bluuebunny/crossref_metadata_2025 huggingface dataset:
ATIM-24. DOSE FINDING AND DOSE EXPANSION TRIAL OF D2C7 IMMUNOTOXIN (D2C7-IT) ADMINISTERED INTRATUMORALLY VIA CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMA (MG)
Authors: Desjardins Annick , Randazzo Dina , Chandramohan Vidya , Peters Katherine , Johnson Margaret , Threatt Stevie , Bullock Chevelle , Jackman Jenny , Healy Patrick , Lipp Eric , Sampson John , Friedman Allan , Friedman Henry , Ashley David , Bigner Darell
Published: November 2019

BACKGROUND

D2C7-IT is a recombinant immunotoxin comprised of a dual-specific antibody fragment targeting EGFRwt and EGFRvIII and a genetically engineered form of the Pseudomonas exotoxin, PE38-KDEL. We report results of a phase 1 trial, with dose expansion at the selected phase 2 dose, evaluating D2C7-IT delivered intratumorally by CED.

METHODS

Eligible patients are adults with recurrent supratentorial WHO grade III or IV MG; solitary tumor; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS >70%. Two patients per dose level (DL) were to be enrolled in the dose escalation portion (dose range: 40ng/mL to 23,354ng/mL), followed by dose expansion at the selected phase 2 dose (DL13).

RESULTS

As of 6/07/2019, 51 patients have been treated; 10 patients on the phase 2 dose. Observed dose limiting toxicities include: grade 4 seizure (n=1) on DL3, grade 3 confusion and pyramidal tract syndrome (n=1) on DL13, and grade 4 cerebral edema (n=1) and grade 3 dysphasia (n=1) on DL17. Grade 3 or higher adverse events possibly related to D2C7-IT include: seizure (grade 4, n=2, grade 3, n=3), cerebral edema (grade 4, n=1), hydrocephalus (grade 3, n=5), headache (grade 3, n=4), hemiparesis (grade 3, n=4), dysphasia (grade 3, n=4), lymphopenia (grade 3, n=3), thromboembolic event (grade 3, n=3); and one each of grade 3 elevated ALT, urinary tract infection, fall, wound complication, generalized muscle weakness, confusion, encephalopathy, and somnolence. Fourteen patients are alive. Three patients have partial radiographic response and remain alive without additional therapy more than 46, 27 and 21 months after D2C7-IT infusion.

CONCLUSION

Dose level 13 was selected as the optimal phase 2 dose and patient accrual is ongoing on the dose expansion arm. Encouraging efficacy results have been observed. A trial of D2C7-IT with checkpoint inhibitor is planned to start in the near future.
ATIM-25. PD-1 INHIBITION CAN BE COMBINED WITH IL-12 IN SUBJECTS WITH RECURRENT GLIOBLASTOMA
Authors: Chiocca Ennio , Lukas Rimas , Rao Ganesh , Buck Jill , Demars Nathan , Smith Amy , Miao John , Zhou John , Gelb Arnold , Cooper Laurence
Published: November 2019

Monotherapy with intratumoral Ad-RTS-hIL-12 (Ad), a novel gene therapeutic conditionally expressing IL-12 under the transcriptional control of oral veledimex (V, 20 mg) acting via the proprietary RheoSwitch Therapeutic System® (RTS®), was shown in a phase 1 Main study (NCT02026271) to elicit a sustained intra-tumoral activated cytotoxic T-cell response with co-expression of PD-1. Additionally, the Main study showed improved median overall survival (mOS), compared to historical controls, in subjects with recurrent glioblastoma (rGBM) receiving Ad + V. Herein, we report updated findings from on an ongoing open label, dose-escalation Phase 1 substudy (NCT03636477) evaluating safety and tolerability of local, controlled IL-12 plus nivolumab in adult subjects with rGBM. Ad was administered by single intratumoral injection (2 x 1011 viral particles) on Day 0 plus V (10 and 20 mg) PO QD x 15 with nivolumab (1 and 3mg/kg) IV on Days -7, 15, then Q2W. Subjects have been accrued into three cohorts and follow-up is ongoing. Data from all three cohorts regarding dose escalation of V and nivolumab will be presented. The initial safety profile during V dosing period was similar to Ad+V monotherapy with adverse reactions being dose-related and rapidly reversible upon discontinuation of V. And those adverse reactions during the follow on nivolumab dosing were tolerable and manageable and consistent with nivolumab labeling, with no synergistic toxicities, and drug-related deaths. In the first two cohorts (where data is available), combination therapy improved the biomarker “cytoindex” (ratio of circulating CD8+ T cells to FoxP3+ regulatory T cells). (In the Main study, cytoindex correlated with overall survival). Controlled IL-12 production using Ad+V with nivolumab is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile. Further phase 2 investigation of Ad+V plus a checkpoint inhibitor in rGBM is planned.
ACTR-01. PHASE I/II STUDY OF TEMOZOLOMIDE PLUS NIMUSTINE CHEMOTHERAPY FOR RECURRENT MALIGNANT GLIOMAS: KYOTO NEURO-ONCOLOGY GROUP
Authors: Aoki Tomokazu , Arakawa Yoshiki , Ueba Tetsuya , Oda Masashi , Nishida Namiko , Akiyama Yukinori , Tsukahara Tetsuya , Iwasaki Koichi , Mikuni Nobuhiro , Miyamoto Susumu
Published: November 2019

The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemoregimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1–5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70–100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12–35%) and 8% (95% CI, 4–15%). Median PFS was 13 months (95% CI, 9.2–17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67–89%) and 49% (95% CI, 33–57%). Median OS was 11.8 months (95% CI, 8.2–14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS.
ACTR-20. EFFICACY OF INITIAL TEMOZOLOMIDE FOR HIGH-RISK LOW GRADE GLIOMAS IN A PHASE II AINO (ITALIAN ASSOCIATION FOR NEURO-ONCOLOGY) STUDY: A POST-HOC ANALYSIS WITHIN MOLECULAR SUBGROUPS OF WHO 2016
Authors: Rudà Roberta , Pellerino Alessia , Pace Andrea , Maria Carapella Carmine , Dealis Cristina , Caroli Manuela , Faedi Marina , Bello Lorenzo , Migliore Enrica , Marchese Giulia , Bertero Luca , Cassoni Paola , Soffietti Riccardo
Published: November 2019

BACKGROUND

The optimal management of high risk WHO grade II gliomas after surgery is still debated. The efficacy of initial temozolomide to delay radiotherapy and risk of cognitive defects could vary across the molecular subgroups of WHO 2016, but information on this issue are lacking.

PATIENTS AND METHODS

A post-hoc analysis has been performed on a cohort of high risk WHO grade II gliomas, who received initial temozolomide alone in phase II multicenter study, with the objective of re-evaluating the long-term results across the different molecular subgroups of the WHO 2016 classification. The primary endpoint of the study, carried out between 2007 and 2010, was response rate according to RANO, being seizure response, PFS and OS secondary endpoints.

RESULTS

Response rate (partial and minor responses) among oligodendrogliomas IDH-mutant and 1p/19q codeleted (76%) was significantly higher than that among diffuse astrocytomas either mutant (55%) or wild-type (36%). A reduction of seizure frequency >50% was observed in 87% patients and a seizure freedom in 72%. The probability of seizure reduction >50% was significantly associated with the presence of an IDH mutation. Median PFS, PFS at 5 and 10 years, median OS and OS at 5 and 10 years were all significantly longer in oligodendrogliomas IDH-mutant and 1p/19q codeleted. Of patients who did not recur or delay radiotherapy at recurrence for a median follow-up of 8.2 years, 67% and 59%, respectively, were oligodendrogliomas IDH-mutant and 1p/19q codeleted.

CONCLUSIONS

The post-hoc analysis of this phase II trial suggests that the beneficial effects of initial temozolomide prevail in oligodendrogliomas IDH-mutant and 1p/19q codeleted: thus, these tumors, when incompletely resected or progressive after surgery, especially when suffering from pharmacoresistant seizures, could receive temozolomide as initial treatment with radiotherapy and chemotherapy at recurrence. The trial was registered with EU Clinical Trials Register, EudraCT n. 2007/000386-38.
ACTR-38. A SINGLE CENTER STUDY: LONG-TERM OUTCOMES OF COMBINED CHEMORADIATION THERAPY WITH TEMOZOLOMIDE FOR NEWLY DIAGNOSED GLIOBLASTOMA IN KOREAN PATIENT
Authors: Go Kyeong-O , Young Yang Ha , Hwang Kihwan , Ho Han Jung , Soo Choi Hyoung , Jung Kim Yu , Woo Wee Chan , Ah Kim In , Choe Gheeyoung , Kim Chae-Yong
Published: November 2019

In newly diagnosed glioblastoma (GBM), Temozolomide (TMZ) during and after radiation therapy has become standard treatment. This study describes the long-term use and follow-up results of this therapy for GBM. From 2004 to 2013 in a single institute, 112 Korean patients with newly diagnosed GBM were analyzed retrospectively. The Kaplan-Meier method, the two-sided log-rank test and Cox’s regression analysis was used to determine survival and its affecting factors. The toxicities of TMZ were evaluated using CTCAE v5.0. During the median follow-up period of 18.8 months, median PFS and OS were 9.2 and 20.3 months, respectively. This better survival outcome than the Stupp’s original study might be probably a large treatment effect of a single institution, ethnicity, and associated genetic factors. The TMZ during radiation therapy was completed in 108 patients (96.4%) and TMZ after radiation therapy in 59 patients (52.7%). Eight patients presented with grade 3 or 4 hematologic toxic effects during the protocol. Sixty-six patients (58.9%) received salvage treatment because of the poor response to adjuvant treatment or progression of the disease who achieved completion of adjuvant treatment was shown significantly longer median OS (p= 0.007) and PFS (p< 0.001). Age (< 60 years), preoperative KPS score (≥ 90), the extent of resection (≥ 78% by volumetric measurement, gross total resection), and completion of the Stupp’s protocol were significant factors affecting better survival. Between the sexes, and ages over 65 years did not show any significant difference among their groups. With marginal significances, the mutated IDH-1 and the methylated MGMT promoter showed longer median PFS(p= 0.075 and 0.777, respectively) and OS (p= 0.085 and 0.131, respectively). TMZ during and after radiation therapy might be effective and safe for newly diagnosed Korean patients with GBM. Further studies about various clinical and genetic factors affecting better survival are mandatory.
ACTR-50. PRESERVATION OF NEUROCOGNITIVE FUNCTION & PATIENT-REPORTED SYMPTOMS WITH HIPPOCAMPAL AVOIDANCE (HA) DURING WHOLE-BRAIN RADIOTHERAPY (WBRT) FOR BRAIN METASTASES: LONG-TERM RESULTS OF NRG ONCOLOGY CC001
Authors: Armstrong Terri , Deshmukh Snehal , Brown Paul , Gondi Vinai , Benzinger Tammy , Gilbert Mark , Tome Wolfgang , Wefel Jeffrey , Bruner Deborah , Roberge David , Kundapur Vijayananda , Devisetty Kiran , Shah Sunjay , Usuki Kenneth , Baschnagel Andrew , Stea Baldassarre , Yoon Harold , Li Jing , Laack Nadia , Mehta Minesh , Kachnic Lisa
Published: November 2019

BACKGROUND

NRG-CC001 sought to evaluate the neuro-protective effects of avoiding the peri-hippocampal stem cell niche using intensity-modulated radiotherapy during WBRT.

METHODS

Patients with brain metastasis were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+ Memantine (M) (30Gy in 10 fractions). Standardized NCF tests and the M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) were obtained at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure defined using the reliable change index. Pre-specified secondary endpoints included patient-reported symptoms using the MDASI-BT. Time to NCF was reported as cumulative incidence (with death without NCF failure as a competing risk); between-arms differences were tested using Gray’s test. Deterioration at discrete time-points were tested using chi-square tests. MDASI-BT symptom burden, interference, and cognitive and neurologic burden were analyzed using mixed effects models and t-tests within the model using Hochberg’s multiplicity adjustment.

RESULTS

A total of 518 patients were randomized from 7/2016 to 3/2018. Median follow-up for alive patients was 12.1 mos, with no difference between arms in terms of toxicity, overall survival or intracranial progression-free survival. HA-WBRT+M was associated with lower risk of NCF failure (adjusted HR=0.739, 95% CI: 0.577–0.945, p=0.0.016), with differences first noted at 4 mos in Trail Making Test Part-B (23.3% vs. 40.4% deteriorated, p=0.012). Age did not dilute treatment effect. HA-WBRT+M was associated with reduced cognitive symptom burden in an imputed model (estimate=-0.29, p=0.0425), and also reduced overall symptom burden (p< 0.0001) and interference (p< 0.0016) at 6 mos.

CONCLUSIONS

The addition of HA to WBRT+M preserved NCF and reduced patient reported cognitive symptom burden, overall symptom burden and symptom interference and should be considered standard of care for any patient fit enough to have WBRT. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute.
ACTR-51. REMARKABLE RESPONSE OF A PATIENT WITH SECONDARY GBM TO A HISTONE DEACETYLASE INHIBITOR
Authors: Shu Hui-Kuo , Gurbani Saumya , Ramesh Karthik , Weinberg Brent , Voloschin Alfredo , Olson Jeffrey , Shim Hyunsuk
Published: November 2019

Glioblastomas are highly aggressive, grade IV tumors of glial cells that arise either as de novo primary tumors or as secondary tumors, which malignantly transformed from lower grade gliomas. Secondary glioblastomas have a relatively low incidence making up 5–10% of all glioblastoma diagnoses and tend to occur in younger patients. However, these tumors are still quite aggressive with survival outcomes that do not differ substantially from primary glioblastomas. Secondary glioblastomas also often harbor mutation of isocitrate dehydrogenase (IDH) enzyme, which produces the oncometabolite 2-hydroxyglutarate (2-HG) from alpha-ketoglutarate (α-KG). The accumulation of 2-HG has several downstream effects due to its competitive inhibition of α-KG-dependent enzymes, including epigenetic modification via hypermethylation of histones. Histone deacetylase inhibitors (HDACi) are a class of molecules that inhibit histone deacetylation and have been shown to have anti-tumor effect in part due to this epigenetic modification. Thus, because of their shared targets with regard to histone modification, it is plausible that HDACi could counter the oncometabolite effects of accumulated 2-HG in IDH1 mutant tumors. Since belinostat is a pan-HDACi that has improved blood-brain barrier penetration compared to many other HDACis, we conducted a pilot study that enrolled 15 patients examining its upfront use for the treatment of glioblastomas and found that it was well tolerated. One patient in particular, likely with secondary glioblastoma harboring the typical IDH1 mutation, underwent treatment with standard chemoradiation as well as belinostat on this study. For this case, a remarkable improvement in tumor burden with very significant decrease in enhancing residual tumor and restoration of magnetic resonance spectroscopy (MRS)-detectable metabolism was noted. Furthermore, improved neurocognitition and quality-of-life were also observed in this patient during the 18-month follow-up period. Collectively, these outcomes potentially support the use of belinostat as an adjuvant therapy for patients with secondary glioblastoma that harbor a mutant IDH enzyme.
ACTR-54. VIGILANT OBSERVATION OF GLIADEL WAFER IMPLANT (VIGILANT) REGISTRY: INTERIM ANALYSIS
Authors: Lillehei Kevin , Kalkanis Steven , Liau Linda , Olson Jeffrey , Paleologos Nina , Ryken Timothy , Johnson Tania , Scullin Evan
Published: November 2019

INTRODUCTION

The Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) was initiated to evaluate the use of BCNU wafers for treatment of CNS malignancies in contemporary practice and in the new era of molecular analysis.

METHODS

The VIGILANT registry is an observational study. Each patient receives usual care from treating physicians in routine quarterly visits, with no registry-specific visits required. The VIGILANT registry will enroll up to 500 patients at 35 US sites. Patients must be ≥18 years of age with no medical conditions increasing risk through participation. Patient follow-up will last 3 years.

RESULTS

The interim analysis is ongoing, with the following preliminary data. Of the 143 patients enrolled to date (mean age 59.8 ± 13.41 years, 60.1% male, 82.5% white), BCNU wafers have been implanted for newly diagnosed glioblastoma (GBM) in 49 (34.3%); for recurrent GBM in 48 (33.6%); for brain metastases in 28 (19.6%); for anaplastic oligodendroglioma in 4 (2.8%); and for other CNS tumors in 14 (9.8%). For patients with recurrent GBM, the median time from prior to current CNS tumor diagnosis was 341.5 days (IQR 88, 890). The majority of recurrent GBM patients had previously undergone systematic chemotherapy (87.5%) and radiation therapy (70.8%); only 8 (16.7%) had previously received BCNU wafers and only 4 (8.3%) had previously undergone alternating electric-field therapy. Of patients with brain metastases, 15 (51.7%) had previously undergone stereotactic radiosurgery. Of GBM patients with baseline biomarker assessments, MGMT promoter status was methylated in 52.1% (37/71), and IDH1 mutation status was positive in 15.9% (11/69). Median survival and contemporary practice patterns will be available at the time of presentation.

CONCLUSIONS

In the VIGILANT registry to date, BCNU wafers have been implanted most often and with equal frequency for treatment of newly diagnosed and recurrent GBM. Preliminary safety and efficacy data are pending.
SURG-15. SURVIVAL OUTCOMES FOLLOWING RE-RESECTION FOR RECURRENT GLIOBLASTOMA MULTIFORME
Authors: Hennessy Maeve , Dablouk Mohamed , Mullally William , O’Halloran Philip , MacNally Stephen , Morris Patrick
Published: November 2019

BACKGROUND

While the treatment of primary Glioblastoma Multiforme (GBM) is well defined, the role of surgical resection in recurrent GBM is not firmly established.1 Treatment options for recurrent GBM include second-line chemotherapy, re-irradiation and surgical re-resection.2 This review examines current practice in a national neuro-oncology centre. AIMS: To investigate survival outcomes in patients undergoing surgical re-resection for recurrent GBM in our institution and to compare our findings to the relevant published literature.

METHODS

A retrospective review of our institution’s neuro-oncology database was performed. We evaluated all patients who underwent re-resection for recurrent GBM following standard adjuvant treatment between 2015–2018. Patients who did not have an initial diagnosis of Grade 4 GBM and patients who were re-operated on within one month were excluded. We analysed overall survival using Kaplan Meier curves. Patients not known to have died were censored to the last known alive date. We also examined factors which may affect patient outcome, including age, sex, extent of resection, tumour characteristics and tumour location.

RESULTS

34 patients were eligible for inclusion into this study, of these 21 (61%) were male. Median age was 52. A radiologically confirmed initial resection of > 80% was achieved in 52% of patients. Median time from initial surgery to re-resection was 13.5 months. Median survival from initial surgery was 28.6 months and median survival after re-resection was 9.5 months.

CONCLUSION

Re-operation appears to have a role in the management of recurrent GBM in carefully selected cases. Overall survival in this patient cohort remains poor and further studies into the benefit of re-resection in comparison to second-line chemotherapy and re-irradiation would be of value.
SURG-18. 5-AMINOLEVULINIC ACID FLUORESCENCE (5-ALA) GUIDED RESECTION OF GLIOBLASTOMA, LESSON LEARNED FROM 19 CASES
Authors: Cho Jinmo
Published: November 2019

BACKGROUND

5-ALA is known as useful tool for high grade glioma resection and the accumulation extent of 5-ALA is known as far beyond gadolinium enhancement. Extent of resection is key factor for favorable outcome and long-term survival for high grade glioma patients and 5-ALA might increase extent of resection. We present our experience of 5-ALA guided glioma surgeries

METHODS

Total 19 patients were performed 5-ALA guided surgery. They ingested 20mg/kg, four hours before craniotomy. We tried to perform supra-total resection rather than gross total resection according to the tumor consistency and if the tumor located relatively non-eloquent area, we tried to perform lobectomy rather than lesionectomy. After tumor resection, we inspect the tumor bed under 5-ALA fluorescence, and we confirmed the complete loss of fluorescence on the tumor resected bed. We check the MRI within 48 hour after operation and assess the extent of resection

RESULTS

Among the 19 patients, 15 patients were confirmed glioblastoma and 3 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. We confirmed all enhancing lesion was completely removed, however, 2 patients show residual non-enhancing lesion in post-operative MRI. Two patients suffered temporary hemiparesis and 2 patients show permanent visual field defect.

CONCLUSION

5-ALA is useful tool for glioma surgery. Resection extent could be increased, however, non-enhancing lesion in the high grade gliomas, might be missed under 5-ALA guidance.
ACTR-60. A PHASE 2, HISTORICALLY CONTROLLED STUDY TESTING THE EFFICACY OF TTFIELDS WITH ADJUVANT TEMOZOLOMIDE IN HIGH-RISK WHO GRADE II AND III ASTROCYTOMAS (FORWARD)
Authors: Tran David , Ghiaseddin Ashley , Allen Anne
Published: November 2019

BACKGROUND

A long-standing observation in neuro-oncology concerns a group of patients with WHO Grade II and III gliomas expressing isolated hTERT promoter mutations, which exhibit indolent histological features but are highly aggressive and resistant to standard chemoradiation therapy. These patients show an overall survival rate similar to glioblastoma WHO Grade IV, necessitating new treatment options. This represents the first study of its kind testing novel treatment for this rare subgroup of lower grade gliomas with high-risk cytogenetics.

METHODS

This Phase 2, single arm, multicenter open label study [NCT03906448] will enroll 100 adult patients with newly diagnosed WHO grade II and III astrocytoma without IDH mutations and 1p/19q codeletions and with isolated hTERT promoter mutations who have completed standard radiotherapy with concurrent temozolomide, followed by adjuvant temozolomide for 12 cycles in combination with 24 months of TTFields therapy. The primary endpoint is overall survival compared to historical controls. Secondary endpoints are safety, quality of life, and progression free survival. Correlative studies will examine the effect of TTFields on intratumoral immune microenvironment and the role of electric field distribution on disease control and outcomes. Sample size was based on improvement in median OS versus historical controls (N=59; median survival 22 months). Improvements in median overall survival was based on a one-sided Wald test of the Weibull regression coefficient (H0: beta=0, alpha=0.05). A consortium of 15 institutions across the US will participate, with the first enrollment May 2019. Total accrual of 100 is planned over 36 months. The survival results and the correlative studies are designed to provide new insights for future therapeutic development for these patients.
SURG-25. LASER INTERSTITIAL THERMAL THERAPY (LITT) FOR INTRACRANIAL LESIONS: A SINGLE- INSTITUTIONAL SERIES, OUTCOMES AND REVIEW OF THE LITERATURE
Authors: Dabecco Rocco , Yu Alexander , Ranjan Tulika , Xu Linda , Aziz Khaled
Published: November 2019

INTRODUCTION

Laser interstitial thermal therapy (LITT) is a minimally invasive treatment method that provides surgeons with cytoreductive techniques to treat neurosurgical conditions such as primary brain neoplasms, brain metastases, radiation necrosis, and epileptogenic lesions, many of which are located in operative corridors that would be difficult to address via open surgical or are amenable via minimally invasive approaches. Although the use of lasers is not a new concept in neurosurgery, advances in technology have enabled surgeons to perform laser treatment with the aid of real-time MRI thermography as a guide. In this report, we present our institutional series and outcomes of patients treated with LITT for 8 glial neoplasms 12 brain metastases.

METHODS

We retrospectively evaluated 20 patients (7 male, 13 female; age range, 28–77 years) who underwent LITT at one or more targets from 2015–2019.

RESULTS

In our series, all patients included had prior craniotomy for either primary glioma or metastatic disease. Mean extent of ablation (EOA) was 98% on post-op MRI. Mean progression free survival varied depending on the intracranial pathology, with the glioma cohort (5 months (SDD: 3.51)) demonstrating worse outcomes than metastatic disease (8.2 months (SDD: 4.83)). Only 1 patient experienced immediate post-operative morbidity, 1 patient experienced post-operative mortality secondary to hemorrhage. Mean follow-up was 9.7 months (SDD: 5.35), with one patient lost to follow up immediately post-procedure and excluded from the study. Average hospitalization was 2.4 days (SDD: 1.0). Mean overall survival, post-diagnosis of intracranial lesion, is more favorable for metastatic lesions (48 months (SDD: 27.14)), as compared to primary glial neoplasms (31 months SDD: 11.63)).

CONCLUSION

Laser interstitial thermal therapy (LITT) is a safe, minimally invasive treatment method that provides surgeons with cytoreductive techniques to treat neurosurgical conditions. In properly selected patients, this modality offers improved survival outcomes in conjunction with other salvage therapies.
SURG-31. SPECTROSCOPIC MRI TO GUIDE BIOPSY OF LOWER GRADE GLIOMAS
Authors: Olson Jeffrey , Weinberg Brent , Gurbani Saumya , Ramesh Karthik , Schreibmann Eduard , Shu Hui-Kuo , Shim Hyunsuk
Published: November 2019

Primary brain tumors are serious and life-threatening; thus, accurate histopathologic diagnosis is critical for determining the proper clinical treatment regimen. Grade II/III gliomas (lower grade gliomas, or LGGs), including astrocytomas and oligodendrogliomas, are heterogeneous and potentially contain low- and high-grade areas within the same tumor. Therefore, it is critical to target biopsies to the most aggressive portion of the tumor to avoid tumor under-grading and under-treatment. While glioblastomas are typically targeted based on contrast-enhanced MRI, LGGs have little contrast enhancement to define targets for biopsy treatment guidance. Spectroscopic MRI (sMRI) is a high-resolution MRI imaging method which allows for detection of metabolic abnormalities such as choline and NAA in the entire brain without injection of a contrast agent. We have previously evaluated the relationship between sMRI Cho/NAA ratios and tumor infiltration in surgical specimens from high grade gliomas, demonstrating a strong correlation between sMRI results and glioma infiltration. We also used the location information to correlate sMRI data to genetic and histologic biomarkers (such as 1p19q, IDH, and MGMT). An IRB-approved pilot study to obtain sMRI prior to stereotactic biopsy has been done in 20 non-enhancing LGG cases. Patients with a suspected LGG diagnosis underwent sMRI at the time of their surgical planning MRI. sMRI images were then registered to the T1w-CE and T2/FLAIR images and imported into the Stealth neuronavigation system for biopsy planning. We found that all astrocytomas (regardless of grades) showed strongly elevated Cho/NAA, while the LGGs were hardly delineated on T1w and T2/FLAIR. We found that pathology-confirmed grade II oligodendroglioma do not have choline elevation; however, NAA was mildly decreased, myo-inositol was elevated, and creatine (Cr) was mildly elevated. sMRI is a useful tool to improve biopsy targeting in LGG patients by ensuring that the highest risk regions are sampled.
SURG-32. THE USE OF 5-AMINOLEVULINIC ACID IN LOW-GRADE GLIOMA RESECTION: A SYSTEMATIC REVIEW
Authors: Almekkawi Ahmad , El Ahmadieh Tarek , Abi-Aad Karl , Aoun Salah , EL Tecle Najib , Patel Toral , Bendok Bernard
Published: November 2019

BACKGROUND

5-aminolevulinic acid is a reliable tool for optimizing high-grade glioma resection. However, its efficacy in low-grade glioma resection remains unclear.

OBJECTIVE

To study the role of 5-aminolevulinic acid in low-grade glioma resection and assess positive fluorescence rates and effect on the extent of resection.

METHODS

A systematic review of PubMed, Google Scholar, and Cochrane was performed from the date of inception to February 1, 2019. Studies that correlated 5-aminolevulinic acid fluorescence with low-grade glioma in the setting of operative resection were selected. Studies with biopsy only were excluded. Positive fluorescence rates were calculated. Quality index of the selected papers using the Downs and Black criteria checklist was provided.

RESULTS

Twelve articles met the selection criteria with 244 histologically-confirmed low-grade glioma patients who underwent microsurgical resection. All patients received 20 mg/kg body weight of 5-aminolevulinic acid. Only 60 patients (n=60/244; 24.5%) demonstrated visual intra-operative 5-aminolevulinic acid fluorescence. The extent of resection was reported in 4 studies, however, the data combined low- and high-grade tumors. Only 2 studies reported on tumor location. Only 3 studies reported on clinical outcomes. The Zeiss OPMI Pentero microscope was most commonly used across all studies. The average quality index was 14.58 (range: 10–17) which correlated with an overall good quality.

CONCLUSION

There is an overall low correlation between 5-aminolevulinic acid fluorescence and low-grade glioma. Advances in visualization technology and using standardized fluorescence quantification methods may further improve the visualization and reliability of 5-aminolevulinic acid fluorescence in low-grade glioma resection.
TMIC-07. SYMBIOTIC MACROPHAGE-GLIOMA CELL INTERACTIONS REVEAL SYNTHETIC LETHALITY IN PTEN NULL GLIOMA
Authors: Chen Peiwen , DePinho Ronald , Alan Wang
Published: November 2019

Heterotypic interactions across diverse cell types of the tumor microenvironment (TME) can enable tumor progression and offer points for potential therapeutic intervention. Employing Glioblastoma Multiforme (GBM) as a model system, we sought to (i) understand the nature of specific oncogenic signals in glioma cells that affects immune cells, and (ii) identify immune cell factors which may support glioma growth and survival. Combined profiling and functional studies of glioma cells established that PTEN deficiency, a signature GBM alteration, specifically tracks with an immune profile dominated by tumor-associated macrophages (TAMs, a key type of immune cells in GBM which can constitute up to half of the tumor mass) via upregulation of lysyl oxidase (LOX). Mechanistically, the PTEN-SRC/AKT axis regulates YAP1, which directly upregulates LOX expression and secretion in glioma cells via binding to the LOX promoter. The secreted LOX from glioma cells functions as a potent macrophage chemoattractant to promote macrophage recruitment via activation of the beta1 integrin-PYK2 pathway in macrophages. Consequently, these infiltrating macrophages secrete SPP1 (secreted phosphoprotein 1) which sustains glioma cell survival and stimulates angiogenesis. In human and mouse PTEN-null GBM models, but not PTEN-intact GBM models, LOX inhibition markedly inhibits tumor growth and extends the survival of tumor-bearing mice by decreasing macrophage infiltration, impairing SPP1 expression and attenuating angiogenesis. In silico analysis of human GBM shows that increased YAP1-LOX and b1 integrin-SPP1 signaling positively correlates with higher macrophage density and lower overall survival. Together, the symbiotic glioma (PTEN-YAP1-LOX) and macrophage (beta1 integrin-PYK2-SPP1) interactions provide novel therapeutic targets for this intractable disease.
TMIC-09. MULTIMODAL VISIBLE LIGHT OPTICAL COHERENCE MICROSCOPY AND FLUORESCENCE IMAGING OF GLIOBLASTOMA REGIONAL SAMPLES
Authors: Gesperger Johanna , Lichtenegger Antonia , Roetzer Thomas , Widhalm Georg , Kiesel Barbara , Woehrer Adelheid , Baumann Bernhard
Published: November 2019

Optical coherence tomography (OCT) is an imaging modality based on the inherent backscattering of light within different tissue types. OCT was introduced in the early 1990s and has since become a standard diagnostic tool in ophthalmology. Images can be acquired non-destructively, in real time and three dimensions at micrometer resolution. Only recently, OCT has been increasingly recognized in other fields such as neuroimaging. Here we present a multimodal imaging approach using a custom-built visible light optical coherence microscope (OCM) combined with a fluorescence imaging mode for the evaluation of different tumor compartments in glioblastoma (GB) samples retrieved during 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery. 18 biopsies of ten GB patients were imaged using the visible light OCM system, providing the three-dimensional morphologic structure of the tissue on a cellular level (axial resolution in brain tissue 0.88 µm, penetration depth 100 µm). Attenuation coefficients, i.e., indicators for light penetration and scattering, were calculated for each sample. Tumor-specific contrast enhanced by 5-ALA was evaluated in co-registered images from the fluorescence channel. Samples were ultimately processed for histopathologic work-up and compared to OCM findings. Three different groups of biopsies could be defined based on quantitative 5-ALA fluorescence [normalized between 0 and 1], attenuation [mm-1] and histological H&E stainings: tumor core (n=8; fluorescence [median ± standard deviation]=0.72±0.13, attenuation [median ± standard deviation]=3.9±0.66), infiltration zone (n=6; fluorescence=0.5±0.19, attenuation=4.4±0.5), and adjacent brain parenchyma (n=4; fluorescence=0.3±0.12, attenuation=5.0±0.79). Concurrent increase in fluorescence intensity and cell density was significantly associated with tissue malignancy (tumor core: 3849±1028 nuclei/mm²; brain parenchyma: 1364±236 nuclei/mm². p=0.024). Furthermore, a negative correlation between fluorescence and attenuation coefficient was detected (r=0.51, p=0.032). Aforementioned results suggest that this multimodal imaging setup is a promising approach for non-destructively investigating the three-dimensional morphologic structure at microscopic resolution whilst at the same time leveraging tumor-specific contrast through 5-ALA fluorescence.
TMIC-10. THE ROLE OF THE BRAIN MICROENVIRONMENT IN THE MIGRATION OF BREAST CANCER CELLS IN BRAIN METASTASES
Authors: Kersch Cymon , Muldoon Leslie , Morris DreeAnna , Neuwelt Edward
Published: November 2019

BACKGROUND

Breast cancer brain metastases have poor prognosis and few treatment options. When breast cancer cells invade the brain they interact with the vasculature and resident brain cells including microglia and astrocytes. We hypothesize that brain cells produce factors that enhance the growth and invasion of breast cancer cells in the brain.

METHODS

Human breast cancer cell lines (MDA-MB231BR-HER2 and HCC1954) were inoculated intracranially in athymic rats as xenograft models of brain metastasis. Brains were analyzed for pro-tumorigenic factor expression in the tumor microenvironment using fluorescent immunohistochemistry. In vitro assays assessed factors involved in breast cancer cell proliferation, morphology, and migration.

RESULTS

The tumor xenografts showed infiltration intothe perivascular space. Galectin-3 (Gal3), heparin-binding epidermal growth factor (HB-EGF), and Neuregulin (NRG1), factors known to interact with receptors expressed by breast cancer cells, co-localized with reactive microglia (Gal3) and astrocytes (HB-EGF and NRG1) in and around xenografts. In vitro, these factors individually increased HCC1954 cell proliferation and/or migration. In transwell co-culture assays, BV2 microglial cells increased the migration of HCC1954 cells >25 fold, which was prevented by cilengitide, an inhibitor of αvβ3-integrin cell adhesion protein. ELISA analysis demonstrated that BV2 microglia secrete Gal3 in the presence of HCC1954 cells. Gal3 is known to bind and induce clustering of αvβ3-integrin which is expressed on metastatic breast cancer cells. Immunohistochemistry of clinical specimens revealed that Gal3 is expressed in/around human breast cancer brain metastases.

CONCLUSIONS

These data suggest that factors produced in the tumor microenvironment promote the growth and migration of breast cancer cells in the brain. Gal3, produced and secreted by activated microglia in vitro and expressed in and around brain metastases, increases the invasive capability of breast cancer cells. The interactions of neoplastic cells with the brain environment may provide a target to improve therapy of brain metastases.
TMIC-15. HYPERACTIVATING THE HIPPO PATHWAY EFFECTOR TAZ DIFFERENTIALLY DISTORTS THE TUMOR MICROENVIRONMENT, PROMOTES TUMOR-ASSOCIATED NEUTROPHIL INFILTRATION, AND PHENOCOPIES MESENCHYMAL-GLIOBLASTOMA
Authors: Yee Patricia , Wei Yiju , Liu Zhijun , Guo Hui , Manjibhai Vekariya Umeshkumar , Anderson Benjamin , Li Wei
Published: November 2019

Glioblastoma (GBM), the deadliest and most common adult brain malignancy, is molecularly and clinically heterogeneous. The most common subtype (both primary and recurrent), mesenchymal (MES)-GBM, has the worst prognosis and highest treatment resistance. MES-GBM exhibits hyperactive transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo tumor suppressive pathway effector whose expression in GBMs predicts short survival. Yet, how Hippo-TAZ dysregulation might drive GBM MES transition remains elusive, precluding subtype-specific treatments. Tumor evolution requires signaling dysregulation and co-opting the tumor microenvironment (TME). Understanding GBM heterogeneity was recently complicated by the notion that subtypes vary in TME immune composition. The MES-GBM TME is differentially-distorted in silico, with more tumor-associated macrophages/microglia (TAMs) and neutrophils (TANs). Yet, how TAZ hyperactivity, MES transition, and GBM TME distortion interrelate and impact tumor progression remains unknown. We suspected that TME distortion facilitates immune evasion, MES transition, and tumor progression, worsening treatment responses. To test this, we devised an orthotopic xenograft mouse model phenotypically and histopathologically recapitulating human MES-GBM by expressing constitutively-active TAZ (TAZ4SA) in human GBM cells lacking MES signatures (GBM4SA). GBM4SA mice lived significantly shorter compared to mice with GBM expressing vector (GBMvector) or mutant TAZ unable to bind its effector, TEAD (GBM4SA-S51A). Moreover, more myeloid cells infiltrate the GBM4SA TME than the GBMvector or GBM4SA-S51A TMEs. While most myeloid cells infiltrating the GBMvector and GBM4SA-S51A TMEs were TAMs, most infiltrating the GBM4SA TME were TANs, suggesting TAZ hyperactivation differentially distorts the TME. Next, to delineate the roles of TANs in GBM4SA tumor progression, mice were depleted of neutrophils by administering Ly6G antibody. Serial blood smears and flow cytometry revealed effective depletion was achieved. We are currently investigating the impact of systemic neutrophil depletion on GBM mesenchymal transition and tumor progression in hopes of informing future GBM clinical management and novel TME-targeted immunotherapies.
TMIC-24. COLONY STIMULATING FACTOR 1 INHIBITION DECREASES TUMOR GROWTH AND MACROPHAGE INFILTRATION, AND INCREASES NEUTROPHIL INFILTRATION IN XENOGRAFT MICE MODELS OF GLIOBLASTOMA
Authors: Khan Sabbir , Piao Yuji , Mittal Sandeep , McGee Kain , Park Soon , Alfaro-Munoz Kristin , Balasubramaniyan Veerakumar , DeGroot John
Published: November 2019

Glioblastoma (GBM) is the most common, highly aggressive and lethal primary brain tumor in adults, and has a median overall survival ranging from 12 to 15 months. Several human cancers including glioma are infiltrated with numerous immune cell types which play a critical role in tumor growth, invasion and resistance to treatment. Previous studies, including our group, have shown that resistance to anti-VEGF therapy is associated with myeloid cell infiltration and mesenchymal transition in GBM. Notably, most glioma patients have shown increase in CD68+ cells due to overproduction of colony stimulating factor 1 (CSF-1) by tumor cells, a growth factor for macrophages. Therefore, we hypothesized that CSF-1 inhibition may reduce macrophage and/or myeloid cell infiltration in glioma, thereby increasing animal survival as monotherapy or in combination with VEGF inhibitors in xenograft GBM mouse models. We tested two CSF-1R inhibitors (AZD 7507 and JNJ-28312141) alone and in combination with VEGF inhibition to prevent macrophage infiltration in xenograft GBM mouse models. CSF-1R and VEGF inhibitors reduced macrophage infiltration (F4/80 staining), tumor volume, and mesenchymal transition (YKL-40 staining), and there was a marginal survival benefit in this model. Interestingly, despite significant reduction in tumor macrophages, we observed a significant increase in neutrophil infiltration and hypoxia (HIF1α staining), particularly in the combinatorial treated. Considering these observations, we further evaluated tumor-associated neutrophil (TAN) infiltration in GBM patient tumors by fluorescence-activated cell sorting (FACS). FACS-isolated TANs were identified as CD11b+/CD15+/CD66b+ triple positive. Our results shown that the infiltrating TAN population vary from 0.5 to 5% in GBM patient tumors. Detailed characterization of TAN population and polarization in patient tumors are ongoing. Our findings revealed that CSF-1 and VEGF inhibition reduced macrophage infiltration and tumor growth, but significantly increased TAN infiltration which will likely hamper the potential therapeutic benefit of anti-CSF1-directed inhibitors.
TMIC-37. INTERCELLULAR COMMUNICATION BETWEEN NORMAL AND TUMOR CELLS IN GLIOMA MICROENVIRONMENT
Authors: Hossain Anwar , Hasan Irtiza , Adachi Satoshi , Ledbetter Daniel , McDonald Malcolm , Gumin Joy , Daou Marc , Phillips Lynette , Parker-Kerrigan Brittany , Lang Frederick
Published: November 2019

The interactions between tumors cells and their microenvironment are increasingly recognized as contributors to tumor growth and therapeutic resistance in glioblastoma (GBM). Mesenchymal Stem Cells (MSCs) have been implicated as components of the microenvironment of several cancers, but their contribution to GBM remains obscure. Recently we reported that GBMs contain cells resembling human mesenchymal stem cells, called Glioma-associated-MSCs (GA-hMSCs), based on our ability to isolate these cells from patient tumors (Figueroa, et al. Can Res 2017. 77, 5808–5819). In order to characterize the function of these cells in vivo, we used a PDGFRb promoter driven mouse model to track and modulate the behavior of endogenous MSCs (PDGFRb + cells). To generate tumors that mimic gliomas, we injected the RCAS-PDGF avian retrovirus into PDGFRb EGFP/nTVA mice. These mice express EGFP in PDGFRb expressing cells and RCAS receptor TVA under the control of the Nestin promoter and develop tumors. Immunostaining these tumors for GFP and CD31 determined that MSC like cells reside around blood vessels and are likely the major contributor of microvascular proliferation often seen in human gliomas. Additionally, we sought to see if there was communication between MSCs localized around blood vessels and the tumor. To this end, mice with Cre recombinase expression under the PDGFRb promoter were implanted with a GL-261 tumor harboring a dsRed/eGFP Cre recombinase/LoxP site. In these mice, tumor color change from red to green indicates transfer of Cre mRNA or protein from PDGFRb+ cells (MSCs) to tumor cells (GL-261dsRed/eGFP). We observed red to green transition in tumors, indicating that there is transfer of mRNA or protein, and further suggesting that there is direct communication between the tumor microenvironment and the tumor. Taken together, our findings emphasize the crucial role of MSCs in the tumor microenvironment.
TMIC-41. PROSTATE SPECIFIC MEMBRANE ANTIGEN EXPRESSION IN PRIMARY AND RECURRENT GLIOBLASTOMA
Authors: Lozinski Mathew , Fay Michael , Bowden Nikola , Graves Moira , Tooney Paul
Published: November 2019

Patients with glioblastoma almost always suffer a recurrence of an aggressive treatment resistant tumour and succumb within months highlighting the need to develop treatment options for recurrent glioblastoma. One potential target is prostate specific membrane antigen (PSMA) expressed on the new vessels in primary glioblastoma tumours. This study compared the expression of PSMA in primary and recurrent glioblastoma tumours. Formalin-fixed paraffin-embedded sections of primary and matched recurrent tumours from 13 patients with glioblastoma were processed for PSMA immunohistochemical labelling. PSMA expression was scored from digitally scanned sections using a categorical system (Total PSMA expression = PSMA label intensity (0–3) x percent PSMA-positive blood vessels). Little PSMA labelling was observed in any adjacent ‘unaffected’ brain tissue. PSMA was localised to blood vessels including those displaying microvascular proliferation in 12/13 primary and 9/13 recurrent glioblastoma tumours. Total PSMA expression scores ranged from 0 – 230 (maximum score = 300) and was divided into low and high expression based on a median split (median = 57) of PSMA expression across all tumours. Regression analysis showed a significant difference in PSMA expression between primary and recurrent glioblastoma (p = 0.04) with PSMA being highly expressed in ~70% of primary and only 31% of recurrent glioblastoma. Three cases displayed high expression in both primary and recurrent glioblastoma and one case had no PSMA expression at all. In conclusion, whilst higher expression of PSMA was detected in more primary tumours, 70%+ of all primary and recurrent tumours expressed PSMA to some extent adding evidence that this may be a useful target for treatment of glioblastoma. Larger cohorts and other techniques for detecting PSMA are needed to provide further evidence for PSMA’s utility as a target and to further define which glioblastoma patients are most likely to benefit from this approach.