bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACTR-43. GENOMIC ANALYSIS OF RESPONDERS OF PHASE II TRIAL OF TEMOZOLOMIDE AND TRC-102 (BASE EXCISION REPAIR INHIBITOR) IN BEVACIZUMAB-NAÏVE GLIOBLASTOMA AT FIRST RECURRENCE
Authors: Ahluwalia Manmeet , Dhruv Harshil , Fallah Jaleh , Berens Michael , Drappatz Jan , Ye Xiaobu , Lesser Glenn , Cloughesy Timothy , Walbert Tobias , Holdhoff Matthias , Peereboom David , Nabors Louis , Wen Patrick , Grossman Stuart , Rogers Lisa 
Published: November 2019

Abstract

BACKGROUND
Temozolomide forms O6-methylguanine (O6mG), 7-methylguanine (N7mG), and 3- methyladenine (N3mA) DNA adducts. The O6mG DNA adduct is repaired by MGMT. N7mG and N3mA DNA adducts are removed by the base excision repair (BER) pathway, initiated by N- methylpurine DNA glycosolase (MPG). TRC-102 is a BER inhibitor that binds to the apurinic site created through the action of MPG.

METHODS
A phase II study of adult glioblastoma in first recurrence was performed in the Adult Brain Tumor Consortium with temozolomide, 150 mg/ m2 and TRC-102, 150 mg (1–5/ 28 days). Primary objective included radiographic response rate. Secondary objectives included safety and PFS-6. Exploratory objectives included tumor expression of N-methylpurine DNA glycosylase (MPG). The study tested hypothesis that combination therapy will achieve 30% RR. To understand the context of vulnerability to TRC102 we performed RNA sequencing on treatment naïve tissue from 7 patients.

RESULTS
Nineteen patients were enrolled in first stage. Median age was 60 years (range: 48–76), 53% females, median KPS was 80 (range: 70–90). Median cycles of treatment was 2 (range: 1–12). No responses were observed. Median OS was 11.0 months (95% CI: 8–18 months), median PFS was 2.0 months (95% CI: 1.8–3.6 months). PFS-6 rate was 10.5 % (2/19). The combination was safe. MPG staining was negative in six, 1+ in five and 2+ in three patients. PFS of 11 + months in two patients (exceptional responders) was associated with MPG expression. Preliminary analysis on RNA sequencing revealed significant enrichment for DNA Damage Response pathways (MsigDB), chromosomal instability gene signature (CIN70 and CIN25), and proliferative gene signature (PCNA25) in these 2 patients.

CONCLUSIONS
TRC 102 with temozolomide has acceptable safety but did not meet the primary endpoint of response. Gene signature of MsigDB, CIN70, CIN25 and PCNA25 was seen in exceptional responders and biomarker driven study is planned.
ACTR-55. OPTIMIZED TREAT-RESECT-TREAT STUDY DESIGN FOR CONVECTION-ENHANCED DELIVERY OF A FIRST-IN-CLASS BIOLOGIC IN THE TREATMENT OF GLIOBLASTOMA
Authors: Immidisetti Amanda , Nwagwu Chibueze , Shawn Carbonell W , Carbonell Anne-Marie 
Published: November 2019

Abstract

INTRODUCTION
Development of effective treatments for high-grade glioma (HGG) including glioblastoma is hampered by 1) the blood brain barrier, 2) an infiltrative growth pattern, 3) rapid development of adaptive therapeutic resistance, and 4) dose-limiting toxicity due to systemic exposure. Novel therapeutics and delivery techniques are warranted to overcome these obstacles and meaningfully improve patient outcomes. OS2966 is the first ever clinical-ready therapeutic candidate against the adhesion receptor subunit, CD29/β1 integrin. CD29 is highly overexpressed in glioblastoma and has been shown to drive tumor progression, invasion, and resistance to multiple modalities of therapy including immunotherapies. Here, we present a novel phase I trial design addressing all four obstacles plaguing effective treatment of HGG, while also enabling biomarker development.

STUDY DESIGN
This 2-part, ascending concentration, phase I clinical trial will enroll patients with recurrent/progressive HGG requiring a clinically-indicated resection. In part 1, patients will undergo stereotactic tumor biopsy followed by placement of a purpose-built catheter which is used for intratumoral convection-enhanced delivery (CED) of OS2966. Subsequently, patients undergo their clinically-indicated tumor resection followed by CED of OS2966 to the surrounding tumor-infiltrated brain. Matched, pre- and post-infusion tumor specimens will be utilized for biomarker development and validation of target engagement by receptor occupancy. Dose escalation will be achieved using a unique concentration-based accelerated titration design.

DISCUSSION
The present study design leverages multiple innovations including: 1) the latest CED technology, 2) two-part design including neoadjuvant intratumoral administration, 3) a first-in-class investigational therapeutic, and 4) concentration-based dosing. A U.S. Food and Drug Administration (FDA) Investigational New Drug application (IND) for the above protocol is now active.
SURG-04. INTRAOPERATIVE HAND-HELD LINE-SCANNED DUAL-AXIS CONFOCAL MICROSCOPY FOR VISUALIZING LOW-GRADE GLIOMAS
Authors: Fujita Yoko , Wei Linpeng , Liu Jonathan T C , Sanai Nader 
Published: November 2019

Abstract

BACKGROUND
Extent of resection is a prognostic factor for low- and high-grade gliomas. Fluorescence guided surgery (FGS) using five-aminolevulinic acid (5-ALA) is associated with greater extent of resection in high-grade gliomas. However, for low-grade gliomas, intraoperative imaging technologies such as FGS, have not been optimized to distinguish tumor from normal tissue. Intraoperative confocal microscopy can better visualize tissue cytoarchitecture in real-time. Here we report on the feasibility of a newly-developed, hand-held, line-scanned dual-axis (LS-DAC) confocal microscope in distinguishing tumor vs. normal cells in ex vivo human low-grade glioma tissue.

METHOD
Ten low-grade glioma patients who underwent craniotomy were enrolled. Resected specimens were labelled with acridine orange (1mM) for one minute, and exposed surfaces were immediately imaged by our device. Subsequently, specimens were cut into sections and stained with H&E for histopathological analysis.

RESULTS
LS-DAC confocal microscope visualized nuclei of tumor cells vs. surrounding tissue, demonstrating clear differences in cellularity in the two compartments. Acquired images were comparable to those observed on matched H&E-stained sections. Live images provided minimal motion artifact due to the higher frame rate of 16 Hz.

CONCLUSION
LS-DAC confocal microscope provided real-time, high-contrast mosaic images of human low-grade glioma tissue ex vivo. The ability to distinguish tumor vs. normal tissue at the cellular level with little motion artifact, as well as the device’s hand-held design, suggests this technology merits additional investigation as an intraoperative adjunct for low-grade glioma surgery.
ACTR-59. A PHASE 1 STUDY OF BPM31510 PLUS VITAMIN K IN SUBJECTS WITH HIGH-GRADE GLIOMA THAT HAS RECURRED ON A BEVACIZUMAB-CONTAINING REGIMEN
Authors: Recht Lawrence , Thomas Reena , Bertrand Sophie , Yerballa Priya , Li Gordon , Iv Michael , Narain Niven , Sarangarajan Rangaprasad , Granger Elder , Nagpal Seema 
Published: November 2019

Abstract

BACKGROUND
High-grade gliomas (HGG) are characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone (coenzyme Q10) containing lipid nanodispersion, causes a switch in cancer energy sourcing from glycolysis towards mitochondrial oxidative phosphorylation in vitro, reversing the Warburg effect and suggesting potential as an anti-tumor agent. The current study is a phase I study of BPM31510 + vitamin K in GB with tumor growth after bevacizumab (BEV).

METHODS
This is an open-label phase I study of BPM31510 continuous infusion with weekly vitamin K (10mg IM) in HGG patients using an mTPI design, starting at 110mg/kg, allowing for a single dose de-escalation and 2 dose-escalations. Patients had received first-line ChemoRadiation and were in recurrence following a BEV containing regimen.

RESULTS
9 eligible and evaluable patients completed the 28 day DLT period. 8 patients had primary GB, 1 had anaplastic astrocytoma with confirmed pathologic transformation to GB. Median age was 55 years (27–67) and median KPS 70 (60–90) at enrollment. 4 patients were treated at the highest dose 171mg/kg, where there was a single DLT: Grade 3 AST & ALT. The most common grade 1–2 AEs possibly, probably or definitely related to drug were elevated AST, rash, and fatigue, each occurring in 3 patients. Median OS for 9 eligible/evaluable patients was 128 days (95% CI: 48–209) while PFS was 34 days (CI of mean 8.9). 3 patients are currently alive; 2 patients have survived >1 year. PK/PD data are being processed and will be presented.

CONCLUSION
This study confirms that BPM 31510 + vitamin K is safe and feasible in treatment-refractory HGG patients. Though this study demonstrates safety at 171mg/kg, the proposed dose for future studies in GB, based on additional pre-clinical and non-GB clinical data is 88mg/kg.
SURG-19. REORGANIZATION OF LANGUAGE ENABLES SAFE RESECTION OF TUMORS IN AND AROUND BROCA’S AREA
Authors: Holmes Emma , Kerr Keith , Kadipasaoglu Cihan , Tandon Nitin 
Published: November 2019

Abstract

INTRODUCTION
Since its discovery in the 1800s, Broca’s area has been viewed as a critical node for language production. Previously, pathologies in this area have been considered unresectable due to concern for producing iatrogenic language production deficits. Emerging literature suggests that although acute lesions in this area can cause widespread deficits, slow growing lesions are less correlated with these deficits due to cortical language reorganization. Based on this data, we managed a cohort with Broca’s area lesions with surgical resection using awake intra-operative language mapping.

METHODS
All 150 awake craniotomies performed by the senior author over a twelve-year period (2006–2017) at a single institution were reviewed. For each patient the imaging was carefully evaluated to localize the neoplasm relative to pars triangularis or pars opercularis in the language dominant hemisphere. Language dominance was confirmed using WADA testing or fMRI. All patients underwent cortical language mapping using a battery of tasks coupled with cortical stimulation.

RESULTS
A total of 31 surgeries in 29 patients (65.5% male, 86.2% righthanded) were identified. The average age was 41. Patients presented with seizures (64.5%), speech difficulties (35.5%) or headaches (19.4%). A gross or near total resection was achieved in 26/29 (89.7%) of patients. Pathological evaluation revealed grade 2 gliomas (8), grade 3 gliomas (13) and glioblastoma (9). Post-operatively, 8 (25.8%) patients had new or worsening speech deficits, all of which resolved to baseline at follow-up.

CONCLUSION
Broca’s area lesions can be safely resected in patients using an awake craniotomy technique with language mapping. In our series, the majority of patients had gross or near total resections, few patients had new deficits, and none had permanent new deficits. Considering the increasing evidence in favor of cytoreduction to manage glial neoplasms, this technique should be employed routinely for pathologies in this area to optimize patient outcomes.
SURG-21. STEREOTACTIC BIOPSY FOR DEEP SEATED BRAIN LESIONS USING THE LEKSELL STEREOTACTIC FRAME SYSTEM
Authors: Fujimaki Takamitsu , Hirata Sachiko , Terano Naruhiko , Wakiya Kenji , Adachi Jun-ichi , Nishikawa Ryo , Sasaki Atsushi , Kobayashi Masahito 
Published: November 2019

Abstract

PURPOSE
To evaluate the results of stereotactic biopsies.

PATIENTS AND METHODS
Fifty-two patients with intraaxial lesions suspected of brain tumor. The locations of lesions includes, 19 deep cerebral white matter, 9 basal ganglia, 10 thalamus, 4 midbrain and 6 pons. Patients age ranged from 9 to 86 years (median 65 years), 33 were men and 19 were women. Under local anesthesia the Leksell stereotactic frame was fixed and the MRI were taken. Neuroimages such as enhanced CT scan or PET study were also used as references. After MRI patients were transferred to OR and under general anesthesia, several samples were taken with 2.1mm diameter needle by aspiration. Most of the cases the biopsy was done through frontal lobe, but in some cases through temporal lobe or through cerebellum. The samples were taken deeper and nearer regions of the designed targets with same trajectory, also. If there were cysts, aspiration of the cyst was performed as much as possible. The trajectory should avoid sulci, cortical veins or ventricular system. After biopsy inside the needle were irrigated repeatedly with 0.1 - 0.2 ml saline using thin plastic tube until the fluid does not contain bloody fluids to ensure hemostasis.

RESULTS
In all patients appropriate samples for pathological diagnosis were obtained. The diagnoses were 28 gliomas (pilocytic 1, grade II 8, grade III 11, grade VI (GBM) 6, high grade 1, glial tumor 1), 17 lymphomas, 3 germinoma and 2 were non-tumorous pathology. There were no symptomatic bleeding nor neurological complications.

CONCLUSION
With detailed planning, stereotactic biopsy was safely performed even from basal ganglia or brainstem. Trajectories other than from frontal can be also considered for some lesions. Repeated irrigation with saline might effective to prevent symptomatic bleeding and this case series shows lower complication rates compared to the published literatures.
SURG-23. INTRAPARENCHYMAL MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA: A NOVEL DISEASE PRESENTATION
Authors: Fatehi Mostafa , Haw Charles 
Published: November 2019

Abstract

INTRODUCTION
Low grade B-cell lymphomas arising from the marginal zone of secondary lymphatic follicles constitute less than 10% of lymphomas. This condition was initially described in the stomach and the nasopharynx. However, there have been several reports of isolated dural-based intracranial lesions.

METHODS
A review of the literature using the EMBASE and MEDLINE databases yielded 12 previous cases of dural MALT lymphomas but none that were entirely intra-parenchymal.

RESULTS
Here, we present the case of a 67 year male who was found to have a convexity meningioma; and another, intra-parenchymal, lesion with radiologic features consistent with a low grade glial tumor. Upon resection of both lesions, the intra-axial tumor was found to be a mucosa-associated lymphoid tissue lymphoma. He has subsequently been referred for initiation of needing adjuvant therapies.

CONCLUSIONS
In addition to posing challenges for radiologic diagnosis, this case presents questions regarding the oncologic management of MALT lesions in the brain.
SURG-24. A RISK SCORE FOR PREDICTING DEVELOPMENT OF DIABETES INSIPIDUS AFTER PITUITARY ADENOMA RESECTION
Authors: Jackson Christina , Vo Chau , Daniels Marcus , Chaichana Kaisorn 
Published: November 2019

Abstract

INTRODUCTION
The development of diabetes insipidus (DI) after pituitary adenoma resection is associated with worse post-surgical morbidity and longer hospital stay. Identification of clinical predictors of development of DI would allow for appropriate stratification of patients to optimize preoperative counseling and postoperative management.

METHODS
We conducted a retrospective review of 349 patients who underwent pituitary adenoma resection at Johns Hopkins Hospital between 2003 and 2017. We used unadjusted and adjusted logistic regression to identify predictors of developing DI. Factors which were associated with DI development (p< 0.1), were included in our multivariable model. Factors which remained associated with DI development were then used to develop a DI risk score. RESULT: 67 (19.2%) patients developed post-surgical DI. Patients who had symptoms of prolactinoma, surgery through one nare, or were on steroid treatment were more likely to develop DI. Conversely, patients who had unilateral cavernous sinus invasion were less likely to develop DI. We used these predictors to generate the DI risk score. Patients were assigned 1 point for each risk factor (symptoms of prolactinoma, steroids, or surgery through one nare) for developing DI, but 1 point was subtracted if they had a protective factor (unilateral cavernous sinus invasion). Patients with 0 points had a 10.7% probability of developing DI, patients with 1 point had a 18.5% probability of developing DI, patients with 2 points had a 41.2% probability of developing DI, and patients with 3 points had a 44.4% probability of DI.

CONCLUSIONS
We identified several predictors of DI development after pituitary adenoma resection, and used these to generate a DI risk score. The DI risk score could help stratify patients’ likelihood of postsurgical DI development, although validation through larger prospective multi-center studies are needed.
SURG-30. CLINICAL COURSE OF IDH-MUTATED LOW-GRADE GLIOMAS DURING THE POSTSURGICAL ACTIVE MONITORING PHASE: ASYMPTOMATIC PATIENTS, WELL CONTROLLED SEIZURES, BUT CONTINUOUS GROWTH OF TUMOR RESIDUES
Authors: Wijnenga Maarten , Daftari Besheli Matin , French Pim , Dubbink Hendrikus , Smits Marion , Kros Johan , Bromberg Jacoline E C , Taal Walter , Dirven Clemens , Vincent Arnaud , van den Bent Martin 
Published: November 2019

Abstract

INTRODUCTION
Postponing adjuvant treatment after resection in IDH-mutated low-grade glioma (LGG) seems appropriate in selected patients. Here we describe the clinical course of these patients during post-resection active monitoring with MRI scans, as literature on this topic is scarce.

METHODS
We included IDH-mutated LGG patients that underwent surgery between 2003–2016, with clinical follow-up including MR scans available. Samples were classified according to the 2016 WHO classification. We collected baseline clinical information, estimates of seizure control during follow-up, longitudinal evolution of post-resection LGG volumes when adjuvant therapy was postponed, and the clinicians’ reasons to either start immediate adjuvant treatment or postpone treatment, and reasons to initiate adjuvant treatment in later stage. We compared patients that underwent immediate postsurgical adjuvant treatment with patients that underwent active MRI monitoring until further progression.

RESULTS AND CONCLUSIONS
197 patients were included, of which 108 were IDH-mutated astrocytomas, and 89 were oligodendrogliomas. Of these, 97 patients were actively followed with MRI scans, and 100 patients underwent immediate adjuvant therapy after initial surgery. Patients that received immediate adjuvant therapy were older and had less extensive resections than patients wherein adjuvant treatment was postponed (median age 45 years vs. 37 years, P< 0.001; median postoperative tumor volume 31cm3 vs 2.68cm3, P< 0.001). The duration of the active surveillance period in the patients wherein adjuvant treatment was postponed correlated with the extent of resection, with shorter time until adjuvant treatment in case of larger postoperative tumor volumes. All LGG lesions showed continuous growth during the active surveillance period, with median growth rates of 3mm/year for oligodendrogliomas and 4mm/year in IDH- mutated astrocytomas (P = 0.0093). Seizures were well controlled, with the majority of patients using only one anti-epileptic drug. The majority of patients stayed asymptomatic during follow-up, and the reason to initiate further adjuvant treatment was always radiological growth.
TMIC-05. GLIOBLASTOMA CONTAINS TOPOLOGICALLY DISTINCT PROLIFERATIVE AND METABOLICALLY DEFINED SUBPOPULATIONS OF NESTIN AND GLUT1-POSITIVE CELLS
Authors: Prosniak Michael , Kenyon Lawrence , Craig Hooper D , Andrews David 
Published: November 2019

Abstract
Glioblastoma (GBM), the most aggressive primary brain malignancy, consists of diverse cell subpopulations expressing a variety of cell lineage markers. Improvements in GBM therapy and survival require a deeper knowledge of the shifting subpopulations of tumorigenic cells within typical GBMs and their relative vulnerabilities. GBM development is associated with the appearance of highly proliferative tumor cells that lead to a hypoxic, metabolically reprogrammed, immunosuppressive microenvironment that favors tumor progression. In addition, GBM contains self-renewing, tumorigenic cancer stem cells (CSC) that contribute to tumor initiation and therapeutic resistance. Using a combined multicolor immunofluorescent and Hematoxylin and Eosin (H&E) staining approach with archival formalin-fixed, paraffin embedded tissue from primary, recurrent, and autopsy glioblastoma specimens, we have investigated the complex topology of the GBM microenvironment with particular focus on the association and distribution of several important functional and metabolic markers. High-resolution tissue image analysis permitted precise colocalization and quantification of four biomarkers (Ki-67, GLUT1, Nestin, Hif-1a) of the entire specimen image and at the single cell level. Our results demonstrate discrete subpopulations with specific regional localization with respect to blood vessels and to each other. In particular, highly proliferative Nestin-positive cells are preferentially located near blood vessels. These cells do not express GLUT1 and are Hif-1a positive. In contrast, GLUT1-positive cells are negative for Nestin, demonstrate low proliferation, and are preferentially located at the zones of pseudopalisading necrosis, furthest from blood vessels. In addition, GLUT1-positive cells show reduced Hif-1a expression compared to Nestin-positive cells. Our novel approach provides a means to identify, characterize, and monitor the changing nature of GBM before and after various treatment modalities with the ultimate aim of revealing selective vulnerabilities in order to retard or cure this neoplasm.
ACTR-62. PHASE I TRIAL OF TG02 PLUS DOSE-DENSE OR METRONOMIC TEMOZOLOMIDE FOR RECURRENT HIGH-GRADE ASTROCYTOMA IN ADULTS
Authors: Wu Jing , Bryla Christine , Su Yu-Ting , Grajkowska Ewa , McCoy Ann , Boris Lisa , Antony Ramya , Garren Nancy , Siegel Christine , Cordova Christine , Aboud Orwa , Vera Elizabeth , Lawhon Tracy , Penas-Prado Marta , Theeler Brett , Mendoza Tito , Armstrong Terri , Yuan Ying , Gilbert Mark 
Published: November 2019

Abstract

BACKGROUND
Therapies targeting multiple survival pathways are desirable for high-grade gliomas. TG02 (Zotiraciclib), a CDK9 inhibitor, regulates transcription and metabolism of tumor cells and synergizes with temozolomide. A phase I/II trial was launched to test the TG02/temozolomide combined treatment in recurrent high-grade astrocytomas. Phase I results are reported here.

METHODS
Adults with recurrent high-grade astrocytoma, KPS≥60, adequate organ function, < 2 prior relapses were enrolled. Primary endpoint was dose limiting toxicity (DLT) in cycle1 in each arm. Bayesian optimal interval design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days1,12,15, and 26) and temozolomide, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm1) or metronomic (MN; 50mg/m2/d, Arm2) dosing schedule on a 28-day cycle.

RESULTS
Thirty-eight patients were evaluable; median age 50.7, KPS 90. Of 18 evaluable patients in Arm1, at TG02 dose-level 200mg, 1/6 had a DLT: Gr3 diarrhea; at dose-level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm2, at TG02 dose-level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia; at dose-level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia; at dose-level 300mg,1 of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST. TG02 dose-level of 250mg was declared as the MTD in both Arms. Using the MDASI-BT, patients with high symptom burden had increased symptoms during cycle1 but became stable as they continued treatment.

CONCLUSION
The combination of TG02 at the MTD of 250mg with DD or MN temozolomide was tolerated. Cohort expansion continues at the MTD in both arms. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation.