bluuebunny/crossref_metadata_2025 huggingface dataset:
BSCI-12 BREAST TO BRAIN METASTASIS IS EXACERBATED WITH CHEMOTHERAPY THROUGH BLOOD-CEREBRAL SPINAL FLUID-BARRIER AND INDUCES ALZHEIMER’S-LIKE PATHOLOGY
Authors: Neman Josh , Saatian Behnaz , Herrera Robert , Martirosian Vahan , Eisenbarth Rachel , Iyer Mukund , Julian Alex , Lowman Allison , LaViolette Pete , Remsik Jan , Boire Adrienne , Sankey E , Fecci Peter E , Shiroishi Mark , Chow Frances , Hurth Kyle
Published: August 2022

Control of breast to brain metastasis remains an urgent unmet clinical need. While chemotherapies are essential in reducing systemic tumor burden, they have also shown to promote non-brain metastatic invasiveness and drug-driven neurocognitive deficits through formation of neurofibrillary tangles (NFT) independently. Now, in this study we investigated the effect of chemotherapy on brain metastatic progression and promoting tumor-mediated NFT. Results show chemotherapies promote increased brain-barrier permeability and facilitate enhanced tumor infiltration, particularly through the blood-cerebrospinal fluid-barrier (BCSFB). This is attributed to increased expression of matrix metalloproteinase 9 (MMP9) which, in turn, mediates loss of Claudin-6 within the choroid plexus cells of the BCSFB. Importantly, increased MMP9 activity in the choroid epithelium following chemotherapy results in cleavage of Tau released from breast cancer cells. This cleaved Tau forms tumor-derived NFT that further destabilize the BCSFB. Our results underline for the first time the importance of the BCSFB as a vulnerable point of entry for brain-seeking tumor cells post-chemotherapy and indicate that tumor cells themselves contribute to Alzheimer’s-like tauopathy.
BSCI-20 STING EPIGENETIC SILENCING IN GLIOMAS CAN BE RESCUED BY METHYLTRANSFERASE INHIBITION: IMPLICATIONS FOR NOVEL THERAPEUTIC APPROACHES
Authors: Low Justin , Chandramohan Vidya , Bowie Michelle , Brown Michael , Waitkus Matthew , Briley Aaron , Stevenson Kevin , Fuller Rebecca , Hostettler Janell , Reitman Zachary , Charbonneau Casey , Keir Stephen , Khasraw Mustafa , Ashley David
Published: August 2022

The stimulator of interferon genes (STING) is a key component of the innate immune response to pathogenic cytosolic DNA, resulting in IRF3- and NFκB-dependent transcription of type I interferons (IFN) and pro-inflammatory cytokines. STING activation primes endogenous antitumor immunity and is disrupted in a variety of cancers. Here we investigate STING signalling in glioblastoma (GBM) patient samples. STING agonist treatment of ex vivo gliomas leads to inconsistent induction of type I IFN responses that are restricted to tumor associated myeloid cells. Indeed, single-cell transcriptome and multiplex immunofluorescence analyses demonstrate that STING expression is suppressed in neoplastic cells but not tumor-associated immune cells or stroma. Methylation analyses reveal a STING promoter region that is highly methylated in bulk tumor samples from glioma and other neuroectoderm-derived cancers, but not in most extracranial cancers. Methylation in this region strongly correlates inversely with STING RNA expression. STING epigenetic silencing is also present in normal fetal and adult brains. We demonstrate that STING expression in glioma cell lines may be rescued by decitabine, a DNA methyltransferase inhibitor (DNMTi) that is commonly used to treat hematologic malignancies. However, transduction of a STING-expressing vector into these glioma cell lines is insufficient to reconstitute STING signalling, suggesting that additional decitabine-stimulated mechanisms are necessary for STING pathway rescue. Collectively, our results suggest that epigenetic silencing of STING occurs early in brain development and may provide an immunosuppressive context for the genesis of brain tumors. Furthermore, our work raises the potential of epigenetic modulation to reconstitute STING signalling as a therapeutic strategy for glioblastoma and potentially other STING-silenced, immunologically-cold cancers.
BSCI-23 ANEUPLOIDY PROFILING IN GLIOBLASTOMA IDENTIFIES MECHANISMS OF DISEASE PROGRESSION AND TREATMENT VULNERABILITIES
Authors: Jermakowicz Anna , Stukenberg P Todd , Ayad Nagi
Published: August 2022

Glioblastoma (GBM) is the most common and malignant adult brain tumor. Despite years of research, few advancements have been made in its management. One challenging area of glioblastoma research is patient stratification in clinical trials based on genomic features. Although several regions of aneuploidy have been known to drive disease progression in GBM, the degree of aneuploidy across the genome varies widely and the significance of regions of aneuploidy has not been assessed. Using whole genome sequencing profiles for matched tumor and non-tumor samples, we were able to accurately determine the degree of aneuploidy and loss of heterozygosity for a set of primary GBM tumors. Next, using machine learning techniques, distinct patterns of aneuploidy and loss of heterozygosity emerged among a set of GBM tumors, allowing us to define distinct aneuploidy subgroups. Interestingly, these aneuploidy subgroups showed distinctly different rates of patient survival, suggesting that regions of aneuploidy may be driving disease progression. Differing rates of various GBM genomic subtypes including IDH mutation, EGFR mutation, MGMT methylation, and tumor subtypes was also seen among the aneuploidy subgroups. We were able to derive a gene expression signature for each of these aneuploidy subgroups and revealed distinct pathways that were driving tumor growth. Furthermore, using a perturbagen-response dataset we were able to predict compounds to distinctly target each subgroup. Collectively, this suggests that aneuploidy profiling provides important clues to varying mechanisms of disease progression and is a promising approach for targeted therapy in a patient-specific manner.
CLRM-02 SINGLE CENTER EXPERIENCE OF DOPAMINE ANTAGONIST ONC-201 FOR RECURRENT H3K27M-MUTANT GLIOBLASTOMA IN ADULTS
Authors: Ekhator Chukwuyem , Rak Ramin , Tadipatri Ramya , Fonkem Ekokobe , Grewal Jai
Published: August 2022

OBJECTIVE

To report the single center experience of three adult subjects receiving ONC-201 as part of the ONC018 expanded access clinical trial [NCT03134131].

BACKGROUND

ONC-201 is an oral investigational antagonist against the D2 dopamine receptor that has shown encouraging results for malignant gliomas harboring the H3K27M mutation in the H3 histone complex. Responses have been reported in pediatric subjects with such tumors. H3K27M tumors are generally located in the midline of the central nervous system which co-localize, for unknown reasons, with key dopaminergic pathways. An expanded access clinical trial (ONC018) was available to eligible patients allowing them access to this agent pending FDA review.

DESIGN/METHODS

Our site enrolled three subjects on the ONC018 trial. We present the demographic, clinical, and molecular characteristics for our enrolled subjects. We report the tolerability, adverse events, and outcome measures including survival, time-to-progression, response, Karnofsky Performance Status [KPS] and quality-of-life measured by the MD Anderson symptom inventory instrument [MDASI].

RESULTS

Three subjects were registered at our site onto ONC018 with age range 18-44yrs, 2/3 female, residing in Norway, India and United states. Tumor locations: brainstem, corpus callosum and thalamus. Pathology: glioblastoma(3/3), MGMT methylated (2/3), IDH1 mutant (0/3), EGFR amplification (0/3) and ATRX (3/3). Median change from baseline KPS: ≤20% decrease; MDASI:2/3 experienced decrease from baseline [median 6%],consistent with improved quality of life. No clinically significant laboratory abnormalities. No serious adverse events observed in any cases. All adverse events grade I-II.

CONCLUSIONS

In three subjects with H3K27M-mutant malignant glioma that received ONC201 as part of this expanded access clinical trial, we found that study drug was quite tolerable. No serious adverse events nor radiographic responses were seen. Analyses of larger study cohort and additional randomized controlled trials are necessary to provide insight into the safety and efficacy of this agent for this patient population.
CLRM-03 INCIDENCE OF INTRACRANIAL HEMORRHAGE IN GLIOMA PATIENTS WITH VENOUS THROMBOEMBOLISM CONVERTED FROM LMWH TO APIXABAN
Authors: Aboud Orwa , Ye Xiaobu , Grossman Stuart
Published: August 2022

Venous Thromboembolism (VTE) occurs in approximately 15-30% of patients with glioma 1,2 who are treated with therapeutic anticoagulants. Anticoagulation treatment increases the incidence of intracranial hemorrhage (ICH) with variable incidence between studies 1.9% to 20s% 3-6. The “common practice” treatment for VTE in glioma patients includes subcutaneous administration of low molecular weight heparin (LMWH, enoxaparin) injection, which requires daily self-injection. Switching glioma patients with VTE from LMWH to oral anticoagulants would limit the difficulty and the inconvenience of daily self-injecting in primary brain tumor patients and decrease the room for error in administering the dose along and the risk for heparin induced thrombocytopenia7. The goal of this project is to evaluate the incidence of intracranial hemorrhage in glioma patients with VTE converted from LMWH to Apixaban. We hypothesize that patients with brain tumors and Venous Thromboembolism can be converted safely from LMWH to Apixaban. To examine this hypothesis, we will enroll adult patients with pathologically confirmed supra-tentorial glioma and VTE, patient must have been treated with LMWH for ≥ 5 days. We will exclude patients with bleeding diathesis, severe hypersensitivity to Apixaban or pregnant or unable to provide informed consent. To assess the validity of our hypothesis: Primary Objective: To estimate the incidence of ICH in glioma patients with history of VTE after the conversion from LMWH to oral Apixaban. Secondary Objective: To estimate the incidence of recurrent VTE in glioma patients with history of VTE after the conversion from LMWH to oral Apixaban. To our knowledge, this is the first of its kind study to estimate the risk of ICH in glioma patients with VTE treated with oral anti-coagulation. Successful completion of our trial will provide answers to an important clinical question that could allow our patients using more convenient yet effective treatment by establishing and implementation of best practices.
CLRM-06 PROSPECTIVE CLINICAL STUDY OF CONVENTIONALLY FRACTIONATED CONCURRENT CHEMORADIOTHERAPY AND HYPOFRACTIONATED CONCURRENT CHEMORADIOTHERAPY AFTER THE SURGERY OF HIGH-GRADE GLIOMAS
Authors: Weiyan Shi
Published: August 2022

PURPOSE

To observe and evaluate the efficacy and safety of conventional fractionated concurrent chemoradiotherapy and hypofractionated concurrent chemoradiotherapy for adjuvant treatment of newly treated high-grade glioma.

METHOD

For newly treated patients with high-grade gliomas with WHO grade III-IV, all patients started concurrent chemoradiotherapy within 1 month after surgery, and received concurrent temozolomide 75 mg/m2 during radiotherapy until the end of radiotherapy. Sequential temozolomide chemotherapy at 200 mg/m2 for at least 6 cycles. All patients were randomly divided into groups, one group was given conventional fractional irradiation, 60Gy/30f in high-risk areas, 46Gy/23f in low-risk areas, and the other group was given low-fractionated irradiation, 53Gy/15f in high-risk areas, and 53Gy/15f in low-risk areas 43Gy/15f. The overall survival (OS), progression-free survival (PFS), radiation-induced cerebral edema and radiation-induced brain necrosis were evaluated.

RESULT

As of December 31, 2022, a total of 60 patients were enrolled, including 30 in the conventional fractionation treatment group and 30 in the hypofractionated treatment group. At present, 58 patients survived and 2 died, 2 in the conventional fractionation group, one due to tumor recurrence and one due to cardiac accident; 7 patients recurred, including 4 in the conventional fractionation group and 3 in the low fractionation group. Radiation cerebral edema occurred in 9 cases, 6 cases in the hypofractionated group and 3 cases in the conventional fractionation group, all of which were completely relieved after dehydration with mannitol, which did not affect the progress of radiotherapy. No radiation necrosis occurred during follow-up.

CONCLUSION

Compared with the standard stupp regimen, using 53Gy/15f in the high-risk area and 43Gy/15f in the low-risk area as an adjuvant therapy with concurrent temozolomide and sequential temozolomide, there was no increased risk of disease recurrence, no increased risk of death, and no increased risk of death.
CLRM-07 A MULTIVARIATE RETROSPECTIVE ANALYSIS OF 159 PATIENTS WITH HIGH-GRADE GLIOMAS: OVERALL SURVIVAL, PROGRESSION-FREE SURVIVAL, AND PROGNOSTIC FACTORS
Authors: Liu Shiyu , Jiang Xin , Dong Lihua
Published: August 2022

BACKGROUND AND PURPOSE

High-grade gliomas are highly malignant, aggressive, high incidence rate, and mortality. The purpose of this study was to analyze retrospectively and identify prognostic factors of patients with high-grade gliomas diagnosed by biopsy or postoperative pathological examination.

METHODS

In this retrospective study, we analyzed the patient’s demographic data, tumor characteristics, treatment approaches, immunocytochemistry results, the overall survival (OS) time, and the progression-free survival (PFS) time in a series of 159 histologically proven high-grade gliomas recruited from January 2011 to December 2019. OS time and PFS time were analyzed by Kaplan-Meier survival analysis with log-rank test and found the independent factors by using Cox regression analysis.

RESULTS

Survival analysis showed that an OS of 84.90%, 55.35% and 13.20% was observed at 1, 2 and 5 years, respectively. And a PFS of 56.6%, 25.26% and 3.14% was observed at 1, 2 and 5 years, respectively. The mean OS was 52.73 months and mOS was 35 months. Univariate analysis showed that postoperative pathological classification and grade and age were statistically significant for patient outcome (P < 0.01). 147 patients underwent concurrent chemoradiotherapy and 80 of them died; 12 patients did not undergo concurrent chemoradiotherapy and 10 died (P = 0.03); There were statistically significant differences in the prognostic impact of Ki-67 expression, MGMT, IDH1R132H and p53 mutations by immunohistochemistry (P = 0.001; P = 0.016; P = 0.003; and P = 0.021, respectively). Similarly, we concluded that different grades, age, pathological classification, Ki-67 and IDH1R132H expression by immunohistochemistry were statistically significantly associated with PFS (P < 0.01; P = 0.004; P = 0.003; P = 0.001; P = 0.028).

CONCLUSIONS

Tumor grade and concurrent chemoradiotherapy after surgery were independent prognostic factors affecting patients’ survival, and grade was also an independent factor affecting PFS.
CLRM-10 METIS (EF-25): A PIVOTAL, RANDOMIZED CONTROLLED STUDY OF TUMOR TREATING FIELDS IN PATIENTS WITH 1–10 BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER
Authors: Mehta Minesh , Brown Paul , Gondi Vinai , Ahluwalia Manmeet
Published: August 2022

BACKGROUND

Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell division. TTFields treatment showed efficacy in preclinical non-small cell lung cancer (NSCLC) models. Furthermore, TTFields therapy improved survival with a tolerable safety profile in patients with glioblastoma. The objective of the pivotal METIS trial [NCT02831959] is to evaluate the efficacy and safety of TTFields therapy in NSCLC patients with brain metastases.

METHODS

NSCLC patients (N=270) with 1–10 brain metastases will be randomized 1:1 to stereotactic radiosurgery (SRS) followed by continuous TTFields therapy using NovoTTF-200M (150 kHz, recommended >18 h/day) with best standard of care (BSC) or SRS followed by BSC alone. Follow-ups will be conducted every 2 months until second intracranial progression. Key inclusion criteria are: Karnofsky Performance Status ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS, and optimal therapy for extracranial disease. Key exclusion criteria are: prior whole brain radiotherapy, single operable, or recurrent brain metastases. Primary endpoint is time to first intracranial progression. Secondary endpoints include time to neurocognitive failure, overall survival, radiological response rate (RANO-BM and RECIST V1.1), quality of life, adverse events, time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases, bi-monthly intracranial progression rate from 2–12 months, and time to second intracranial and distant progression. The study is powered at 80% (2-sided alpha of 0.05) to detect a hazard ratio of 0.57. In July 2021, an independent Data Monitoring Committee (DMC) reviewed the study data and recommended continuation as planned. The trial is currently recruiting at 92 sites in North America, Europe, Israel, mainland China and Hong Kong.
CLRM-11 CURRENT STATE OF CLINICAL TRIALS FOR PATIENTS WITH MELANOMA BRAIN METASTASES
Authors: Elghawy Omar , Banfield Walter , Horton Bethany , Kaur Varinder
Published: August 2022

INTRODUCTION

Clinical trials have traditionally excluded patients with melanoma brain metastasis (MBM), despite evidence of CNS activity of systemic therapy. The true extent of variation in MBM-related enrollment criteria in ongoing melanoma clinical trials has not been evaluated.

METHODS

A systematic search of clinicaltrials.gov website was performed to characterize trends in clinical trial enrollment of MBM patients in interventional drug trials. Trial data search was limited to “open”, “interventional studies” and advanced stage melanoma in adult patients. Logistic regression was used to model inclusion of active MBMs. Covariates considered were phase of study, location, therapy type, melanoma specific, and sponsor category

RESULTS

Of a total of 475 trials identified, 365 met inclusion criteria. 230 (63.0%) were phase I, 119 (32.6%) were phase II, 14 (3.8%) were phase III and 2 (0.5%) were phase IV trials. 184 (50.4%) were pharmaceutical industry sponsored, 183 (50.1%) were specific for melanoma. Forty-seven (12.8%) trials strictly excluded brain metastasis and 173 (47.3%) strictly excluded leptomeningeal disease (LMD). 261 (71.5%) trials allowed patients with previously treated MBM, and 73 (20.0%) allowed patients with active MBMs. No explicit mention of CNS metastasis was made in 13.6% of trials and no mention of LMD was made in 43.8% trials. In univariate models, trials not employing immunotherapy (odds ratio 2.23; 95% CI: 1.2, 4.3; p = 0.0174) and non-pharma trials (odds ratio 1.98; 95% CI 1.0, 3.9; p= 0.0461) were twice as likely to include MBM patients. In a combined model, only therapy type remained significant at the α=0.05 level.

CONCLUSION

Despite the evidence of CNS activity of immunotherapy in randomized trials, only 20% ongoing trials are enrolling patients with active MBMs. Efforts should be made to tailor future clinical trial designs to include MBM patients to assess CNS activity of systemic therapeutics early on in drug development.
CLRM-13 RELEVANCE OF RECURSIVE PARTITIONING ANALYSIS (RPA) CLASSIFICATION IN THE CURRENT CARE OF PATIENTS WITH BRAIN METASTASES (BMETS)
Authors: Sarai Guneet , Amidon Ryan F , Bovi Joesph A , Thomas Alissa A , Novicoff Wendy , Schuetz Samantha , Singh Rohit , Chang Amy , Sheehan Jason P , Fadul Camilo E
Published: August 2022

BACKGROUND

Patients diagnosed with BMETS want to know their prognosis and the benefit of treatment to make informed decisions. Clinician and patient biases frequently provide survival estimates that are too optimistic or pessimistic. We postulated that that RPA remains a useful tool to communicate prognosis and potential benefit from brain-directed treatment (BDT). We evaluated real-world data on RPA class and survival of patients with newly diagnosed BMETS from three academic institutions.

METHODS

We retrospectively reviewed the records of patients with BMETS between 2017 and 2019 who had at least 6 months of follow up. Excluded were patients with leptomeningeal or only dural/calvarial metastases. We calculated the RPA and according to class compared Kaplan-Meier survival curves.

RESULTS

We have data on 642 cases with median age of 65 years; 80% had lung, breast, melanoma, and renal as the primary cancer. Sixty (9.3%) patients received palliative care only, while 582 (90.7%) had BDT. The median survival of all patients according to RPA in months was 18.0 (I), 9.4 (II), and 2.4 (III) and for those receiving BDT (n=582), it was 19.2 (I), 11.2 (II), and 2.9 (III). There were statistically significant differences for BDT survival curves adjusted for multiple comparisons (I-II p=0.0124; II-III p<0.0001; I-III p<0.0001). For patients in RPA class III who received WBRT (n=62), the median survival was 2.9 months, and, for SRS (n=37), it was 3.5 months. We will present updated data including additional 238 cases and propose predictive/prognostic models based on our cohort that optimizes the RPA application in clinical practice.

CONCLUSION

In contemporary practice, the RPA classification remains significantly relevant in making care decisions for patients diagnosed with BMETS. Treatment recommendations for patients in RPA class III should be the result of multidisciplinary discussions with consideration for early palliative care involvement to de-escalate and avoid inefficacious BDT.
LOCL-06 SUPERVISED MACHINE LEARNING IDENTIFIES RISK FACTORS ASSOCIATED WITH LEPTOMENINGEAL DISEASE AFTER SURGICAL RESECTION OF BRAIN METASTASES
Authors: Morshed Ramin , Saggi Satvir , Cummins Daniel , Young Jacob , Viner Jennifer , Villanueva-Meyer Javier , Boreta Lauren , Braunstein Steve , McDermott Michael , Theodosopoulos Philip , Berger Mitchel , Hervey-Jumper Shawn , Aghi Manish , Daras Mariza
Published: August 2022

BACKGROUND

Resection of brain metastases (BMs) can help with local disease control, yet predictors of leptomeningeal disease (LMD) after surgery are not well defined. This study examined rates and predictors of LMD in patients who underwent resection of a BM.

METHODS

A retrospective, single-center study was conducted examining LMD risk for adult patients with a BM that underwent resection with postoperative adjuvant radiation. Logistic regression analyses and a supervised machine learning algorithm (Random forest) were implemented to identify factors within the cohort that were associated with LMD.

RESULTS

Of the 182 patients in the cohort, 43 patients (23.6%) developed LMD in the postoperative setting with 18 cases of classical LMD (9.9%) and 25 cases of nodular LMD (13.7%). Median censored time to LMD was not reached, and 6-, 12-, and 24-month LMD-free rates from surgery were 93%, 86.3%, and 71.8%, respectively. Median time from surgery to classical and nodular LMD were 13.1 and 9.5 months, respectively (Log-rank p=0.71). Patients diagnosed with classical LMD had worse survival outcomes from LMD diagnosis compared to nodular LMD (2.6 vs 9.7 mo, Log-rank p=0.02), and LMD-subtype was significantly associated with overall survival from the date of surgery (classical vs nodular vs none: 16.1 vs 20 vs 36.7 mo, p <.0001). Random forest analysis identified primary cancer type, absence of extracranial disease, and tumor volume as the top 3 factors associated with LMD. On multivariate regression analysis, absence of extracranial disease at index surgery was associated with any LMD (OR 2.65, 95% CI 1.15-6.10, p=0.02). Treatment with postoperative checkpoint inhibitors, type of radiation, and performing additional craniotomies were not associated with risk of LMD.

CONCLUSIONS

Classical-type LMD is associated with worse prognosis compared to nodular-type LMD. Absence of extracranial disease at the time of surgery was the most consistent factor associated with LMD on follow-up.
LOCL-08 SAFETY AND FEASIBILITY OF RHENIUM-186 NANOLIPOSOME (186RNL) IN RECURRENT GLIOMA: THE RESPECT™ PHASE 1 TRIAL
Authors: Brenner Andrew , Hedrick Marc , LaFrance Norman , Bao Ande , Ohillips William , Patel Torel , Weinberg Jeffrey , Floyd John
Published: August 2022

BACKGROUND

Liposomal rhenium-186 (186RNL) is a potent source of electrons with short path length, low dose rate, high radiation density and gamma emission. Preclinically, 186RNL via convection enhanced delivery (CED) achieves very high doses of targeted radiation and a wide therapeutic index. We report the updated results of ReSPECT, the first in man, dose escalation phase 1 trial of 186RNL in recurrent glioma.

METHODS

Following computer assisted treatment planning and placement of intracranial catheter(s), we performed a single administration of 186RNL by CED. Whole body planar and SPECT/CT imaging was obtained on days 1-8 following treatment for dosimetry and distribution. Patients were followed for safety, progression and survival.

RESULTS

Twenty-one patients across 7 cohorts received 1.0-22.3mCi in a tumor volume of 0.6-8.80mL. Mean tumor volume was 8.3mL (0.9-22.8mL). Patients had a mean of 1.7 recurrences, 5 with prior bevacizumab. 19 (91%) were grade 4 gliomas, and 100% were after cohort 4. We used a CED rate of 5-20µl/min per catheter, with 1-4 catheters per patient. Tumor mean absorbed radiation dose was 255Gy (8.9-740Gy) while exposure outside the brain was negligible. The mean percentage tumor in the treated volume (Tu/Tv) was 60.3% (19.8%-100%). Thus far, we have observed no dose limiting toxicities, one grade 3 treatment related adverse event (AEs), and the majority of AEs were mild in intensity. The incidence and severity of AEs did not correlate with increasing dose. Mean Tu/Tv in patients not receiving prior bevacizumab was 75% vs. 48% in those that had. Thus far, overall survival (OS) in 16 bevacizumab naïve patient is 49 weeks with 7 patients still alive and a positive correlation of OS to Tu/Tv.

CONCLUSIONS

186RNL achieves high absorbed doses without significant toxicity with favorable overall survival. Updated delivery feasibility, safety and overall survival will be presented.
LOCL-13 SURGICAL RESECTION PLUS STEREOTACTIC RADIOSURGERY (SRS) VERSUS SRS ALONE FOR LARGE POSTERIOR FOSSA BRAIN METASTASES: OUTCOMES AND FACTORS GUIDING THE DECISION OF TREATMENT MODALITY
Authors: Lau-Rodriguez Ruth , Kalyvas Aristotelis , Gutierrez-Valencia Enrique , Weiss Jessica , Conrad Tatiana , Millar Barbara-Ann , Laperriere Normand , Berlin Alejandro , Bernstein Mark , Zadeh Gelareh , Schultz David , Kongkham Paul
Published: August 2022

INTRODUCTION

Approximately 20% of brain metastases (BM) occur in the posterior fossa (PF). However, the criteria to treat large PF BM with surgery (S) followed by stereotactic radiosurgery (SRS) or SRS alone are still unclear. We aim to identify parameters that can help in the decision of treating PF BM with S+SRS or SRS and to compare outcomes between the two groups.

METHODOLOGY

We reviewed a prospective registry database (2009 to 2020) and identified all patients with PF BM (≥4cc in volume) treated with SRS or S+SRS. Clinical and radiological, parameters were analyzed. We examined two endpoints: Overall Survival (OS) and Local Failure (LF).

RESULTS

64 patients were identified; 30 were treated with S+ SRS and 34 with SRS. Gait imbalance and Intracranial pressure symptoms were significantly different between the groups; 97% and 80% for S+SRS vs 47% and 35% for SRS, respectively. Radiologically, there were significant differences in the mean volume of the lesions [6.7 cm3 in SRS vs 29.8cm3 in S+SRS cohort] (p<0.001), compression of the IV ventricle (47% in SRS vs 96% in S+SRS cohort, (p<0.001)) and hydrocephalus (0% in SRS vs 29% in S+SRS cohort, (p<0.001)). One surgical patient required salvage SRS and two SRS patients required salvage S. Patients with S+SRS (HR 0.35, p<0.001) and higher GPA scores (HR 0.62, p=0.007) correlated with better OS. There was no significant difference in rates of LF between the 2 groups.

CONCLUSIONS

Patients treated with S+SRS were more likely to be symptomatic, have larger tumors, and have compression of the IV ventricle with hydrocephalus. Non-symptomatic patients with moderately sized lesions were safely managed with SRS. S+SRS treatment and higher GPA were associated with improved OS.
MMAP-06 INTEGRATED TEAM-BASED BRAIN METASTASIS CARE REDUCES PATIENT VISITS AND SHORTENS TIME TO ADJUVANT IRRADIATION
Authors: Moss Nelson S , El Ahmadieh Tarek Y , Brown Samantha , Chen Justin , Imber Brandon S , Pike Luke , Reiner Anne S , Panageas Katherine S , Brennan Cameron , Tabar Viviane , Beal Kathryn
Published: August 2022

PURPOSE

Timely surgical cavity stereotactic radiosurgery (SRS) is an important adjuvant to brain metastasis resection, with earlier treatment associated with less frequent recurrence. The logistical complexity of treatment organization, however, has resulted in suboptimal start times post-surgically. We implemented a team-based process improvement approach to reduce the time from surgery to adjuvant irradiation of resected brain metastases.

METHODS

A multidisciplinary working group used process-mapping to identify opportunities to reduce visits and shorten treatment times. The care delivery process was modified to streamline perioperative SRS preparation with (1) early patient identification, (2) preoperative intra-team communication, and (3) consolidation of required steps. Plan-Do-Study-Act cycles were used for process improvement. The surgery-to-SRS initiation time interval was the primary outcome. Secondary outcomes included the number of associated patient encounters.

RESULTS

Following implementation, the median (IQR) interval from surgery to SRS was reduced 48% from 27 (21,34) to 14 (13,17) days (p<0.001). The rate of surgical-cavity SRS within 30 days increased from 64% (n=63/98) to 97% (n=60/62; p<0.001). The median (IQR) number of CNS-associated encounters between resection and SRS decreased from 5 (4,6) to 4 (3,5; p<0.001). The proportion of patients who had >1 MRI/CT between surgery and SRS decreased from 45% (44/98) to 13% (8/62; p<0.001). The time from surgery to systemic therapy resumption/initiation among patients treated within 90 days post-operatively decreased from 35 (24,48) to 32 days (23,40; p=0.074). There were no wound complications in either group.

CONCLUSION

Adjuvant SRS latency and treatment-associated encounters were significantly reduced after care-coordination implementation. This approach reduces patient and healthcare system burden and can be applied to other scenarios where early post-operative SRS administration is critical.
MMAP-07 IMPACT OF SINGLE AND DUAL IMMUNE CHECKPOINT BLOCKADE ON RISK OF RADIATION NECROSIS AMONG PATIENTS WITH BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY
Authors: Vaios Eugene , Shenker Rachel , Hendrickson Peter , D’Anna Rachel , Niedzwiecki Donna , Carpenter David , Floyd Warren , Winter Sebastian , Dietrich Jorg , Floyd Scott , Kirkpatrick John , Mullikin Trey , Allen Karen , Salama April , Clarke Jeffrey , Reitman Zachary
Published: August 2022

PURPOSE

While stereotactic radiosurgery (SRS) is often an efficacious treatment for brain metastases, it carries a significant risk of radionecrosis (RN). Single and dual immune checkpoint inhibition (ICPI) have emerged as common treatment options for many patients, particularly those with melanoma and non-small cell lung cancer (NSCLC). While data suggest a cancer control benefit of combining SRS and ICPI, we hypothesized that concurrent receipt of dual ICPI with SRS increases the risk for RN.

METHODS

We performed a retrospective review of serial patients with metastatic melanoma or NSCLC treated with SRS for intact brain metastases from 2014-2020 at our single institution. Patients were stratified by receipt of dual vs. single ICPI vs. SRS alone. RN was biopsy confirmed or determined radiographically, in combination with clinical assessment and steroid use. Kaplan-Meier estimates were used to compare rates of RN between cohorts.

RESULTS

673 brain lesions from 93 patients met inclusion criteria [median (Q1, Q3): 5.0 (2.0-10.0) lesions per patient]. Median follow-up of lesions was 8.1 months (95% CI: 7.3, 8.7). Most (82.8%) lesions were supratentorial and histologies included melanoma (53.5%), adenocarcinoma NSCLC (27.3%), squamous cell NSCLC (6.1%), and NSCLC NOS (6.1%). In the entire cohort, 88 lesions from 25 patients (27%) developed RN. 77 (87%) lesions were diagnosed clinico-radiographically and 11 (13%) were biopsy-proven. ICPI use was highly enriched among lesions that developed RN (85.2%) versus those that did not (19.8%). Freedom from RN at 6 months was 80% for dual ICPI, 82% for single ICPI, and 97% for SRS alone; 12 month rates were 78% in each of the ICPI cohorts and 95% with SRS alone (P=0.0002).

CONCLUSIONS

In a large cohort of SRS-treated brain metastases, we observed an increased risk of RN among patients who received either dual or single ICPI concurrently with SRS.
MMAP-09 CHARACTERISTICS CORRELATING WITH SURVIVAL IN PATIENTS TREATED FOR LARGE BRAIN METASTASES
Authors: Gutierrez-Valencia Enrique , Kalyvas Aristotelis , Millar Barbara-Ann , Laperriere Normand , Conrad Tatiana , Berlin Alejandro , Weiss Jessica , Zadeh Gelareh , Bernstein Mark , Kongkham Paul , Shultz David B
Published: August 2022

BACKGROUND

We aimed to identify factors predicting survival following treatment to large (>4cc) BrM.

METHODS

From a prospective registry database, we identified 364 adult patients treated for brain metastases (BrM) or surgical cavities larger than >4 cc: 127 and 237 treated with surgery plus stereotactic radiosurgery (S+SRS) and SRS alone, respectively. We compared the 2 treatment arms using propensity score-matched (PSMA) and multivariate analyses (MVA). P values <0.05 were considered statistically significant.

RESULTS

Median target volume was 6.6cc (4-36.9cc) for intact BrM and 15cc (4-54) for cavities. Median OS was 19 and 12 months for the S+SRS and SRS groups, respectively [HR 1.73 (1.35-2.22) (P<0.001)]. On UVA, number of BrM [HR 1.13 (1.06-1.22) (P<0.001)], ECOG 3-4 [HR 2.78 (1.73-4.46) (P<0.001)], and extracranial disease (ECD) at BrM treatment [HR 1.82 (1.37,2.40) (P<0.001)], correlated inversely with OS. GPA [HR 0.61 (0.52,0.70) (P<0.001)] and receipt of systemic therapy after BrM treatment[HR 0.58 (0.45-0.75) (P<0.001)] correlated to improved OS. On MVA, S+SRS [HR 1.81 (1.19,2.74) (P<0.0054)], reduced target volume [HR 1.03 (1.01,1.06) (P<0.0042)], and receipt of immune/targeted therapy [HR 0.68 (0.50,0.93) (P<0.015)] correlated with OS. PSMA comparing the treatment arms matched by ECD, number of BrM, ECOG, and SRS target volume, demonstrated that treatment arm remained correlated to OS [HR 1.62 (1.20-2.19) (P=0.0015)]. The cumulative incidence (CI) of LF requiring surgical resection at 12 months was 3% versus 7% for S+SRS and SRS groups, respectively [(HR 2.04 (0.89-4.69) (P =0.091)]. CI of PMD at 12 months was 16% versus 0% for S+SRS and SRS groups, respectively.

CONCLUSION

Reduced SRS target volume, treatment with systemic therapy following BrM treatment, and surgical resection prior to SRS correlate with survival in patients with large BrM. PMSA supports the hypothesis that surgery prior to SRS improves survival in patients with large BrM.
MMAP-11 VOLUMETRIC STUDY OF BRAIN METASTASES IN EGFR-POSITIVE NSCLC TREATED WITH OSIMERTINIB WITH OR WITHOUT CNS-DIRECTED RADIATION THERAPY
Authors: Ni Lisa , Phuong Christina , Chen Jie Jane , Chen William , Daras Mariza , Raleigh David , Nakamura Jean , Boreta Lauren , Sneed Penny , Braunstein Steve
Published: August 2022

BACKGROUND

In patients with brain metastases (BM) from EGFR-positive non-small cell lung cancer (NSCLC), recent data indicated that treating with CNS-penetrant tyrosine kinase inhibitors such as osimertinib may enable deferring radiotherapy (RT) in select patients. The purpose of this study was to describe the radiographic response of newly diagnosed BM to osimertinib with or without stereotactic radiosurgery or whole brain radiotherapy, to identify parameters that may guide early versus delayed salvage RT.

METHODS

In this single-institution retrospective study, 35 patients with 186 newly diagnosed BM started on osimertinib between 2014 and 2020 were reviewed. BM with tumor volume ≥ 0.1 cm3 were included in the volumetric analyses (N=106 BM). Survival was estimated with the Kaplan-Meier method, and univariable analysis was performed using log-rank tests. Cox proportional hazards was used for multivariable analyses for local control (LC), distant brain failure (DBF), and overall survival (OS).

RESULTS

Of the 35 patients, 8 (23%) received osimertinib alone. Median follow-up was 29 months. The 1- and 2-year LC rates were 94% and 86%. The 1- and 2-year OS rates were 89% and 66%. Median time to DBF was 24 months. Patients treated with osimertinib and RT were more likely to have a significant radiographic volumetric response at early follow-up (4-12 weeks after treatment initiation) compared to osimertinib alone (median volumetric response of –80% vs. –41%, p=0.05). On per lesion analysis, early volumetric response of ≥ 80% was associated with improved LC (3-year LC 98% vs 72%, p=0.04).

CONCLUSIONS

The combination of osimertinib and CNS RT is associated with greater early volumetric response in patients with BM from EGFR-positive NSCLC compared to osimertinib alone. BM with significant initial radiographic response remain well-controlled in the long term. Patients whose BM demonstrate limited initial volumetric response may benefit from targeted RT to provide long term control.
SPCR-02 NEUROCOGNITIVE FUNCTION IN PATIENTS WITH LEPTOMENINGEAL METASTASIS TREATED WITH PROTON CRANIOSPINAL IRRADIATION
Authors: Correa Denise , Koch Adrian , Baser Raymond , Pentsova Elena , Wolden Suzanne , Imber Brandon , Boire Adrienne , Yang Jonathan
Published: August 2022

BACKGROUND

Proton craniospinal irradiation (pCSI) as a potential treatment for patients with solid tumor leptomeningeal metastasis (LM) is being assessed in a phase II randomized study comparing it with photon involved-field radiotherapy (RT). We report the preliminary results of prospective neurocognitive function in a subset of patients treated with pCSI.

METHODS

Patients with LM and without evidence of CNS disease progression completed standardized neurocognitive tests of attention and working memory, executive function, and verbal memory at baseline (pre-pCSI), and 3 and 6 months post-pCSI. All patients received chemotherapy (baseline and follow up) and memantine (follow up). Means across the three timepoints were estimated for each neurocognitive test score using a linear mixed model (LMM) predicting the score by timepoint. Mean changes between pairs of timepoints were similarly estimated from the LMMs and tested for statistical significance using model-based contrasts.

RESULTS

Baseline, 3-month and 6-month neurocognitive data were available for 12, 11, and 8 patients, respectively. Linear mixed model analyses showed a significant decline in graphomotor speed (Trails A, p=0.03), verbal learning (HVLT-R Total Learning, p<0.001), and verbal recognition memory (HVLT-R Discrimination, p=0.03) from baseline to 3 months post-pCSI, with scores remaining stable at 6 months post-pCSI. There was a significant decline in timed set-shifting (Trails B, p=0.04) from baseline to 6 months post-pCSI. There were no significant changes in attention and working memory over the follow-up period.

CONCLUSION

Preliminary results in a subset of patients showed a decline in graphomotor speed and verbal memory at 3 months and executive function at 6 months post-pCSI, possibly related to the early adverse effects of RT. These results are overall consistent with findings in other populations treated with whole-brain RT. However, there was no change in attention and working memory and most cognitive domains remained stable at six months with pCSI.
SPCR-03 NEUROCOGNITIVE OUTCOMES FROM PHASE 1 TRIAL OF BMX-001 IN COMBINATION WITH CONCURRENT RADIATION THERAPY AND TEMOZOLOMIDE IN NEWLY DIAGNOSED HIGH-GRADE GLIOMA PATIENTS
Authors: Peters Katherine , Kirkpatrick John , Batinic-Haberle Ines , Affronti Mary Lou , Woodring Sarah , Lipp Eric , Herndon James , Boyd Kendra , Spasojevic Ivan , Penchev Sara , Gad Shayne , Silberstein David , Johnson Margaret , Desjardins Annick , Friedman Henry , Ashley David , Crapo James
Published: August 2022

INTRODUCTION

Neurocognitive dysfunction can result from radiation therapy which is the mainstay of treatment for high-grade glioma, particularly glioblastoma. Preclinical observations found that BMX-001, a novel metalloporphyrin, acts as a radioprotectant for normal CNS cells yet as a radiosensitizer to cancer cells in human GBM xenograft experiments. In a phase 1 study evaluating the safety of BMX-001 in combination with concurrent radiation therapy and temozolomide, we further studied neurocognitive function before and after concurrent radiation therapy and temozolomide in newly diagnosed high-grade glioma patients.

METHODS

We performed a phase 1 study of BMX-001 combined with radiation therapy (6-week total of 59.4-60 Gy) and temozolomide (75 mg/m2/day for 42 days). We administered BMX-001 as a subcutaneous injection at a loading dose before radiation therapy and temozolomide and then subsequent doses twice weekly for eight weeks. A key secondary endpoint was the evaluation of neurocognition. We performed neurocognitive testing with the computerized program CNS Vital Signsâ. This battery consists of seven tests: verbal memory, visual memory, finger tapping, symbol digit coding, the Stroop Test, a test of shifting attention, and a continuous performance test. We defined neurocognitive impairment at baseline as a z-score ≥ 1.5 SDs below the normative mean. We described improvements or declines in neurocognition at 2 and 6 months from baseline.

RESULTS

Fifteen patients (age 19-80 years) enrolled and underwent neurocognitive testing before and after RT. All patients had WHO grade 4 glioblastoma. Most subjects had neurocognitive impairment ranging from 46.7-to 80% on specific neurocognitive tests. At two months (N=15) and six months (N=9), most testing demonstrated improved neurocognitive performance.

CONCLUSIONS

Neurocognitive function is maintained and can improve after concurrent radiation therapy and temozolomide in this high-grade glioma cohort treated with BMX-001 during concurrent radiation therapy and temozolomide.
SYST-02 PHASE ⅡB CLINICAL TRIAL OF NEOADJUVANT CHEMOTHERAPY REVERSING GLIOMA STEM CELLS CHEMORESISTANCE IN NEWLY DIAGNOSED GBM WITH MGMT PROMOTER UNMETHYLATION
Authors: Dong Jun , Wang Liping , Chen Yanming
Published: August 2022

PURPOSE

To evaluate clinical efficacy and safety of combination of nicardipine and valproic acid on temozolomide (TMZ) neoadjuvant chemotherapy targeting on glioma stem cells (GSCs) in newly diagnosed glioblastoma multiforme (GBM) patients with O6-methylguanine-DNA-methyltransferase (MGMT) promoter unmethylation.

METHODS

From June 2018 to April 2021, newly diagnosed GBM patients after tumor surgical removal and concurrent radio-chemotherapy with TMZ, with MGMT promoter unmethylation were randomly assigned to two groups. The control group was applied standard TMZ regimen. The trial group was administered standard TMZ regimen, plus nicardipine(20mg/d) and valproic acid (1.2g/d) as neoadjuvant treatment against GSCs chemoresistance. The relevant treatment data and adverse reactions of the patients were collected, Karnofsky performance status (KPS) score, progression-free survival (PFS) and overall survival (OS) were evaluated during patient follow-up.

RESULTS

33 patients were enrolled in this study, eighteen patients were randomly assigned in the trial group and 15 patients were in the control group. There was no statistical difference in gender composition, age, degree of surgical resection, or KPS score before treatment between the two groups. The median progression-free survival (mPFS) in the trial group was 10.8 months (95%CI 5.81-15.79 month), and the mPFS in the control group was 7.1 months (95%CI 5.12-9.08 month), which was a statistically difference (Log-Rank test P=0.033). The median overall survival (mOS) increased from 12.1 months (95%CI 9.18-15.00 month) in the control group to 15.7 months (95%CI 7.67-23.73 month) in the trial group (Log-Rank test P=0.015). There was no statistically significant difference in the incidence of adverse reactions between the two groups, and there were no treatment regimen related deaths.

CONCLUSIONS

TMZ combined with neoadjuvant of nicardipine and valproic acid against GSCs chemoresistance can prolong the survival time of patients who was newly diagnosed glioblastoma with MGMT promoter unmethylation. The preferred regimen can be applied safely without serious adverse events, which deserved further multi-center clinical investigations.
Multiscale dynamical cross-talk in zeolite-catalyzed methanol and dimethyl ether conversions
Authors: Lin Shanfan , Zhi Yuchun , Liu Zhiqiang , Yuan Jiamin , Liu Wenjuan , Zhang Wenna , Xu Zhaochao , Zheng Anmin , Wei Yingxu , Liu Zhongmin
Published: August 2022

Establishing a comprehensive understanding of the dynamical multiscale diffusion and reaction process is crucial for zeolite shape-selective catalysis and is urgently demanded in academia and industry. So far, diffusion and reaction for methanol and dimethyl ether (DME) conversions have usually been studied separately and focused on a single scale. Herein, we decipher the dynamical molecular diffusion and reaction process for methanol and DME conversions within the zeolite material evolving with time, at multiple scales, from the scale of molecules to single catalyst crystal and catalyst ensemble. Microscopic intracrystalline diffusivity is successfully decoupled from the macroscopic experiments and verified by molecular dynamics simulation. Spatiotemporal analyses of the confined carbonaceous species allow us to track the migratory reaction fronts in a single catalyst crystal and the catalyst ensemble. The constrained diffusion of DME relative to methanol alleviates the high local chemical potential of the reactant by attenuating its local enrichment, enhancing the utilization efficiency of the inner active sites of the catalyst crystal. In this context, the dynamical cross-talk behaviors of material, diffusion and reaction occurring at multiple scales is uncovered. Zeolite catalysis not only reflects the reaction characteristics of heterogeneous catalysis, but also provides enhanced, moderate or suppressed local reaction kinetics through the special catalytic micro-environment, which leads to the heterogeneity of diffusion and reaction at multiple scales, thereby realizing efficient and shape-selective catalysis.