bluuebunny/crossref_metadata_2025 huggingface dataset:
CTNI-63. A STUDY OF NIRAPARIB COMBINED WITH RADIOTHERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Jiang Wei , Wang Zheng
Published: November 2022

BACKGROUND

There is no standard therapy for recurrent glioblastoma (rGBM), which has a poor survival, from 3 to 10 months. Radiotherapy is an available option for patients with rGBM, and it could invoke DNA damage, thus leading to tumor cell death. Niraparib is a poly(ADP-ribose) polymerase inhibitor. Preclinical data showed that Niraparib enhances the radiosensitivity of glioblastoma cells. Thus we hypothesize that radiotherapy synergizes with Niraparib to improve the clinical efficacy of anti-tumor.Method:We conducted a phase 2 study combining Niraparib, radiotherapy, and maintenance Niraparib in 30 patients with rGBM. Niraparib(300mg QD) was started at cycle 1 of radiotherapy (55Gy total) and continued until progression or unacceptable toxicity The primary endpoint was 6 month PFS. Secondary endpoints included toxicity, QoL, and OS Result：As of 4/31/2022, 14 patients with a median age of 47 years old (range 26-69) were enrolled. 64.29% were female. Eight patients（57.1%）had experienced ≥ 2 previous therapy（range 1-4）. The MGMT methylation status was available for 12 patients, and 9（64.3%）had unmethylated MGMT. The median follow-up was 167 days (95%CI 124-263). PFS 6 was 36% (95%CI 12.17%-60.92%), OS 6 was 82.61%(95%CI 46.51%-95.34%). The mPFS was 157 days (95%CI 93-188), the mOS was not reached (95%CI 188-NA), three patients had an OS of more than 10 months by the data submitted. The ORR was 35.7%, one patient achieved CR,four achieved PR. Niraparib combined radiotherapy showed efficacy in controlling local lesions. At 1 and 3 months, local control rate was 85.7% and 64.3% ,respectively. The most common serious adverse event was thrombocytopenia（28.57%）which could be controlled by adjusting the dosage of Niraparib.

CONCLUSION

Niraparib combined radiotherapy is well tolerated and shows efficacy in rGBM patients. Survival data will be updated.Clinical registration number: NCT04715620
DNAR-05. A ROLE FOR TAZ/YAP IN DNA DAMAGE REPAIR IN GLIOBLASTOMA
Authors: Bhat Krishna , Bhat Krishna , Tang Tiffany
Published: November 2022

Previous studies have shown that glioma stem-like cells (GSCs) evade conventional cytotoxic therapies and repopulate as recurrent tumors. A fuller understanding of the molecular mechanisms underlying the biology and therapy resistance of GSCs is required. Our group has shown that TAZ, a transcriptional co-factor is highly expressed in about 70% of glioblastomas (GBMs). TAZ and its paralog YAP are oncogenic drivers of brain tumor progression. GSCs overexpressing TAZ undergo a proneural (PN) to mesenchymal (MS) subtype transition, which is accompanied by aggressive phenotypes such as increased grade and treatment resistance in GSC xenografts. Although the oncogenic functions of TAZ/YAP are well established, the exact molecular mechanisms underlying TAZ/YAP mediated cell fate transition and therapy resistance in GBM are not fully understood. Here, we present novel functional interaction between TAZ/YAP and DNA-dependent protein kinase (DNA-PK) in response to exposure to ionizing radiation in GSCs. Mass-spectrometric analyses of TAZ-binding proteins showed that DNA-PK complex composed of the catalytic subunit (DNA-PKcs) and a Ku heterodimer of Ku70 and K80 interacted with TAZ. Immunoprecipitation of DNA-PK showed interaction of both YAP as well. Interaction of YAP/TAZ with DNA-PK complex and TEAD was enhanced by ionizing radiation. DNA-PKcs phosphorylated both YAP and TAZ, and phosphorylation level of these proteins were increased after irradiation, consistent with an increased interaction of these proteins. Intriguingly, siRNA knockdown of YAP and TAZ resulted in inactivation of DNA-PKcs, although protein stability of DNA-PKcs was not affected. Pharmacological inhibition of TAZ/YAPTEAD resulted in increased DNA damage and suppressed cell proliferation, and this effect was synergized by irradiation. We conclude that TAZ and YAP are integral components of DNA damage response and that pharmacological targeting of TAZ/YAP/TEAD pathway can overcome radiation resistance in GSCs.
DNAR-10. THE EFFICACY OF TEMOZOLOMIDE AND LOMUSTINE IN GLIOBLASTOMA CELL LINES MAY BE ENHANCED BY CONCOMITANT TREATMENT WITH TUMOR TREATING FIELDS (TTFIELDS)
Authors: Fishman Hila , Monin Roni , Dor-On Eyal , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram
Published: November 2022

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Temozolomide (TMZ) is part of the standard of care for patients with newly diagnosed GBM (ndGBM). Expression of the enzyme MGMT involved in TMZ-induced DNA damage repair is associated with irresponsiveness of some patients to TMZ. The addition of lomustine (CCNU) to TMZ demonstrated clinical benefit in patients with ndGBM. Tumor Treating Fields (TTFields) are electric fields that display anti-mitotic effects and lower expression levels of proteins from the FA-BRCA DNA repair pathway in cancerous cells. TTFields therapy concomitant with TMZ is approved for the treatment of ndGBM. The aim of the current study was to examine the effect of TTFields in conjunction with TMZ and CCNU in GBM cells. Human GBM cell lines with different MGMT expression levels (U-87 MG, LN229, U118, and LN18) were treated with TTFields (0.83 V/cm RMS, 200 kHz) concomitant with TMZ and/or CCNU. Cell counts, colony formation, and apoptosis were used to measure effectiveness. The effect of TTFields with concomitant TMZ was additive in all cell lines, regardless of MGMT expression levels. TTFields in conjunction with CCNU displayed an additive effect in cell lines with high MGMT expression, and tendency to synergism in cell lines with low or no MGMT expression. TTFields concurrent with both TMZ and CCNU further increased treatment efficacy. Mechanistically, TTFields elevated the levels of DNA double strand breaks and lowered expression of FA-BRCA pathway proteins, as detected by fluorescence microscopy and western blot, respectively. The involvement of the FA-BRCA pathway in repair of DNA damage induced by CCNU and the BRCAness state induced by TTFields rationalize the synergy seen for TTFields with CCNU, especially in cells absent of MGMT. The results suggest a potential benefit of TTFields therapy concomitant with TMZ/CCNU for the treatment of GBM.
DDEL-02. LUMBAR OMMAYA RESERVOIR- A COST EFFECTIVE ALTERNATIVE TO INTRAVENTRICULAR OMMAYA RESERVOIR FOR TREATMENT OF LEPTOMENINGEAL DISEASE
Authors: Peo Ivo , Kumar Jay , Krafft Paul , Tran Nam
Published: November 2022

Introduction

Lumbar puncture (LP) is a well-established approach for intrathecal (IT) delivery of chemotherapeutics for leptomeningeal disease (LMD). Intraventricular Ommaya reservoir (OR) has supplanted LPs as an easier and safer route for IT administration. Radiotherapy for treatment of LMD must be delayed in order for surgical wound healing following OR placement. Furthermore, prior cranial radiation can thin the scalp, predisposing to wound breakdown. Placement of lumbar Ommaya reservoir (LOR) provides an alternative to IT delivery, but this has not reached a wide-spread acceptance. Objective Provide cost-analysis and report patient outcomes after placement of LOR.

METHODS

Following IRB approval, all patients undergoing LOR placement between 2018 and 2020 were retrospectively reviewed. Patients age, primary tumor, survival lengths and complications were reviewed. Average procedure-related treatment cost was obtained from an uncomplicated representative case excluding the surgeon’s fee.

RESULTS

Fourteen patients (mean age 46.35 years) were identified. The mean follow-up was 440.7 (25-1003) days post-surgery. Acute lymphoblastic leukemia (n = 4), acute myeloblastic leukemia (n = 3), breast carcinoma (n = 3), ependymoma (n = 3), lymphoma (n = 2) and lung adenocarcinoma (n = 1) were identified as underlying malignancy. LMD was diagnosed on average after 581.1 days after the diagnosis of the underlying malignancy. 8 patients succumbed to their malignancy on average after 463.9 and 314.6 days after the diagnosis of LMD and LOR surgery, respectively. There were 2 complications – pain at the site of the LOR and a fractured catheter caused by inadvertent puncture of the catheter. No infections or wound healing complications were noted. Typical cost for placement of LOR and OR was – 17,350 USD and 29,052 USD, respectively. Placement of the LOR proved to be more cost-effective in this cohort by approximately 40% cost reduction.

CONCLUSION

Placement of LOR is a cost effective alternative to cranial OR with low complication profile, and well tolerated by patients.
DDEL-03. ASSESSING THE DEPTH OF DRUG PENETRATION INTO BRAIN PARENCHYMA FROM LOCAL DRUG DELIVERY SYSTEMS IN AN ORTHOTOPIC HIGH GRADE GLIOMA ALLOGRAFT USING ORBITRAP-SECONDARY ION MASS SPECTROMETRY
Authors: Moloney Cara , McCrorie Phoebe , Bastianchich Chiara , Ucakar Bernard , Alexander Cameron , Marlow Maria , Préat Véronique , Rahman Ruman
Published: November 2022

Local intracranial drug delivery for high-grade glioma has been developed over the last two decades with chemotherapeutic agents administered immediately adjuvant to neurosurgery to overcome poor blood brain barrier permeability. In addition to this, the incorporation of nanoparticles (NPs) into local drug delivery systems (DDS) can result in increased penetration of chemotherapeutics through brain parenchyma, transporting the drug further from the administration site than by drug molecule diffusion alone.Here we adopted two model local DDS containing NPs to compare the depth of penetration through brain parenchyma. Approach one consisted of a thermosensitive in situ assembling polymer matrix loaded with polymer-doxorubicin conjugated NPs which can line the resection cavity walls, while approach two consisted of drug-loaded (etoposide and olaparib) poly(lactic acid)-poly(ethylene glycol) polymeric NPs held within a bioadhesive pectin hydrogel and delivered via a spray device.We assessed the efficacy of both DDS at preventing recurrence of high-grade glioma in an orthotopic rat 9L gliosarcoma model following surgical resection. In addition to monitoring long-term survival, the effect of each DDS was measured histologically by H&E and by caspase-1 (inflammatory response) and ki67 (cell proliferation) immunostaining staining. Depth of drug penetration was evaluated on post-sacrificial sections using Orbitrap-Secondary Ion Mass Spectroscopy (OrbiSIMS) and fluorescent microscopy. In vivo data suggests that the delivery mechanism of the NPs affects the efficacy of the DDS, whereby long-term survival was observed in rats treated with the sprayed olaparib/etoposide NP formulation, relative to rats where olaparib/etoposide was simply pipetted into the resection cavity. OrbiSIMS confirmed the presence of doxorubicin, olaparib and etoposide in brain tissue. Our work encourages consideration of mass spectrometry modalities to complement in vivo efficacy studies, as an analytical tool to assess brain distribution of systemically administered drugs, or localised brain penetration of drugs released biomaterial-based DDS.
DDEL-07. DETERMINATION OF TOTAL AND UNBOUND LEVELS OF A POTENT INHIBITOR OF POLY ADP-RIBOSE POLYMERASE, NIRAPARIB, IN HUMAN PLASMA, CEREBROSPINAL FLUID AND BRAIN TUMOR BY A VALIDATED LC-MS/MS ASSAY
Authors: Knight William , Margaryan Tigran , Sanai Nader , Tovmasyan Artak
Published: November 2022

BACKGROUND

Niraparib is an orally available inhibitor of poly ADP-ribose polymerase with high selectivity for PARP1 and PARP2. It is currently approved in the United States for the treatment of ovarian, fallopian tube, and primary peritoneal cancer. Herein we present the development and validation of an LC-MS/MS method for determination of total and unbound levels of niraparib in human plasma, cerebrospinal fluid (CSF) and glioblastoma tissue.

METHODS

Niraparib was extracted from human plasma, CSF and glioblastoma homogenate samples by protein precipitation with methanol. Unbound fractions of niraparib in plasma and brain tissues were determined by equilibrium dialysis. Validation was performed using Sciex ExionLC UHPLC system coupled with Sciex QTRAP 6500+ MS/MS detector using positive electrospray ionization mode. The method was validated according to FDA guidelines and CAP/CLIA regulations.

RESULTS

The method was validated for 1-10,000 nmol/L concentration range using plasma as matrix for all biospecimens. The chromatographic separation was performed on Phenomenex Kinetex™ PS C18 column with total run time of 3.5 min with gradient elution. Maximum coefficient of variation for intra- and inter-day precision was 10.6% and the accuracy was within 92.8-118.5% in all matrices. The analyte is stable in plasma and brain homogenate for at least 6 hours at room temperature (RT) and at least 32 days at -20°C. Stability of stock and working solutions was demonstrated for at least 21 hours (RT) and 41 days (4°C). The fraction unbound of niraparib in human plasma and brain were determined to be 0.15 and 0.05, respectively.

CONCLUSIONS

A sensitive and rapid bioanalytical method is developed and validated to quantify total and unbound niraparib levels in human plasma, CSF and glioblastoma tissue. This method is currently employed to assess plasma pharmacokinetics and CNS penetration of niraparib in newly-diagnosed glioblastoma and recurrent IDH1/2(+) ATRX mutant glioma patients (NCT05076513).
DDEL-15. METHOTREXATE AREA UNDER THE CURVE IN PRIMARY CNS LYMPHOMA
Authors: Moussalli Dana , Vo Anh Huan , Turchan Maria , Fu Rochelle , Ambady Prakash
Published: November 2022

INTRODUCTION

There is consensus that high-dose methotrexate-based (HD-MTX) chemotherapy is the first line treatment for primary central nervous system lymphoma (PCNSL) but there is no consensus on drug dosing and duration. Area under the curve of Methotrexate (MTX-AUC) is a measure of exposure, and we hypothesize that a high MTX-AUC is associated with improved overall survival (OS) and progression free survival (PFS).Method: This retrospective study was approved by the institutional review board. HIV negative PCNSL patients who received Rituximab and HD-MTX at our institution from 2002-2020 were included. HD-MTX dose ranged from 1.2 gm/m2-8 gm/m2 based on creatinine clearance. MTX-AUC was calculated using mtxpk.org. OS and PFS were analyzed using Kaplan-Meier method and Cox proportional hazard regression. Result: 34 PCNSL patient’s charts (mean age: 67 yrs ± 15, 22F/12M) were reviewed. The mean MTX dose (5313 mg/m2) strongly correlated with the mean MTX-AUC (3648 μmol*l−1h, range: 698 – 6634). Patients with MTX-AUC < 3648 μmol*l−1h median PFS is 44.6 months (95% CI: 3.8– non-estimable), not significantly different from patient with MTX-AUC > 3648μmol*l−1h (PFS: 53.2 months, 95% CI: 4.3– non-estimable; P = 0.96). Results were similar after adjusting for patient characteristics in the Cox regression with hazard ratio (HR): 0.84; 95% CI: 0.29–2.43; P = 0.75). The median OS was 44.6 months (95% CI, 12.5– non-estimable) for patients with MTX AUC < 3648 μmol*l−1h and not estimable for patients with MTX-AUC > 3648 μmol*l−1h , HR of 0.43 (95% CI: 0.08–2.33; P = 0.33). Higher KPS prior to chemotherapy was associated with improved PFS/OS with HR: 0.95 (95% CI: 0.93–0.98; P = 0.0006) and HR: 0.91 (95% CI: 0.87–0.96; P = 0.0005) respectively.

CONCLUSION

Our patients PFS and OS is improved compared to historical control but our data suggests that there is no statistically significant association with MTX-AUC in PCNSL.
DDDR-02. CDK4/6 INHIBITION WITH ABEMACICLIB SENSITIZES INTRACRANIAL TUMORS TO CHECKPOINT BLOCKADE IN PRE-CLINICAL MODELS OF BRAIN METASTASIS
Authors: Nayyar Naema , de Sauvage Magali , Sullivan Emily , Chuprin Jane , Yamazawa Erika , Michael Brehm , Brastianos Priscilla
Published: November 2022

Although immune checkpoint inhibitors (ICI) have become a useful tool in the management of central nervous system (CNS) metastases, only a subset of patients experience durable clinical responses and prognosis continues to remain poor. In particular, the role of ICI for CNS metastases from breast cancer has also not been adequately explored. CDK4/6 inhibition has been shown to sensitize extracranial tumors to ICI, and we previously reported intracranial efficacy of combination CDK4/6 inhibition with abemaciclib and anti-PD-1 in preclinical models of melanoma brain metastasis. We have now investigated this combination strategy further in a mouse model of triple negative breast cancer brain metastasis. 4T1 mammary carcinoma cells were first injected into the mammary fat pad and then intracranially 3 days later. While single agent anti-PD-1 antibody or abemaciclib were both ineffective at reducing tumor growth, we found a significant reduction in intracranial and extracranial tumor burden when abemaciclib was combined with anti-PD-1. Immunofluorescence for CD8 and CD3 revealed a significant increase in tumor-infiltrating CD8+ T cells with abemaciclib monotherapy as well as combination therapy in intracranial 4T1 tumors. We observed a similar increase in intracranial tumor-infiltrating CD8+ T cells in two melanoma brain metastasis models, YUMM1.7 and B16-F10, following combination therapy. We conclude that combination with abemaciclib can improve intracranial efficacy of ICI by driving CD8+ T cell infiltration into intracranial tumors. Future work will focus on investigating additional treatment-induced changes in the tumor immune microenvironment and dissecting the effect of CDK4/6 inhibition on T cell activation and function.
DDDR-04. CA-4948 IN COMBINATION WITH BRAF/MEK INHIBITION IN MELANOMA BRAIN METASTASES
Authors: Doonan Bently , Von Roemeling Christina , Archibald Vincent , Klippel Kelena , Elliott Tyler , Matich Erica , Hoang-Minh Lan , Mitchell Duane
Published: November 2022

Melanoma brain metastases (MBM) remain a primary driver of melanoma morbidity and mortality. It is estimated that as many as 60% of all metastatic melanoma patients will develop MBM during the course of their disease. Once found, dual checkpoint inhibitor therapy or BRAF/MEK inhibition in BRAF mutated cancers, are the best options currently available. Even with these treatments, the response to therapy is less than what is seen with disease outside the. In BRAF mutated cancers, which constitute 50% of all patients, initial response to targeted therapy is rapid but resistance to therapy develops 3 months sooner than resistance outside of the brain. Novel strategies to prevent onset of resistance or to work in concert with BRAF/MEK inhibition are needed for this treatment population. The exact mechanism of resistance to targeted therapy in MBM is not known, but mutations in EphA2, PI3K, pAKT, and re-activation of MAPK signaling through secondary mechanisms have all been identified as drivers of resistance. One pathway of MAPK reactivation is through activation of phospho-ERK (eIF2alpha kinase) which also activates the JNK pathway. Our group has previously shown that MBM express high levels of the inflammatory transcription factor IRAK-4, the terminal chaperone of the inflammatory myddosome downstream of TLR and IL1R signally. This increase in IRAK-4 results in constitutive activation of NF-KB, JNK, and MAPK. We have additionally shown the novel oral IRAK-4 inhibitor CA-4948 can reach therapeutically relevant concentrations past the blood brain barrier in both tumor-bearing and naïve mice. We additionally show CA-4948 inhibits MAPK expression in melanoma and suppresses the escape pathways pERK and JNK signaling which can contribute to the prevention of resistance to targeted therapy. This study supports further investigation into the combination potential of CA-4948 with BRAF/MEK inhibitors as triplet therapy to delay intracranial resistance.
DDDR-21. REGULATORY REDUCTASE SUBUNIT RRM2 AND DEHYDROGENASE IMPDH2 INTERACT IN GLIOBLASTOMA IN A TMZ-DEPENDENT MANNER
Authors: McManus Graysen , Perrault Ella , Shireman Jack , Ventarapragada Divya , Lahmadi Linna , Lin Peiyu , Ali Eunis , Park Cheol , Baisiwala Shivani , James David , Ben-Sahra Issam , Pott Sebastian , Basu Anindita , Miska Jason , Ahmed Atique
Published: November 2022

Glioblastoma (GBM) is an aggressive primary brain tumor characterized by poor prognostic outcomes. Nearly all GBM tumors recur, due to cellular resistance against chemotherapies, including temozolomide (TMZ), which develops during active treatment. To investigate these adaptive mechanisms, our lab conducted a single-cell RNA sequencing analysis utilizing an in vivo patient-derived xenograft (PDX) model of GBM, prior to, during, and post TMZ-based therapy. Our data revealed 149 genes to be uniquely expressed in the during-TMZ condition (p < 0.0001), including two regulatory enzymes involved in purine metabolism: the Ribonucleotide Reductase (RNR) Regulatory Subunit 2, RRM2, and inosine monophosphate dehydrogenase 2, IMPDH2. Previous work in this lab has independently established both RRM2 and IMPDH2 as significant drivers of TMZ-resistance in GBM, through their respective abilities to alter tumor metabolism during therapy. Network analysis of genetic pathways enriched during TMZ therapy revealed a previously unidentified interaction between IMPDH2 and the RRM1 subunit of the RNR enzyme. Given these data, we aimed to determine if there was also an interaction between IMPDH2 and RRM2 in GBM. Immunocyto- and histochemistry of GBM-PDX primarily demonstrated significant co-localization between RRM2 and IMPDH2 during TMZ therapy. Immunoprecipitation (IP) and reverse-IP analyses were subsequently conducted, and revealed a previously unreported molecular interaction between the two proteins in GBM lines, which increased in a TMZ-dependent manner. These results were not corroborated in neural stem cell lines. Additionally, immunoblot analyses revealed that in RRM2-knockdown GBM-PDX, IMPDH2 protein expression is decreased compared to controls. We hypothesize the dynamic interaction of RRM2 and IMPDH2 to enhance the metabolic adaptations underlying GBM chemoresistance. The efforts of this study are now focused on investigating the potentially synergistic mechanisms of FDA-approved RRM2 and IMPDH2 inhibitors, previously shown to enhance the efficiency of TMZ. This novel and targetable interaction may present a promising clinical opportunity for GBM therapy.
DDDR-28. EGFR AND SRC-MEDIATED ACTIVATION OF STAT3 DRIVES RESISTANCE TO MITOTIC INHIBITORS IN GLIOBLASTOMA, AND CAN BE REVERSED WITH FDA-APPROVED DRUGS
Authors: Kenchappa Rajappa , Dovas Athanassios , Argenziano Michael , Meyer Christian , Stopfer Lauren , Banu Matei , Pereira Brianna , Griffith Jessica , Mohammad Afroz , Talele Surabhi , Zarco Natanael , Elmquist William F , White Forest , Quaranta Vito , Sims Peter , Canoll Peter , Rosenfeld Steven
Published: November 2022

While the allure of targeted therapies in oncology has been their high degree of specificity and potency for key tumor drivers, they have been disappointing in glioblastoma (GBM), even for drugs that are blood brain barrier permeable and CNS retained. This point is highlighted by the experience with mitotic spindle inhibitors, drugs which block the G2M transition and induce mitotic catastrophe—a phenotype characterized by cell enlargement and polyploidy that leads to apoptotic cell death. We have shown that one of these, a potent inhibitor of the mitotic kinesin Kif11 (ispinesib), is highly active against GBM tumor initiating cells and prolongs survival in murine models of this disease. However, tumors eventually progress, reflecting the development of drug resistance. Although ispinesib resistant GBM cells develop mitotic catastrophe, they become highly resistant to the apoptosis that typically follows and continue to proliferate. We find that this apoptosis resistance requires phosphorylation of the transcription factor STAT3 at two residues—Y705 and S727. Phosphorylation of Y705, mediated by SRC kinase, translocates STAT3 to the nucleus where it induces transcription of anti-apoptotic proteins. Phosphorylation at S727, mediated by EGFR, translocates STAT3 to the mitochondria where it blocks release of cytochrome c—the penultimate effector in apoptosis. Simultaneously inhibiting both SRC and EGFR with FDA-approved, CNS permeant inhibitors reverses this resistance and significantly prolongs survival in ispinesib-treated GBM-bearing mice. Furthermore, we find that resistance to several other mitotic inhibitors also utilizes this STAT3-driven mechanism and can likewise be reversed with combined EGFR and SRC inhibition. Thus, our work demonstrates how a promising therapeutic approach, which has been disappointing in GBM, can in fact be rendered effective by anticipating and prospectively treating ab initio the mechanism that drives treatment resistance.
DDDR-34. RECURRENT RELA FUSION-POSITIVE EPENDYMOMA TREATED WITH VAL-083 UNDER EXPANDED ACCESS: A CASE REPORT
Authors: Kamiya-Matsuoka Carlos , Knight Stephanie , Langlands John , Brown Dennis , Puduvalli Vinay
Published: November 2022

Ependymoma is a relatively rare central nervous system tumor accounting for 2-9 % of all neuroepithelial tumors. RELA fusion-positive ependymoma is a subgroup associated with supratentorial location, higher WHO grade and worse prognosis. In addition, there is no standard systemic chemotherapy treatment for adults with recurrent disease. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand DNA cross-links at N7-guanine inducing double-strand breaks causing cell death and acts independent of MGMT DNA-repair in high-grade gliomas. We report a 40-year-old male who was initially diagnosed with a right parieto-occipital high-grade glioma, with no somatic mutations including IDH1/2 genes, and with unmethylated MGMT promoter status. He initially underwent gross total resection, followed by chemoradiation with concurrent and adjuvant temozolomide for 12 cycles. Sixteen months later, he developed recurrent disease and had a second resection. Inter- and intragenic fusion analysis of tumor tissue revealed C11orf95-RELA fusion and the diagnosis of RELA fusion-positive ependymoma was established. The patient was not eligible to participate in any clinical trial and received VAL-083 under an expanded access program. He was then treated with VAL-083 (30 mg/m2 for 3 consecutive days every 21 days) and completed 12 cycles during a period of 9 months. No grade 3/4 adverse events such as thrombocytopenia, anemia, neutropenia, or lymphopenia were observed. His liver and renal functions were normal. No dose reduction was required. He also received levetiracetam, alprazolam and prochlorperazine, with no drug interactions. Steroid were not required. He has been under surveillance since completion of systemic treatment with VAL-083 and has remained radiologically stable, with no CSF dissemination, after 12 months. This case highlights that VAL-083 may be a treatment option for recurrent RELA fusion-positive ependymoma refractory to temozolomide-based regimens. Clinicaltrials.gov Identifier: NCT03138629. The treatment plans for this EAP patient were approved by MD Anderson Cancer Center IRB.
EOLP-01. PALLIATIVE CARE REFERRAL ACROSS THE DISEASE TRAJECTORY IN HIGH-GRADE GLIOMA
Authors: Crooms Rita , Taylor Jennie , Jette Nathalie , Morgenstern Rachelle , Agarwal Parul , Goldstein Nathan , Vickrey Barbara
Published: November 2022

BACKGROUND

Patients with high-grade glioma (HGG), WHO grade 3 or 4, have substantial palliative care needs. As evidence suggests early palliative care consultation (PCC) yields improved quality of life in advanced cancer, our aim was to determine the occurrence, timing, and factors associated with PCC in HGG.

METHODS

Adults with HGG diagnosed between 8/3/2011 and 1/23/2020 were identified retrospectively from a large, academic, multi-center health system cancer registry. Patients were stratified by any prior PCC (yes/no), and timing of PCC by disease phase: (1) diagnosis (before radiation), (2) initial treatment (first-line chemotherapy/radiation), (3) second-line treatment (second-line to last chemotherapy), and (4) end-of-life (after last chemotherapy). Univariate analyses (e.g., Chi-square test) were conducted to compare PCC to non-PCC groups, based on data distribution.

RESULTS

Of 621 HGG patients, 134 (21.58%) received PCC, with 14 (10.45%) referred during phase 1; 35 (26.12%) in phase 2; 20 (14.93%) in phase 3; and 65 (48.51%) in phase 4 with a median of 74 days (IQR 15, 277) from initial PCC to death. The majority of referrals were inpatient (111 (82.84%)). The PCC group did not differ significantly from non-PCC in age, sex, language, race, or ethnicity, but did differ by marital status: single (263 (42.35%) vs 187 (38.4%)), divorced/separated (37 (27.61%) vs 107 (21.97%)), married/civil union (17 (12.69%) vs 154 (31.62%)); (Chi-square p < .01). Compared to non-PCC, more patients in the PCC group had glioblastoma histopathology (89.55% vs. 82.14%, p = .04).

CONCLUSION

A minority of HGG patients ever received PCC, which primarily occurred in the inpatient setting, and half of those referred for PCC received it during the end-of-life phase. Thus, only about one in 10 patients in the entire cohort potentially received the benefits of early PCC. Further studies should elucidate barriers and facilitators to early palliative care in HGG.
EOLP-05. POSTMORTEM TISSUE DONATION: GIVING FAMILIES THE ABILITY TO CHOOSE
Authors: Ramaswamy Vijay , Lyons Nicole , Frenkel Elizabeth , Gerismov Elena , Gustafson Allen , Gustafson Patti , McLean Ginny , Ochasi Aloysius , Waanders Angela
Published: November 2022

To our knowledge, Gift From a Child (GFAC) is the only dedicated consortium providing autopsy resources for children with brain tumors. Using the parental data and the experience of being a multi-institutional post mortem CNS tumor collection program, GFAC seeks to inform medical professionals of the need to approach families about post-mortem donation and demonstrate how barriers to donation can be overcome. Much like the one that occurred for organ donation, a cultural shift is needed with the goal to offer every family the option to donate. Collected survey data shows, 98% of families who donated were satisfied with their decision, compared to 20% of families who did not donate being satisfied with their decision. Most families want to be provided the opportunity to chooseto donate, citing the desire to advance research and help future families. For families who donated, over 71% initiated the donation conversation with their clinician. Among those who did not donate, 58% reported they had not been asked. The healthcare team initiated the donation conversation only 20% of the time for both groups. Without the conversation being initiated, many families remain unaware of the necessity and impact of donation on advancing research. The timing and structure of how donation is brought up impacts if families proceed with donating, however, data shows that withholding this option is frequently more distressing for families. Parent interviews and survey data indicate the majority of families are most open to this conversation once it’s evident a child will not survive and during transition to hospice care. Presentation donation as a driver for research, helping the next child, and as a key step in the family’s grieving process positively correlate with a family’s decision to donate.
EPID-01. PROFILE AND OUTCOME OF PATIENTS WITH BRAIN METASTASES IN YOGYAKARTA, INDONESIA
Authors: Malueka Rusdy , Hartanto Rachmat , Setyawan Nurhuda , Rismawan Alfian , Dananjoyo Kusumo , Basuki Endro , Asmedi Ahmad , Dwianingsih Ery
Published: November 2022

BACKGROUND

Metastatic brain tumors cause significant morbidity and mortality and often have a poor prognosis. Currently, there are limited epidemiology data on metastatic brain tumors in Indonesia. This study aimed to identify demographic, clinical characteristics, and outcomes of patients with brain metastases in Yogyakarta Province, Indonesia.

METHODS

Demographic and clinicopathological data were collected from medical records of brain tumor patients admitted to six major hospitals in Yogyakarta Province, Indonesia, for five years (2015–2019).

RESULTS

In total, 395 patients were included. Most patients were females (254, 64.3%). The mean age of the patients was 51.6±15.0 years old. Headache was the most common presenting symptom (53.2%), followed by a motoric deficit (48.4%), cognitive impairment (24.3%), loss of consciousness (21.3%), and a seizure (20.8%). The most common primary tumors that metastasize to the brain were lung (36.6%) and breast cancer (32.7%). The median overall survival of patients with brain metastases was 11±2.36 months.

CONCLUSION

Lung and breast cancers are the most common source of brain metastases in Yogyakarta, Indonesia. Overall survival of patients with brain metastases in this area is still relatively short.
EPID-06. IMPROVEMENTS IN SURVIVAL FOR GLIOBLASTOMA IN THE POST-STUPP PROTOCOL ERA
Authors: Neff Corey , Chavez Gordon , Proescholdt Christina , Kruchko Carol , Cioffi Gino , Waite Kristin , Barnholtz-Sloan Jill , Ostrom Quinn
Published: November 2022

BACKGROUND

Introduction of the Stupp protocol for glioblastoma treatment in 2005 led to a significant increase in overall survival in glioblastoma. Prior analyses identified additional survival gains in glioblastoma since this time, though the source of these gains is unknown. In this analysis, we leveraged commercial claims and population-based datasets to better understand potential treatment factors associated with improved survival for glioblastoma.

METHODS

Provider-side commercial claims data were obtained from IQVIA for adults (18+) diagnosed with malignant brain tumor (ICD-9 codes: 191.0-191.9 or ICD-10 codes: C71.0-C71.9) from 2013-2021. Glioblastoma patients were identified as those who received biopsy/resection, radiation and temozolomide within 60 days of their brain tumor diagnosis. Treatment patterns were determined using ICD-9/ICD-10 procedure codes and HCPCS/CPT codes. Date of death was determined by a claim containing the CPT codes 99238 or 99239 or date of last claim followed by at least 30 days of no additional claims. Population-based survival data for microscopically-confirmed adult glioblastoma cases receiving radiation treatment from the National Program of Cancer Registries (NPCR) from 2004-2018 were used as a comparison group. Median survival was estimated using Kaplan-Meier regression, overall in IQVIA and by two-year periods in NPCR.

RESULTS

In the IQVIA cohort, 9,368 individuals (2.5%) were identified as glioblastoma based on treatment criteria. Median survival in the IQVIA cohort 16.6 months (15.2-17.0), and 12 months (95%CI:12-12) in NPCR. Median survival in NPCR increased from 11 months in 2004-2006, to 12 months in 2006-2009, and then 13 months in 2010-2018. Within the IQVIA cohort, 27% had ≥ 1 claim for Bevacizumab and 15% had ≥ 1 claim for tumor treating fields.

CONCLUSIONS

Survival in glioblastoma continues to improve over time, which may be due to developments of new therapeutic approaches. Assessment of population-level survival patterns is essential for understanding the impact of treatment advancements in the general population.
EPID-07. A SYSTEMIC REVIEW OF PHASE II SINGLE-ARM TWO-STAGE DESIGNS IN GLIOBLASTOMA
Authors: Yoo Wonsuk , Mehta Shwetal , Sanai Nader
Published: November 2022

Even though two-stage designs have been popularly in oncology Phase 2 single-arm trials during last decade, none, to our knowledge, has examined the usage for published articles that had applied the two-stage designs in Phase 2 single-arm trials in glioblastoma. It might be valuable to perform a comprehensive review on the phase 2 single-arm two-stage trials in glioblastoma for examination of appropriate application on the two-stage designs. Systematic review has been performed under the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-statement. The search was performed using following key words for the literature search as index terms or free-text words: “phase II trials”, “glioblastoma”, and “two-stage design”. After identifying 81 articles based on online search, we had 32 studies included in review due to exclusion of 49 articles such as duplicates (n = 10), randomized trials (n = 7), single-stage designs (n = 5), and insufficient information (n = 27). We extracted general and two-stage design information (tumor type and setting, drugs, error types, response rates, primary endpoint, two-stage sample size data, study termination status etc). Almost 50% of single-arm two-stage studies failed to provide key information related to study designs and sample size calculation, even wrong power analysis and interpretation. Response rate and progression-free survival are used as popular surrogate endpoints for overall survival. It is time to evaluate other potential endpoints like post-progress survival and hazard ratio, and usefulness of co-primary endpoint. Studies less than 10% provided the historical data source. Investigators should keep transparency of the trials by fully providing and citing historical data source and do conservative choice for historical rates. Meta-analysis can be a good option to accurately estimate the historical control. The appropriate selection on primary endpoint, historical control data, incorporation of adaptive designs, right application of two-stage designs might help overcoming the challenges on glioblastoma therapeutic trials.
EPID-13. CHARACTERIZATION OF PEDIATRIC RADIATION-INDUCED MENINGIOMA: A SEER ANALYSIS
Authors: Matharoo Jashanjeet , Abaricia Jefferson , Opalak Charles , Broaddus William
Published: November 2022

OBJECTIVE

Radiation-induced meningiomas (RIM) are the most common secondary neoplasm arising from radiation therapy. RIM have not been characterized in pediatric populations on a national scale despite displaying shorter latency and higher malignancy rates in institutional studies. The objective of this study was to characterize pediatric RIM and compare latency and malignancy rates to those of adult RIM using the National Cancer Institute’s Surveillance, Epidemiology and End Results Program (SEER) database.

METHODS

From the SEER Research Plus Nov 2020 (1975-2018) dataset, 56161 patients treated with EBRT for ocular/orbital tumors, brain/nervous system tumors, and leukemia were identified. 185 patients meeting criteria for RIM were selected: cranial/spinal EBRT (presumed from diagnostic indication), histologically distinct precedent tumor treated with EBRT, and a minimum 5-year latency from EBRT to meningioma diagnosis. This sub-population was divided into 2 groups – pediatric (ages 0-19, n = 10) and adult (ages > 20, n = 175) RIM – and latency, recurrence rate and multiplicity were compared for each group. The number of tumors classified as malignant (as opposed to benign or borderline malignant) was also compared between groups. Additionally, demographic data were compared for each group.

RESULTS

Of the pediatric RIM patients, 70% were male, 70% were Caucasian, and 10% were African American. No pediatric RIM patients experienced a recurrence or presented with multiple RIMs. The pediatric group showed lower latency (11.00 ± 1.94 years, p < 0.001) and a higher malignancy rate (30%, p = 0.002) than the adult group (latency of 23.38 ± 8.69 years; malignancy rate 5.1%).

CONCLUSION

These data represent the first characterization of pediatric RIM from a national database and support prior findings of shorter latency and higher malignancy rates in pediatric vs adult RIM, as well as lay the groundwork for future nationwide monitoring of this rare yet highly significant complication.
EPID-15. SURGICAL RESECTION OF BENIGN MENINGIOMAS IN THE ELDERLY POPULATION: IMPLICATIONS FROM A PROPENSITY-SCORE MATCHED ANALYSIS
Authors: Ma Jun , Zhu Ping , Chen Clark
Published: November 2022

Object

We characterized the patterns of clinical practice in benign meningioma resection and survival outcome as a function of patient age using the Surveillance, Epidemiology and End Results (SEER) and the SEER-Medicare database.

METHODS

The likelihood for recommendation to proceed with resection and survival in adult, benign meningioma patients were characterized using logistic regression. Survival analysis was performed using a propensity-score matching (PSM)-method (covariates balanced in PSM: socio-demographics, facility features, and comorbidities) through a multivariable logistic regression and accelerated failure time (AFT) models.

RESULTS

The likelihoods of recommendation for surgery were 0.59 (95%CI = 0.53-0.66, P < 0.001) and 0.17 (95%CI = 0.15-0.21, P < 0.001) for meningioma patients age 60-79 and ≥ 80, relative to patients age 40-59. Expectedly, the hazard of death increased with advancing aging strata in patients who underwent meningioma resection. To account for mortality risk associated with normal aging, a PSM analysis was performed to calculate the hazard of death for surgically resected meningioma patients relative to an age- and PSM-matched cancer-free patient cohort. This odds ratio (OR) was 3.84 (95%CI: 3.15-4.67, P < 0.001) for patients age 60-79 and 3.41 (95%CI: 2.56-4.56, P < 0.001) for patients age ≥ 80. These two ORs were not statistically different (ROR: 0.89, 95%CI: 0.63-1.62, P = 0.512), suggesting that the likelihood of death after benign meningioma resection was not significantly elevated in patients age ≥ 80 after accounting for expected age-related mortality.

CONCLUSION

Our study suggests that surgeons exert caution in selecting elderly with meningioma for resection. After accounting for mortality risk associated with normal aging and patient selection by the surgeon, the likelihood of death for patients age ≥ 80 who underwent meningioma resection was comparable to that observed for patients age 60-79.
EPID-16. SEASONAL INCIDENCE PATTERN COMPARISON BETWEEN PRIMARY AND SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMAS
Authors: Yang Rachel , Demopoulos Alexis , Li Jianyi
Published: November 2022

OBJECTIVE

To compare primary CNS lymphoma [PCNSL] and secondary CNS lymphoma [SCNSL] incidence by year, month, week, and time between symptom onset, radiographic study, and tissue diagnosis.

BACKGROUND

PCNSL is a rare non-Hodgkin’s B-cell lymphoma confined to the central nervous system with an increased incidence among immunocompromised patients and immunocompetent patients.1 Epstein Barr Virus [EBV] infection usually accompanies immunocompromised patients with PCNSL. Whether viral infection is etiologic remains uncertain, especially among the immunocompetent, where EBV is not found. A seasonal pattern was described suggesting an infectious etiology.2 We sought to add to the literature our experience regarding patterns of disease onset. Design/

METHODS

We retrospectively identified 96 immunocompetent PCNSL patients and 75 SCNSL patients treated here between 2010-20. Complete data was available for 91 PCNSL and 73 SCNSL patients. Variables collected included symptom onset, initial imaging, and tissue collection dates.

RESULTS

Weekly incidence was noted in both, with peak of incidence in the 10th and 40th week in PCNSL in 9th, 27th, and 31st weeks among SCNSL. Time between symptom onset and first neuroimaging study was significantly different, with PCNSL patients having significantly less time on average. Curiously, the average time between each PCNSL diagnosis was significantly shorter than that for SCNSL diagnosis.

CONCLUSION/RELEVANCE

Due to the rarity of the disease, larger studies are needed to further elucidate potential viral etiologies underlying PCNSL.
EPID-19. CHANGES IN SURVIVAL OVER TIME FOR ALL PRIMARY BRAIN AND OTHER CNS TUMORS IN THE UNITED STATES
Authors: Edelson Jacob , Waite Kristin , Cioffi Gino , Kruchko Carol , Ostrom Quinn , Barnholtz-Sloan Jill
Published: November 2022

BACKGROUND

Despite advances in cancer diagnosis and clinical care, survival for many primary brain and other central nervous system (CNS) tumors remain poor. This study performs a comprehensive survival analysis on these tumors.

METHODS

Survival differences were determined utilizing the National Program of Cancer Registries Survival Analytic file for all primary brain and other CNS tumors. Overall survival and survival of the 5 most common histopathologies within specific age groups (children ages 0-14 years, adolescents, and young adults [AYA] ages 15-39 years, and older adults ages 40+ years) were determined. Overall survival was compared for three time periods: 2004-2007, 2008-2012, and 2013-2017. Kaplan-Meier and multivariable Cox proportional hazards models were used to generate median survival, hazard ratios (HR) and 95% confidence intervals (CI). Models were adjusted for sex, race/ethnicity, and treatment pattern. Malignant and non-malignant brain tumors were assessed separately.

RESULTS

Aside from hemangioma and mesenchymal tumors in older adults, no notable changes in survival were observed across the time periods for non-malignant tumors. For malignant brain tumors, significant survival improvements were observed in children with embryonal tumors (logrank p = 0.00028) and in AYA with anaplastic astrocytoma (logrank p = 0.0043). In older adults, significant improvement was observed in the five most common histopathologies except oligodendroglioma. Adjusted for sex, race/ethnicity, and treatment, there were improvements in survival in 2008-2012 and 2013-2017, when compared to 2004-2007, in children and AYA with malignant tumors (Children: HR = 0.92, 95% CI = 0.87-0.98, p = 0.010 in 2008-2012; HR = 0.91, 95% CI = 0.85-0.97, p = 0.005 in 2013-2017; AYA: HR = 0.92, 95% CI = 0.88-0.96, p < 0.001, in 2008-2012; HR = 0.87, 95% CI = 0.83-0.93, p < 0.001 in 2013-2017).

CONCLUSIONS

Overall survival for malignant brain and other CNS tumors improved slightly in 2013-2017 for all age groups as compared to 2004-2007. No significant changes were observed for non-malignant brain and other CNS tumors.
EPID-21. INCORPORATING RECEIPT OF STANDARD-OF-CARE AS A KEY VARIABLE IN POPULATION-BASED STUDY OF GLIOBLASTOMA SURVIVAL
Authors: Zhu Ping , Chen Clark
Published: November 2022

Object

Populational database research with real-world settings offers epidemiologic insight at scales that cannot be easily recapitulated, especially for rare cancers such as glioblastoma. However, most survival studies were conducted without consideration for whether the patients received the standard of care (SOC).

METHODS

Survival analysis was performed using the National Cancer Database (NCDB) and stratified for Methyl-guanine-methyl transferase (MGMT) promotor methylation. Glioblastoma patients age < 40 were excluded to minimize the prognostic impact of isocitrate dehydrogenase (IDH) mutations. SOC was defined as the receipt of chemotherapy and radiation within 2-6 weeks of surgical biopsy or resection. Sensitivity analyses were performed allowing chemotherapy and radiation start date to differ by 0, 3, 5, and 10 days.

RESULTS

Within the NCDB (N = 11231), 54.7% of newly diagnosed glioblastoma patients did not receive SOC. The median survival time (MST) estimates were significantly shorter for all glioblastoma patients (10.9, IQR: 4.3-21.5, months) relative to SOC treated patients (15.3, IQR: 8.6-26.2, months; p < 0.001). The MST estimates remain stable in sensitivity analysis allowing for 0, 3, 5, and 10-day discrepancy between chemotherapy and radiation start date. These results were recapitulated using the SEER-Medicare database. The MST estimates for MGMT methylated and unmethylated glioblastoma patients after SOC in the NCDB were 21.0 and 14.5-mo, respectively. The overall and MGMT-specific survival estimates mirror those reported by the SOC arms of five recent randomized controlled studies. Analysis of all glioblastoma patients indicates survival benefit of immunotherapy (HR: 0.90, p = 0.020) while such benefit was absent in SOC treated patients (HR: 0.97, p = 0.644) - with the latter observation more reflective with trial results and clinical experiences.

CONCLUSION

Survival analysis in the populational database study can be misleading without information on the receipt of SOC.