bluuebunny/crossref_metadata_2025 huggingface dataset:
RADT-08. DOSIMETRIC FEASIBILITY OF DIRECT POST-OPERATIVE MRI-LINAC-BASED STEREOTACTIC RADIOSURGERY FOR RESECTION CAVITIES OF BRAIN METASTASES
Authors: Sierts M , Seravalli E , Brand E , Maspero M , David S , Philippens M E P , Voormolen E H J , Verhoeff J J C
Published: November 2022

Background

Post-operative stereotactic radiosurgery (SRS) of patients with brain metastases with single resection cavities is typically planned on a post-recovery MRI, 4-6 weeks after resection. However, meanwhile the intracranial metastasis may (re-)grow, and postponing adjuvant systemic treatment increases chance on extracranial progression as well. Anticipating direct post-operative SRS to minimize this interval would enable rapid start of systemic therapy. In this study, we considered treatment with MRI-Linac (MRL) SRS, because of the possibility to execute the post-operative MRI and SRS treatment combined on the MRL instead of on two separate systems, improving logistics and increasing patient comfort. However, it is unclear whether MRL-based SRS may be feasible from a dosimetric perspective. This study aims to shed light on the dosimetric feasibility of MRL-based SRS.

METHODS

We simulated MRL treatments including thirteen patients with resectable single brain metastases treated with single fraction CT-Linac (CTL) SRS. We therefore contoured direct post-operative gross tumor volumes (GTV) and compared them to post-recovery MRI GTV. Next, we compared a non-coplanar VMAT technique for CTL (ncVMAT) to a coplanar IMRT technique for MRL (cIMRT), creating three plans per patient: a ncVMAT plan and a cIMRT plan for the direct post-operative GTV, and a post-recovery ncVMAT plan as current clinical standard. RESULTSCompared to GTVs defined on direct post-operative MRI, on post-recovery MRI 15.5% of cavities shrunk by > 2cc, and 46% expanded by > 2cc. Although direct post-operative ncVMAT plans had lower median gradient index and higher median V3Gy of the skin, they were clinically acceptable according to clinical guidelines.

CONCLUSION

Although slightly inferior to non-coplanar CTL plans, direct post-operative MRL-based SRS for resection cavities of brain metastases is dosimetrically acceptable, at the trade-off between increased patient comfort and logistics. Additionally, MRL-based SRS enables substantially earlier start with adjuvant systemic therapies, thereby maximizing tumor control.
RADT-14. COMBINATION RE-RADIATION AND BEVACIZUMAB THERAPY FOR RECURRENT GLIOBLASTOMA: CLINICAL OUTCOMES OF 337 PATIENTS
Authors: Mekonnen Mahlet , Mozaffari Khashayar , Sparks Othneil , Umesh Amith , Zhang Ashley Bo , Yang Isaac
Published: November 2022

BACKGROUND

High-grade gliomas (HGGs) comprise the most common primary adult brain cancers and universally recur. Glioblastoma (GBM) compromise 60% of HGGs with an extremely poor prognosis and are considered incurable despite many treatment advancements. Combination re-radiation therapy (re-RT) and bevacizumab (BVZ) therapy for recurrent HGG is commonly used, however, there is a paucity of literature with respect to its efficacy.

OBJECTIVE

This study aimed to compare treatment outcomes of patients who received reRT alone versus a combination of reRT and BVZ (reRT ± BVZ ) to establish clear guidelines for the optimal management of recurrent GBM.

METHODS

We identified patients with recurrent GBM treated via reRT ± BVZ. Cohorts were stratified by BVZ treatment status and re-irradiation modality. Primary outcomes of interest included radiation necrosis (RN), progression-free survival (PFS), and overall survival (OS). These parameters were then compared between the reRT + BVZ and the reRT alone cohorts.

RESULTS

A total of 337 patients were included. Mean age at primary resection was 51 years old (range: 5-82). Of those, 223 (66.2%) were male and 114 (33.8%) were female. All patients were initially treated with surgical resection. Mean follow up for the entire cohort was 19.1 months (± 1.14 months). The re-RT + BVZ cohort had a longer median survival at 14 months with 6-, 12-, and 24- month survivals of 84%, 60%, and 19.4%, respectively compared to their re-RT alone counterparts. Our study suggests that the combination of reRT+BVZ is effective in improving overall survival and lowering radiation necrosis rates, compared to reRT alone.

CONCLUSIONS

Combination reRT+BVZ may improve OS and reduce rates of RN in recurrent GBM, but further controlled studies are warranted to validate these effects. Future studies should investigate optimal protocols for reRT+BVZ treatment, and for evaluating subsequent radiologic progression in patients with recurrent GBM.
RADT-24. PHASE II STUDY OF PROTON RADIATION THERAPY FOR LOWER GRADE GLIOMAS
Authors: Slater Jason , Horick Nora , Nachtigall Lisa , Parsons Michael , Zarrella Giuliana , Tritos Nicholas , Dietrich Jorg , Pursley Jennifer , Fullerton Barbara , Wang Irene , Oh Kevin , Loeffler Jay , Yeap Beow , Shih Helen
Published: November 2022

PURPOSE

To report preliminary results on outcomes of patients with lower grade gliomas (LGG) treated with proton therapy.

METHODS

Patients with grade II or IDH mutant grade III glioma and indications for radiation therapy were enrolled in a prospective single arm trial of proton therapy (PRT), receiving a dose of 54 Gy(RBE) or 59.4 Gy(RBE), respectively. Comprehensive baseline and regular post-treatment evaluations of neuroendocrine function, neurocognitive functions (NCF), quality of life (QOL), and progression-free survival (PFS) were performed.

RESULTS

Among 60 patients (median age 40.8) who received PRT, 28 (47%) were men, and 39 (65%) were WHO grade II. Eighteen patients (30%) were IDH mutant+1p/19q co-deleted, 36 (60%) were IDH mutant astrocytoma, and 6 (10%) were IDH wildtype. Treatment was at initial diagnosis (41; 68%) or progression (19; 32%). Median follow-up after PRT was 4.1 years. All current data are reported for 3 years from PRT. PFS at 3 years was 86% for all patients, 84% for grade II (n = 39), and 90% for favorable grade III gliomas (n = 21). PFS was 83% for IDH mutant astrocytoma, and 94% for IDH mutant+1p/19q co-deleted oligodendrogliomas. New endocrine dysfunction was detected in 3 patients (5%). There was one grade 4 case of brain necrosis (2%) but no grade 3 toxicities. NCF decline, defined by Z-score drop of >/= 1SD on clinical trials battery composite, occurred in 7% (n = 3/43). QOL assessment by FACT-Brain showed 16% with decline of >/= 10 points (n = 7/43).

CONCLUSIONS

At 3 years post-treatment, LGG patients receiving PRT have a high PFS, similarly to previous reports on photon therapy, few new neuroendocrine deficiencies, modest treatment toxicities, and minimal decline in NCF or QOL. These positive outcomes may be attributable to limited integral dose to the brain by use of PRT, demonstrating its value in treatment of LGG patients with long survival expectations.
RADT-25. UNDERSTANDING PATTERNS OF TUMOUR INFILTRATION IN PATIENTS WITH MULTIFOCAL GLIOBLASTOMA AND IMPACT ON SURVIVAL OUTCOMES
Authors: Back Michael , Horsley Patrick , Yim Jackie , Drummond James
Published: November 2022

BACKGROUND

Multifocal glioblastoma(MF-G) are often clustered with presumed uniform worse prognosis. This study explores varying patterns of infiltration of MF-G in relation to radiological features, including presence of contiguous MRI T2-weighted abnormalities and adjacent neural tract pathway involvement.

METHODS

Consecutive patients with glioblastoma from 2016-2020 managed under EORTC-NCI(Stupp60Gy) Protocol had manual tumour segmentation on T1gd and T2w sequences. Multifocal disease was defined as T1gd or solid T2w-abnormality a minimum of 10mm from the dominant lesion. Number of foci, maximum dimension, cortical/white matter site and distance from dominant lesion were recorded. Presence of contiguous T2w-abnormality was recorded, and correlated to ten major neural tract pathways. Progression-free(PFS) and overall survival(OS) were analysed.

RESULTS

Forty of 177 patients(23%) were identified with MF-G. These had less near-total resection(p = 0.001), but no difference in ECOG(p = 0.16), or MGMT-methylation(p=0.23). Foci had median size of 14.5mm (q1-3: 10-20); 73% enhancing and 58% solitary. Median distance from dominant lesion was 23mm (q1-3:15-25). Contiguous T2w abnormality and involvement of identified neural tract was evident in 78% and 83% respectively. The multifocal lesion was based in cortex in 33%, and white matter in 67%. Survival outcomes were worse with MF-G: OS (p < 0.01) was 16.0 months (95%CI: 13.6-18.4) versus 19.9 months (95%CI: 17.6-22.2); and PFS (p = 0.01) was 10.8 months (95%CI: 9.9-11.7) versus 13.6 months (95%CI: 11.1-16.1). Improved PFS was associated with larger lesion size(p = 0.04), and cortical lesions(0.04). Those MF-G with contiguous T2w-abnormality(p = 0.06); identified neural tract(p = 0.07) or enhancement(p = 0.08) had trend to worse PFS. MGMT(p = 0.10), ECOG(p = 0.62) and extent of resection(p = 0.07) were not associated with PFS, nor radiological factors of foci number(p = 0.19) and lesion distance(p = 0.16).

CONCLUSIONS

Radiological pattern of infiltration in MF-G is associated with different natural history. Improved PFS was associated with cortical foci without contiguous T2 abnormality or tract involvement. Recognising infiltration patterns may impact on RT target volume delineation and understanding prognosis.
RADT-26. PATTERNS OF RECURRENCE IN PATIENTS TREATED WITH RE-IRRADIATION FOR RECURRENT HIGH-GRADE GLIOMA
Authors: Datta Debanjali , Dasgupta Archya , Meena Lilawati , Chatterjee Abhishek , Sahu Arpita , Chaudhari Amit , Joshi Kishore , Puranik Ameya , Rangarajan Venkatesh , Singh Vikas , Shetty Prakash , Moiyadi Aliasgar , Menon Nandini , Patil Vijay , Sahay Ayushi , Sridhar Epari , Kinhikar Rajesh , Gupta Tejpal
Published: November 2022

Purpose/Objective(s)

Re-irradiation (ReRT) is often used to treat recurrent high grade glioma (HGG). There is limited literature regarding the patterns of recurrence following ReRT, which was investigated in the current study.

Materials/METHODS

Patients with available radiation (RT) contours, dosimetry, and imaging-based evidence of recurrence were included in the retrospective study. All patients were treated with fractionated RT using conformal technique. Recurrence was documented as per decision in tumor board based on imaging with magnetic resonance imaging (MRI) or Flouroethyl-L-Tyrosine (FET) positron emission tomography (PET), which was registered with the planning CT. Failure patterns were classified as in-field, marginal, and out-field as decided by >50% recurrence volume within 95%, 20-95%, and outside 20% isodose lines, respectively.

RESULTS

Study population included 37 patients treated with median dose of 54 Gy (range 50.4-54 Gy). Before ReRT, 92% patients had undergone surgery (biopsy in 3, gross total resection in 9, subtotal resection in 22), 62% received concurrent chemo with ReRT, and 49% received maintenance chemotherapy. Median time to recurrence was 9 months (7-16 months, median 10 and 8 months respectively for in-field and marginal/out-field recurrence). In-field, marginal, and out-field recurrence were seen in 24 (65%), 10 (27%), and 3 (8%), respectively. Recurrence mapping was done using MRI, PET, or both in 27, 3, and 7, respectively. Of 24 patients with in-field recurrence, 8 and 16 had disease volume within gross tumor volume and clinical target volume, respectively. 2 patients had leptomeningeal dissemination (1 with majority of recurrence volume in-field and 1 with marginal failure in addition to metastatic disease).

CONCLUSION

Following ReRT for HGG, the majority of recurrence was in the high dose region, suggesting the use of conservative target volumes. Future studies are required for feasibility of dose-escalation to improve control rates, particularly in patients with long intervals from first course of RT.
RADT-34. ANALYSIS OF A METHYLATION CLASS-GUIDED RADIOTHERAPY IN MENINGIOMA PATIENTS - AND THE PROSPECTIVE PHASE II MARCIE TRIAL WITH CARBON-ION BOOST RADIOTHERAPY
Authors: Deng Maximilian , Hinz Felix , Sievers Philipp , Eichkorn Tanja , Anna Kraemer , Eva Meixner , Elisabetta Sandrini , Juliane Hoerner-Rieber , Semi Harrabi , Katharina Seidensaal , Andreas Unterberg , Wick Antje , Wick Wolfgang , von Deimling Andreas , Combs Stephanie , Klaus Herfarth , Juergen Debus , Sahm Felix , Laila Koenig
Published: November 2022

Meningiomas represent the most common primary brain tumor type, with a recurrence rate of approximately 20% following resection. Classification by molecular classes was demonstrated to be more accurate in identifying patients at high risk of disease progression in meningiomas, compared to WHO grading only. Novel radiotherapeutic modalities using protons or carbon ions provide an increased relative biological effectiveness (RBE) compared to photons, enabling a higher local dose deposition while reducing the radiation dose for organs of risks. The prospective single-arm phase II - MARCIE trial investigated a bimodal radiotherapy using photons (50 Gy in 25 fractions) and a carbon-ions boost with 18 Gy (RBE) in 6 fractions. Local progression-free survival after 3 years was defined as primary endpoint. In total, 33 patients were recruited before termination of the trial. After 3 years, local progression free survival was estimated at 94.7% and overall survival at 89.8%. Serious adverse events in the form of radiation necrosis were observed in 3 cases, requiring a subsequent treatment with bevacizumab. Post-hoc DNA methylation profiling revealed that relapses occur more frequently in high-risk meningiomas following radiotherapy, compared to the intermediate risk-group, confirming the prognostic relevance of the methylation-based meningioma classifier.Subsequently, a retrospective matched-pair analysis was performed to compare irradiated (n > 100) and non-irradiated meningiomas, stratified into the molecular risk groups (ben, int, high). The clinical benefit of postoperative radiotherapy and dose escalation with regard to the local control are currently being assessed for the respective molecular meningioma classes. Postoperative, bimodal radiotherapy with carbon-ion boost represent an auspicious treatment modality with an excellent local tumor control following resection. Molecular risk stratification is crucial in identifying patients who might benefit from postoperative radiotherapy.
RADT-35. A PROSPECTIVE REGISTRY STUDY OF 68GA-DOTATATE PET INCORPORATION INTO TREATMENT PLANNING OF INTRACRANIAL MENINGIOMAS
Authors: Perlow Haley , Prasad Rahul , Siedow Michael , Gokun Yevgeniya , Matsui Jennifer , Blakaj Dukagjin , Beyer Sasha , Thomas Evan , Raval Raju , Chakravarti Arnab , Prevedello Daniel , Hardesty Douglas , Elder James , Palmer Joshua
Published: November 2022

Introduction

The current standard for meningioma radiation planning involves MRI-based image guidance. SSTR ligands such as 68Ga-DOTATATE are being explored for meningioma radiotherapy treatment planning due to universal expression of somatostatin receptor 1/2 in meningioma tissue. We hypothesize that 68Ga-DOTATATE PET utilization can reduce the risk of local failure (LF) through precise radiation planning and may also suggest that patients who have local PET avidity after a perceived GTR may be poor observation candidates.

METHODS

A single institution prospective registry study was created and included intracranial meningioma patients who received a 68Ga-DOTATATE PET scan to assist with radiation oncologist decision-making. These were ordered for all meningioma patients as a departmental standard. Patients who received a PET scan from 1/1/2018-2/25/2022 were eligible for inclusion.

RESULTS

60 patients were treated in this prospective registry. 22%, 72%, and 7% were World Health Organization (WHO) high, intermediate, and low-risk, respectively. After completing their PET scan, 48, 11, and 1 patient(s) proceeded with RT, observation, or redo craniotomy. The median follow up was 16 months (IQR 8.3-23.1). 3 patients (5%) experienced LF between 9.2-28.5 months after diagnosis. 2 patients with LF had PET-avid disease in their post-operative cavity and elected for observation prior to recurrence, and 1 high-risk patient with multifocal disease experienced LF 2 years after a second radiation course and multiple previous recurrences. LF rates after radiation were 0%, 0%, and 8% in the low, intermediate, and high-risk cohorts, respectively. There were no Grade 3 or higher toxicities attributed to PET-guided radiation.

CONCLUSION

This is the largest known population of intracranial meningioma patients followed by physicians who utilized 68Ga-DOTATATE PET guided therapy. Only 1 patient experienced LF after receiving PET-guided radiation therapy, likely due to a radioresistant histology. Incorporating 68Ga-DOTATATE PET into future trials may assist with clinician decision-making and improve patient outcomes.
CTIM-14. COMPREHENSIVE BIOMARKER ANALYSIS OF RESPONDERS AND NON-RESPONDERS IN A PHASE IIA TRIAL OF A CMV VACCINE IMMUNOTHERAPEUTIC CANDIDATE (VBI-1901)
Authors: Wen Patrick Y , Reardon David A , Forst Deborah , Lee Eudocia , Daoud Teresa , Berthoud Tamara , Soare Catalina , Diaz-Mitoma Francisco , Anderson David E , Lassman Andrew , Iwamoto Fabio
Published: November 2022

Cytomegalovirus (CMV) antigens have been reported in over 90% of GBMs. CD4+ and CD8+ T cells are most frequently directed against the gB and pp65 antigens, respectively, which are immunogenic targets in a CMV-based GBM immunotherapeutic. First-recurrent GBM patients were enrolled, with Karnofsky Performance Status of at least 70, to receive VBI-1901 (a gB/pp65 enveloped virus-like particle [eVLP]) adjuvanted with GM-CSF and given intradermally (NCT03382977). Patients were vaccinated with VBI-1901 every 4 weeks, with serologic immune-monitoring 2 weeks after each vaccination and surveillance brain MRI scans every 6 weeks. Sixteen patients (8 women, 8 men) with a median age of 55 (33-67 yrs) were enrolled into the GM-CSF arm. Seven tumor responses, including two durable partial responses, were observed which led to an 18-month OS rate of 25% and mOS of 56 weeks. Detailed immunological testing was performed to identify potential correlations at baseline and after treatment between biomarkers and tumor responses. Analyses included class I and II HLA typing, modulation of plasma cytokine and chemokine responses, boosting of CMV-specific antibody and IFN-g ELISPOT responses, and modulation of CMV-specific CD4 Tem cells, of which only differential trafficking of the CD4 Tem cells appears to distinguish patients with tumor responses from those with tumor progression. Single cell, RNAseq is underway in an attempt to understand mechanistic differences in these immune cell populations in Tumor Responders vs. Non-Responders. The U.S. FDA granted Fast Track Designation to VBI-1901 adjuvanted with GM-CSF in first-recurrent GBM patients, and an expansion of the ongoing trial with this formulation in this patient population, with the addition of randomization with a contemporaneous control arm, is anticipated to begin in Q3 2022.
CTIM-20. PROSPECTIVE RANDOMIZED PHASE II PLACEBO-CONTROLLED TRIAL OF SURVAXM PLUS ADJUVANT TEMOZOLOMIDE FOR NEWLY DIAGNOSED GLIOBLASTOMA (SURVIVE)
Authors: Ahluwalia Manmeet , Ciesielski Michael J , Abad Ajay , Reardon David A , Aiken Robert , Barbaro Marissa , Sinicrope Kaylyn , Peereboom David , Odia Yazmin , Brenner Andrew , Venur Vyshak , Belal Ahmed , Qiu Jingxin , Khosla Atulya , Schilero Cathy , Casucci Danielle , Mechtler Laszlo , Fenstermaker Robert
Published: November 2022

BACKGROUND

Newly diagnosed glioblastoma (nGBM) has a dismal prognosis with survival of 15-18 months. Tumor associated “survivin” protein is expressed in >95% of nGBM and is targetable with the use of SurVaxM, shown to be effective at generating cytotoxic T lymphocytes.

METHODS

nGBM patients are being enrolled in this randomized placebo-controlled trial phase II study. Eligibility Criteria includes age ≥ 18, KPS ≥ 70, IHC confirmed survivin-expression, and residual contrast enhancement of ≤1 cm3 by MRI, within 72 hours of surgical resection. Patients are randomized 3:2 into two arms A:B to treatment with SurVaxM in emulsion with Montanide plus sargramostim (local injection) and standard-of-care TMZ (Arm A), or placebo (saline in emulsion with Montanide) plus saline (local injection) and standard-of-care TMZ (Arm B). There are three active treatment phases in the study with vaccine priming (VP) phase; adjuvant TMZ phase; and Vaccine Maintenance (VM) phase. A total of four (4) priming doses of SurVaxM in Montanide plus sargramostim (“SurVaxM/sargramostim”) or placebo in Montanide/saline (“Placebo/Placebo”) will be administered every two weeks ( ± 3 days) during the priming phase, with subsequent dosing every 8 weeks ( ± 1 week) during the vaccine maintenance phase. After priming doses, SurVaxM/sargramostim or Placebo/Placebo will be administered every 8 weeks ( ± 1 week) until tumor progression or for a maximum of 24 months. The total sample size is of 265 patients, with 159 patients in the SurVaxM arm and 106 patients in the control arm. The primary objective is to determine the overall survival (OS), and the secondary objectives include progression-free survival (PFS), OS at pre-specified time points (OS-15, OS-18 and OS-24), PFS at pre-specified time points (PFS-3, PFS-6 and PFS-12) and evaluation of toxicities. Study duration is expected at 36 months, with enrollment ongoing at several centers and planned for total of 20 participating centers.
CTNI-05. MOLECULAR ANALYSIS OF THE PHASE I D-TERMINED TRIAL ON CONCURRENT AND ADJUVANT TEMOZOLOMIDE WITH MINOCYCLINE IN NEWLY DIAGNOSED HIGH-GRADE GLIOMA
Authors: McKean William , Boucher Kenneth , Yang Jingye , Sonty Karthik , Jensen Randy , Shrieve Dennis , Salzman Karen , Johnson Brett , Thomas Melissa , Moss Whitney , Behunin Amanda , Prystas Elizabeth , Colman Howard , Cohen Adam
Published: November 2022

BACKGROUND

Minocycline blocks microglial TNF signaling and downstream NF-κB activation, which reduces the mesenchymal phenotype in preclinical models of GBM. Primary analysis of the D-TERMINED trial identified a maximal tolerated dose (MTD) of oral minocycline at 150 mg BID in combination with temozolomide and radiation. In the overall population, the secondary objective of improved PFS was not met. Here, response is further stratified by biomarkers delineating mesenchymal subtype (OLIG2, CD44), microglial activation (IBA-1), and NF-κB signaling (P-p65).

METHODS

Patients with newly diagnosed high-grade glioma received continuous oral minocycline during concurrent chemoradiation and adjuvant temozolomide. Twenty patients were included in the MTD efficacy population. Within this cohort, immunohistochemistry for OLIG2, CD44, IBA-1, and P-p65 was performed on nineteen patient tumor samples. For each biomarker, the mean percent positivity or number/HPF was compared between patients who exceeded or did not exceed expected PFS. Spearman correlation coefficients were also generated for pairwise comparison of these biomarkers.

RESULTS

In patients with high PFS, 12.7% of tumor cells were positive for OLIG-2, 36.5% for CD44, and 23.9% for P-p65, with 41.7 cells/HPF positive for IBA-1. Comparatively, in patients with low PFS, 9.4% of tumor cells were positive for OLIG-2 (p = 0.59), 34.1% for CD44 (p = 0.77), and 22.3% for P-p65 (p = 0.85), with 31.1 cells/HPF positive for IBA-1 per HPF (p = 0.38). The only biomarkers demonstrating significant relationship were P-p65 and IBA-1, with a rank correlation of 0.637 (p = 0.007).

CONCLUSIONS

Exploratory analysis of D-TERMINED concludes that OLIG-2, CD44, IBA-1, and P-p65 are not predictive of improved PFS within high-grade glioma patients treated with SOC and minocycline. Concurrent use of minocycline with chemoradiation is therefore not indicated in these or unselected populations. Significant correlation is seen between IBA-1 and P-p65, biomarkers of microglial activation and NF-κB signaling. SPONSORSHIP: Funding provided by the Musella Foundation and NIH grant P30CA042014.
CTNI-46. PIVOTAL STUDY TO EVALUATE SAFETY AND EFFICACY OF EXABLATE MODEL 4000 USING MICROBUBBLE RESONATORS TO TEMPORARILY MEDIATE BLOOD-BRAIN BARRIER DISRUPTION FOR LIQUID BIOPSY IN GLIOBLASTOMA (LIBERATE)
Authors: Ahluwalia Manmeet , de Groot John , Lee John , Mogilner Alon , Schwartz Theodore H , Burns Terry , Shah Bhavya , McDermott Michael , Bettegowda Chetan , Khosla Atulya , Sahgal Arjun , Mishra Mark , Achrol Achal S , Lipsman Nir , Woodworth Graeme
Published: November 2022

BACKGROUND

Glioblastoma (GBM) has dismal outcome of 14-16 months. One of the challenges of drug development in GBM is lack of requisite circulating-free (cfDNA) in blood samples to develop biomarker driven targeted therapy trials. The Exablate focused ultrasound with circulating microbubble resonators uses the concept of real-time imaging to treat small target spots focusing energy in a non-invasive manner, thereby disrupting the Blood-Brain Barrier (BBBD) with potential to increase cfDNA in blood.

METHODS

LIBERATE is a prospective, multi-center, self-controlled pivotal ongoing clinical trial in subjects with suspected GBM evaluating the safety and effectiveness of Exablate Model 4000 to disrupt BBB to achieve a greater proportion of cfDNA in samples taken post-BBB disruption as compared to the sample taken before BBBD. Fifty eligible subjects with suspected GBM who are scheduled to undergo brain tumor resection or biopsy at 10 centers in the U.S. will participate in this study. The primary endpoint is defined for each subject as ratio between his/her cfDNA amount found in the blood sample 1-hour post-BBBD procedure compared to the cfDNA amount found in the blood sample collected pre-BBBD procedure. This study proposes to demonstrate that on average there is at least 2-fold increase in cfDNA (measured by central laboratory) at 1 hour post BBBD. Confirmatory secondary analysis will evaluate correlation between patterns obtained in panel of biomarkers evaluated in the resected tumor tissue and/or biopsy sample and blood sample collected 1-hour post-BBBD. Exploratory endpoints will include: (1) sensitivity of detection of known somatic mutations in the circulating blood samples (circulating tumor DNA) before and after BBBD, (2) time of greatest yield of cfDNA in the samples collected post BBBD blood samples (at 30 min, 1-hour, 2-hour and 3-hour) to determine time of greatest yield, (3) correlation of biomarkers between the imaging and the post-BBBD biomarker samples. (NCT05383872)
CTNI-55. INITIAL TEMOZOLOMIDE MONOTHERAPY WITHOUT RADIOTHERAPY MIGHT BE OF LIMITED BENEFIT IN THE TREATMENT OF ASTROCYTOMA, IDH-MUTANT, CNS WHO GRADE 2 AND 3
Authors: Weller Jonathan , Katzendobler Sophie , Blobner Jens , Thiele Frederic , Becker Hannes , Quach Stefanie , Egensperger Rupert , Niyazi Maximilian , Suchorska Bogdana , Thon Niklas , Weller Michael , Tonn Joerg-Christian
Published: November 2022

QUESTION

The role of temozolomide chemotherapy alone in isocitrate dehydrogenase (IDH)-mutant astrocytomas has not been conclusively determined. Recent studies have linked temozolomide therapy with induction of hypermutation and poor clinical course in some IDH-mutant gliomas.

METHODS

In this retrospective, single-center study, 183 patients with astrocytoma, IDH-mutant, CNS WHO grade 2 or 3 diagnosed between 2003 and 2019 were included. Patients initially monitored by means of a wait-and-scan strategy, or treated with radiotherapy alone, or receiving temozolomide alone, after histological sampling through biopsy or tumor resection, were studied. Progression-free and overall survival was analysed. A matched-pair analysis accounting for post-surgical tumor volume was conducted.

RESULTS

Initial T2 tumor volume and WHO grade were associated with survival in univariate analyses (p < 0.01). The proportion of WHO grade 2 gliomas was highest in the wait-and-scan cohort (p < 0.01). Tumor volumes were largest in the temozolomide cohort (p < 0.01). Radiotherapy was associated with longer progression-free survival than temozolomide (6.2 vs 3.4 years, p = 0.02) and wait-and-scan strategies (6.2 vs 4 years, p = 0.03). Patients treated with radiotherapy showed longer overall survival than patients treated with temozolomide (14.4 vs 10.7 years, p = 0.02). Survival was longer in patients initially monitored by means of a wait-and-scan strategy than in patients treated with temozolomide (not reached vs 10.7 years, p < 0.0001). The same association was seen in a subgroup analysis of WHO grade 2 astrocytomas (p = 0.02) and by trend in a matched pair analysis (p = 0.09).

CONCLUSION

The results suggest superiority for progression-free survival of radiotherapy alone over temozolomide alone or wait-and-scan strategies and for overall survival of radiotherapy alone and wait-and-scan therapies over temozolomide in IDH-mutant WHO grade 2 and 3. Recent study results indicating that temozolomide might compromise prognosis in some patients with IDH-mutant gliomas might be supported by our data.
CTNI-61. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Kawakibi Abed Rahman , Tarapore Rohinton , Gardner Sharon , Chi Andrew , Kurz Sylvia , Wen Patrick Y , Arrillaga-Romany Isabel , Batchelor Tracy , Butowski Nicholas , Sumrall Ashley , Shonka Nicole , Harrison Rebecca , DeGroot John , Mehta Minesh , Odia Yazmin , Hall Matthew , Daghistani Doured , Cloughesy Timothy , Ellingson Benjamin , Kim Michelle , Umemura Yoshie , Garton Hugh , Franson Andrea , Schwartz Jonathan , Li Sunjong , Cartaxo Rodrigo , Ravi Karthik , Cantor Evan , Cummings Jessica , Paul Alyssa , Walling Dustin , Dun Matthew , Cain Jason , Li Jiang , Filbin Mariella , Zhao Lili , Kumar-Sinha Chandan , Mody Rajen , Chinnaiyan Arul , Kurokawa Ryo , Pratt Drew , Venneti Sriram , Grill Jacques , Kline Cassie , Mueller Sabine , Resnick Adam C , Nazarian Javad , Waszak Sebastian , Allen Joshua E , Koschmann Carl
Published: November 2022

Patients with H3K27M-mutated diffuse midline glioma (DMG) have no proven effective therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has shown promise in this population. Clinical and genetic variables associated with ONC201 response in H3K27M-mutant DMG continue to be investigated. A combined clinical and genetic study evaluated patients with H3K27M-DMG treated with single-agent ONC201 at the established phase 2 dose. Clinical outcomes of patients treated on two recently completed multi-site clinical studies (NCT03416530 and NCT03134131, n = 75) were compared with historical control data from patients with confirmed H3K27M-DMG (n = 391 total, n = 119 recurrent). Patients treated with ONC201 monotherapy following initial radiation, but prior to recurrence, demonstrated a median overall survival (OS) of 25.6 months from diagnosis and recurrent patients demonstrated a median OS of 16.2 months from recurrence, both of these more than doubling historical outcomes. Using a Cox model to correct for age, gender and tumor location, OS of ONC201-treated patients with H3K27M-mutant tumors remained significantly better than non-ONC201-treated historical controls (p = 0.0001). A survival and radiographic analysis based on tumor location, revealed stronger responses in thalamic patients. In patients with thalamic tumors treated after initial radiation (n = 16), median OS was not reached with median follow up of 22.1 months (historical control median OS of 12.5 months, n = 83, p = 0.0001). Significant correlations were found between baseline cerebral blood flow (CBF) on perfusion imaging and OS (Pearson’s r = 0.75, p = 0.003) and between nrCBF and PFS (r = 0.77, p = 0.002). Baseline tumor sequencing from treated patients (n = 20) demonstrates EGFR mutation (n = 3) and high EGFR expression as a marker of resistance and improved response in tumors with MAPK-pathway alterations (n = 5). In conclusion, ONC201 demonstrates unprecedented clinical and radiographic efficacy in H3K27M-mutant DMG with outcomes enriched in patients with thalamic tumors, treatment prior to recurrence, MAPK-pathway alterations, and patients with relatively high CBF.
CTNI-62. LONG-TERM EFFICACY AND SAFETY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Perreault Sébastien , Drilon Alexander , Lassen Ulrik N , Geoerger Birgit , Nysom Karsten , Øra Ingrid , Gavrilovic Igor T , Norenberg Ricarda , Bernard-Gauthier Vadim , De La Cuesta Esther , Laetsch Theodore W , Doz François , Van Tilburg Cornelis M
Published: November 2022

BACKGROUND

Larotrectinib is a highly selective TRK inhibitor that demonstrated an objective response rate (ORR) of 30% and a 24-week disease control rate (DCR) of 73% across 33 evaluable adult and pediatric patients with TRK fusion primary CNS tumors, as of July 2020 (Doz et al, Neuro Oncol 2021). We report updated data on an expanded dataset.

METHODS

Patients with TRK fusion primary CNS tumors in two clinical trials (NCT02637687, NCT02576431) were included. Responses were investigator-assessed.

RESULTS

As of July 2021, 38 patients with TRK fusion primary CNS tumors (median age, 10.8 [range 1.3–79.0] years) were identified: high-grade glioma (HGG; n = 23), low-grade glioma (LGG; n = 9), and other (n = 6). Sixteen (42%) patients had ≥ 2 prior systemic therapies. ORR for 37 evaluable patients was 30% (95% confidence interval [CI] 16–47): three complete responses, eight partial responses, 21 stable disease (16 patients ≥ 24 weeks), and five progressive disease. For pediatric patients (n = 28), the ORR was 39% (95% CI 22–59). For pediatric patients with HGG and LGG, ORRs were 43% (95% CI 18–71) and 38% (95% CI 9–76), respectively. ORRs for patients with 0, 1, 2, and ≥ 3 prior therapies were 33%, 20%, 38%, and 38%, respectively. Median time to response was 1.9 months. The 24-week DCR was 73% (95% CI 56–86). Median duration of response (DoR) was not reached; 12-month DoR rate was 64%. Median progression-free survival was 16.5 months (95% CI 6.7–not estimable). Median overall survival (OS) was not reached; 24-month OS rate was 65%. Treatment duration ranged from 0.1+ to 38.7+ months. Treatment-related adverse events (TRAEs) were mostly Grade 1–2. No patients discontinued treatment due to TRAEs.

CONCLUSION

Larotrectinib demonstrated a high DCR, rapid and durable responses, and a manageable safety profile in patients with TRK fusion primary CNS tumors.
DNAR-03. TARGETING POLY (ADP-RIBOSE) SIGNALING TO INDUCE LETHAL DNA DAMAGE IN IDH MUTANT GLIOMA
Authors: Kitagawa Yosuke , Wakimoto Hiroaki , Melamed Lisa , Nasser Ali , Miller Julie , Cahill Daniel
Published: November 2022

Isocitrate dehydrogenase (IDH) 1 or 2 mutant gliomas have unique metabolic characteristics and DNA damage response. Radiotherapy and chemotherapy has been proven to be an effective treatment for IDH mutant gliomas. A key mediator of DNA damage response, Poly(ADP-ribose) (PAR) is regulated by opposing enzymes, poly(ADP-ribose) polymerases (PARPs) that synthesizes PAR through enzymatic polymerization of nicotinamide adenine dinucleotide (NAD), and poly(ADP-ribose) glycohydrolase (PARG) that breaks down and recycles PAR. We recently demonstrated that combining PARG inhibitor (PARGi) and Temozolomide (TMZ) in IDH mutant cells drove an imbalanced sequestration of NAD into PAR, resulting in metabolic lethality through NAD depletion. Here, we sought to characterize the effect of combining PARGi and radiation. Isogenic pairs of IDH1-mutant glioma cells, alongside multiple IDH mutant patient-derived glioma cells, were treated with TMZ, radiation, PARPi, PARGi, and combination thereof. In contrast to PARPi which can have a “trapping” effect, PARGi monotherapy displayed no significant difference between IDH mutant and wild-type isogenic cells. However, we found a substantial augmentation of radiation cytoxicity when combined with PARGi, that was genotype-specific in IDH mutant glioma models, mirroring that seen with PARPi and radiation (Wang et al, Science Advances 2020). Unlike TMZ+PARGi, NAD was not depleted with PARGi and radiation. Conversely, the cytotoxic effect was partially reversed with either PARPi or IDH inhibitor, indicative of a key contribution of PAR mediated DNA damage signaling in the IDH mutant context. Therefore, these results support a model of converging vulnerabilities in IDH mutant cells, with PAR-mediated DNA repair mechanisms independent from NAD metabolism.In summary, this study demonstrates that the combination of PARGi and radiation regulates DNA repair pathways with cytoxicity specific to IDH mutant gliomas. Targeting PAR can potentially be a promising treatment for clinical translation in IDH mutant gliomas, minimizing the radiation effect to surrounding normal cells.
DNAR-11. CHARACTERIZING THE GENOMIC CONSEQUENCES OF G-QUADRUPLEX STABILIZATION IN ATRX-DEFICIENT HIGH-GRADE GLIOMA
Authors: Dharmaiah Sharvari , Chen Brandon , Malgulwar Prit Benny , Tadimeti Vasudev , Farooqi Ahsan , Huse Jason
Published: November 2022

α-thalassaemia/mental retardation X-linked (ATRX) mutations are a critical molecular marker for high-grade glioma (HGG). These mutations lead to accumulations of abnormal DNA secondary G-quadruplex (G4) structures, thereby inducing replication stress and DNA damage. As G4s arise at GC-rich regions (i.e., pericentromeric and telomeric regions), ATRX-deficiency alters genome-wide accessibility of chromatin and causes transcriptional dysregulation. However, the genomic consequences of this in the context of ATRX-deficiency are poorly understood. Our goal is to target ATRX deficiency through G4 stabilizers, a class of novel small molecule compounds that selectively bind to and stabilize G4s. Using a combination of functional experiments such as cell viability, western blot, flow cytometry, RNA-sequencing (RNA-seq), and immunofluorescence (IF), we evaluated the mechanisms that drive selective lethality upon G4 stabilization. Patient-derived glioma stem cells (GSCs) were treated with either vehicle (DMSO) or varying doses of CX-5461 (G4 stabilizer, Senhwa Biosciences). Excitingly, ATRX-deficient GSCs demonstrate dose-dependent enhanced sensitivity to G4 stabilization, compared to ATRX-intact and vehicle controls. Cell viability assays confirmed the specificity of CX-5461 in comparison to other commercially used G4 stabilizers. G4 stabilization activated p53-independent apoptosis and exhibited G2/M arrest in ATRX-deficient GSCs and, interestingly, upregulated expression of both ATR and ATM pathways, indicating enhanced replication stress and DNA damage, respectively. IF staining confirmed enhanced induction of replication stress and DNA damage markers 53BP1 and gH2AX. Our preliminary findings suggest that ATR and ATM activation leads to Cyclin D1 degradation and inhibition of transcription factor NF-κB, thereby driving apoptosis. In fact, RNA-seq analyses revealed positive enrichment of apoptosis, DNA repair, and NF-κB pathways and negative enrichment of the G2/M checkpoint in ATRX-deficient GSCs treated with CX-5461. Our work defines mechanisms of action and efficacy of a novel therapeutic strategy for pre-clinical ATRX-deficient HGG models, with strong implications for other ATRX-deficient cancers and potential translation into clinical practice.
DDEL-06. HEAT-ACTIVATED DOXORUBICIN UPTAKE FACILITATED BY LASER INTERSTITIAL THERMAL THERAPY
Authors: Athukuri Prazwal , Moreno Karina , Yang Yuhui , McDonald Malcolm , Lee Sungho , Latha Khatri , Marisetty Anantha , Rao Ganesh
Published: November 2022

Although surgery has been shown to provide a survival benefit in patients with glioblastoma multiforme (GBM), tumor location and geometry may restrict maximal resection. Additionally, the margin of resection cavity contains infiltrating tumor cells that result in recurrence and therapy resistance. Laser interstitial thermal therapy (LITT) is a treatment modality that uses thermal energy to destroy tumor cells. LITT is useful for tumors that are not appropriate for conventional surgical resection. Our laboratory has developed a LITT model to study LITT in a genetically engineered mouse model of GBM. The combination of heat activated nanoparticles and LITT represents an opportunity to target the infiltrating tumor margin, extending the treatment penumbra. We hypothesized that heat-activated liposomes containing doxorubicin (ThermoDox, Celsion) would demonstrate infiltration into the brain parenchyma after treatment with LITT. We treated tumor-bearing mice with LITT or sham (laser fiber implanted but not activated) after either ThermoDox (5mg/kg) or PBS infusion, 30 minutes before performing LITT or sham treatment. We euthanized these mice 1 hour after LITT or sham treatment, harvested brains, and performed immunofluorescence to identify doxorubicin in parenchymal cells. Doxorubicin was identified in 100% of mice treated with LITT following ThermoDox administration which is in contrast with groups treated with LITT and PBS, sham and ThermoDox, and sham and PBS. Here, we show that heat-activated nanoparticles are disrupted through hyperthermia followed by the release of doxorubicin only in the presence of hyperthermia, which paves way for the clinical use of ThermoDox as adjunct chemotherapy following LITT in treatment-resistant GBM treatment.
DDEL-10. ULTRASOUND-ENHANCED DRUG DELIVERY IN HUMANS ALTERS ENDOTHELIAL PHENOTYPE AND PERTURBS THE ULTRASTRUCTURE OF THE BLOOD BRAIN BARRIER
Authors: Gould Andrew , Korobova Farida , Arrieta Victor , Amidei Christina , Canney Michael , Chen Li , Stupp Roger , Sonabend Adam M
Published: November 2022

The use of low-intensity pulsed ultrasound with concomitant injection of microbubbles (LIPU/MB) achieves local and reversible opening the blood-brain barrier (BBB), enhancing the delivery of systemically administered drugs to the brain parenchyma. Electron microscopic studies conducted in animals proposed that LIPU/MB enhances paracellular diffusion across the cerebral vasculature, by disrupting tight junction proteins between endothelial cells, as well as enhancement of caveolar transcytosis. The effects of LIPU/MB on the ultrastructure of the human BBB and cerebral endothelial phenotype have not been systematically investigated. Here we report a first in-human electron microscopic study, examining endothelial phenotype and BBB ultrastructure in the peri-tumoral brain of humans after undergoing LIPU/MB-enhanced drug delivery. Non-eloquent peritumoral brain was biopsied at different time points (4-63 minutes) following an intraoperative LIPU/MB procedure in three patients who underwent a surgical resection of recurrent glioblastoma through a phase I clinical trial [NCT04528680]. Transmission electron microscopy was used to examine cross sections of the microvasculature and associated components of the BBB. We observed a significant (P = 0.0397) time-dependent decrease in the frequency of endothelial caveolae immediately after sonication compared to non-sonicated control vessels, which resolved within 1 hour of treatment. We also observed a time-dependent increase in membrane-bound vacuoles in the endothelial cytoplasm following sonication (P = 0.0002, one-way ANOVA). Sonicated blood vessels occasionally showed swollen astrocytes, convoluted luminal protections, and lightening of otherwise dense tight junction proteins, not frequently observed in non-sonicated biopsies from the same patients. Our study shows that LIPU/MB changes the endothelial phenotype within the cerebral vasculature, and suggests the accumulation of vacuoles in endothelial cells after BBB opening.
DDEL-14. SYSTEMIC THERAPY USE FOR THE TREATMENT OF MENINGIOMA: A SYSTEMATIC REVIEW
Authors: Taleb Khalid , Laucis Anna
Published: November 2022

INTRODUCTION

Meningiomas are the most common primary central nervous system tumor. Many studies have investigated systemic therapy agents for treating meningiomas, but no study has systematically evaluated the various agents used while comparing outcomes. The goal of this study was to investigate the recent systemic therapy agents used to treat meningioma tumors and to compare relevant clinical outcomes such as progression-free survival and overall survival in patients with meningioma tumors receiving systemic therapy agents as part of their care.Materials and

METHODS

A systematic literature review was performed to investigate systemic therapy agents used to treat meningioma tumors. The PubMed database was used for this review and articles published from 7/4/2011 to 7/4/2021 were evaluated. The exclusion criteria included the following: animal and cell line studies, case reports, review articles, articles in a foreign language (other than English), as well as articles not related to meningioma or to systemic therapy agents.

RESULTS

163 articles were initially evaluated. After excluding 152 articles using the exclusion criteria for our study, a total of 11 articles exploring 14 different systemic therapy agents were ultimately included and compared, mainly focusing on the two clinical outcomes of progression-free survival and overall survival. The study findings suggest that Bevacizumab may have the most promising results for reducing peri-tumoral edema and extending progression-free survival, with the highest observed progression-free survival at six months of 86% compared to lower progression-free survival for other systemic therapy agents.

CONCLUSION

This systematic review study evaluated systemic therapy agents used to treat meningioma tumors. Bevacizumab was found to have the most promising results overall. However, further studies are now needed to evaluate the efficacy and possible side effects of Bevacizumab amongst a larger population of patients with different meningioma tumor grades, locations, and treatment responses.
DDDR-09. TARGETED DYSREGULATION OF SPHINGOLIPID RHEOSTAT BALANCE IN IDH1MUT GLIOMAS TRIGGERS PRO-APOPTOTIC METABOLIC AND SIGNALING ACTIVITY
Authors: Dowdy Tyrone , Yamasaki Tomohiro , Li Aiguo , Zhang Lumin , Zaibaq Faris , Lita Adrian , Gilbert Mark , Larion Mioara
Published: November 2022

BACKGROUND

IDHwt gliomas exhibit sphingolipid rheostat balance that permits tumors to evade apoptosis by elevating the sphingosine-1-phosphate (S1P)-to-ceramide ratio. Overexpression of sphingosine kinase (SPHK) and consequent accumulation of S1P contribute to progression, chemoresistance, migration, and metastasis in malignant glioblastoma (GBM). We discovered that IDH1mut gliomas present a characteristic sphingolipid rheostat in which pro-apoptotic ceramides and sphingosines are elevated over oncopotent S1P. This characteristic involves inherent silencing of the SPHK2; obliging spheroids to rely on SPHK1 exclusively. We postulated that targeting this unique metabolic vulnerability would abrogate the growth-promoting and anti-apoptotic effects of S1P.

METHODS

IDH1mut glioma cell lines (TS603, BT142 & NCH1681) and empty vector-induced normal human astrocytes (NHAEV) were cultured and treated with a combination of SPHK1 inhibitor, N,N-dimethylsphingosine and C17-sphingosine to dysregulate sphingolipid rheostat. Biostatic response (i.e., IC50) was measured via spectrophotometric assay. Metabolic and signaling mechanisms were investigated by LC-MS lipidomic and RNA sequencing analysis. Mechanism of apoptosis was determined via western-blotting.

RESULTS

Following combination treatment, a global increase in ceramides, sphingosines, and their derivatives over S1P was detected in the sphingolipid rheostat. A decline in growth-promoting MAPK signaling enzymes and elevation of enzymes indicative of mitochondria-driven apoptosis occurred. Elevation of TNFα-related regulatory enzymes (NR1H3, MYLIP, INSIG, ABCA1) negatively impacted cholesterol homeostasis along with catalytic enzymes involved in cholesterol (and isoprenoid) biosynthesis. The effective concentration against IDH1mut spheroids was not cytotoxic to NHA spheroids.

CONCLUSION

The combination treatment potentiated a pro-apoptotic shift in sphingolipidome and revealed a novel mechanism of drug action involving concomitant global attenuation of cholesterol metabolism. While previous studies reported that decreasing cholesterol in gliomas compromises viability and induces apoptosis a link between cholesterol and sphingolipid metabolism remains unknown. Our data demonstrated that targeting sphingolipid rheostat triggers a cascade of pro-apoptotic signaling and metabolic activity that lower the threshold for apoptosis in IDHmut gliomas.