survival (PFS), overall survival, and PFS, respectively), compare STaRT to standard-of-care benchmarks. Results will be used to improve awareness and access to this treatment, benchmark clinical outcomes in the real-world setting, allow for comparisons to existing treatments, facilitate the design of future clinical trials, and contribute to the optimal sequencing of treatments for intracranial neoplasms.
DDRE-03. THERAPEUTIC TARGETING OF THE ERK AND CDK PATHWAYS IN PRECLINICAL MODELS OF BRAIN METASTASES
Authors: Singh Mohini , Nayyar Naema , Dahal Ashish , Brastianos Priscilla 
Published: November 2021

Abstract
Brain metastases (BM) are the most common neoplasm to affect the adult central nervous system. BM develop in 40-50% of advanced lung adenocarcinoma (LUAD), but the lack of durable response to chemotherapy, immunotherapy, or targeted therapy results in death within a year of BM diagnosis. Several advances have been made in identifying genetic drivers of primary cancers. The cell cycle, RAS and ERK pathways have all been implicated in as critical oncogenic regulators, with aberrations linked to driving the progression and metastasis of LUAD. Abemaciclib is a targeted CDK4/6 inhibitor, and LY3214996 is selective ERK1/2 inhibitor, and have shown efficacy in preclinical tumor models as well as in clinical trials. Furthermore, both therapeutics can interfere with the cell cycle, abemaciclib through targeting CDK4/6 and LY3214996 through cyclinD1. Here we present data assessing abemaciclib and LY3214996, as single and combined agents, in cell lines across different KRAS and CDKN2A mutational backgrounds. Seven days post-intracranial inoculation of NSCLC and NSCLC-BM line, mice received either abemaciclib, LY3214996, or a combination P.O. daily for 21 days, and were monitored pre- and post-treatment for tumor growth with bioluminescent imaging. In vitro we demonstrated a dose-dependent reduction in cell growth with each treatment, as well as cell arrest in G1 phase. In vivo, whereas cell lines with a combined KRAS mutation and CDKN2A mutation/deletion had no significant reduction in BM growth, cell lines with a CDKN2A del or BRAF mutation had significant BM reduction, with single agents and combined treatment. Further research is necessary to elucidate under what genetic contexts abemaciclib, LY3214996 or the combination are most effective. Nonetheless, this work highlights that abemaciclib and LY3214996 should be further explored for CDKN2A or BRAF mutant BM.
DDRE-04. EFFECTIVENESS AND SAFETY OF OSIMERTINIB FOR PATIENTS WITH LEPTOMENINGEAL METASTASES FORM NON-SMALL CELL LUNG CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Wen Lei , Shan Changguo , Wang hui , Yang yanying , Ye Minting , Hong Weiping , Cai Linbo 
Published: November 2021

Abstract

BACKGROUND
the FLAURA study established Osimertinib to be the priority choice for the treatment of metastatic non-small cell lung cancer (NSCLC) harboring mutated epidermal growth factor receptor (EGFR). However, like many previous studies, the FLAURA study excluded patients with symptomatic CNS metastases. Hence, we performed a systematic review and meta-analyses of studies to assess the efficiency and safety of Osimertinib for the treatment of NSCLC with leptomeningeal metastases (LM).

METHODS
We included studies published between 2010 and 2021 that evaluated the efficacy and toxicity of Osimertinib in NSCLC patients with LM. We searched PubMed, Embase, and oncology meeting abstracts (ASCO, ESMO and WCLC). Primary outcomes were objective response rate (ORR), disease control rate (DCR), any grade 3/4 toxicity rate. We used the random-effects model to generate pooled estimates for proportions. Newcastle-Ottawa Scale (NOS) was used to assess the certainty in the evidence.

RESULTS
Twelve studies reporting on 367 patients were included in the meta-analysis. Most patients (≥90%) received Osimertinib as at least second line of treatment. The objective response rate was 42% (95% CI, 24%-59%; n = 184), and CNS disease control rate was 90% (95% CI, 85%-94%; n = 154). Intracranial progression free survival and overall survival ranged from 3.7 to 15.6 months, and 11.0 to 18.8 months, respectively. Adverse events were similar with previous studies and Common Terminology Criteria for Adverse Events (version 3.0) grade 3 or higher adverse event rates was acceptable.

CONCLUSION
This meta-analysis confirmed that for advanced NSCLC with LM harboring EGFR-TKI-sensitizing mutations, Osimertinib showed impressive antitumor activity and acceptable toxicity.
DDRE-08. A BIOANALYTICAL LC-MS/MS ASSAY TO QUANTIFY TOTAL AND UNBOUND LY3214996, ABEMACICLIB AND ITS ACTIVE METABOLITES IN HUMAN PLASMA, CEREBROSPINAL FLUID AND HUMAN GLIOBLASTOMA
Authors: Margaryan Tigran , Elliott Mackenna , Hook Garry , Sanai Nader , Tovmasyan Artak 
Published: November 2021

Abstract

BACKGROUND
Here, we report on our development and validation of a sensitive and rapid LC-MS/MS method for the determination of total and unbound concentrations of ERK inhibitor LY3214996, CDK4/6 inhibitor abemaciclib and its M2 and M20 active metabolites in human plasma, cerebrospinal fluid and human glioblastoma tissue.

METHODS
Analytes were extracted from patient plasma, CSF and glioblastoma homogenate samples by protein precipitation with methanol. Four levels of quality controls were used during validation. The method was validated according to FDA guidelines and CAP/CLIA regulations. Equilibrium dialysis was performed to determine unbound fraction of four analytes in plasma and brain tissue. The detection was performed on Sciex QTRAP 6500+ mass spectrometer in positive electrospray ionization mode.

RESULTS
The method was validated over a concentration range from 0.2-500 nmol/L for all four analytes. The analytical separation was optimized on Phenomenex Kinetex™ F5 column with total run time of 3.8 min using gradient elution. For all the analytes the maximum coefficient of variation for intra- and inter-day precision was 12.0% and the accuracy was within 90.2-119.7% in all matrixes. The analytes are stable in plasma and brain homogenate for at least 19 hours and 6 hours at room temperature (RT), respectively. Stability of stock and working solutions was demonstrated for at least 15 hours (RT) and 28 days (2-8°C). The unbound fraction of the analytes in pooled human plasma and brain were determined to be 0.371 and 0.065 for LY3214996, 0.026 and 0.013 for abemaciclib, 0.052 and 0.008 for M2, 0.024 and 0.021 for M20, respectively.

CONCLUSIONS
A bioanalytical method to quantify LY3214996, abemaciclib and its M2 and M20 metabolites is successfully developed and validated. The method is currently applied to evaluate plasma pharmacokinetics and CNS penetration of LY3214996 and abemaciclib in recurrent glioblastoma patients in an ongoing Phase 0 clinical trial (NCT04391595).