bluuebunny/crossref_metadata_2025 huggingface dataset:
P17.12.B LEPTOMENINGEAL DISEASE FOLLOWING POSTOPERATIVE RADIOSURGERY IN RESECTED BRAIN METASTASES: LONG TERM FOLLOW UP OF A PHASE 2 STUDY
Authors: Navarria P , Pessina F , Clerici E , Bellu L , Politi L , Vernier V , Raspagliesi L , Bono B , Franzini A , Scorsetti M
Published: October 2024

BACKGROUND

Brain metastases (BMs) affect about 20-40% of patients with solid primary tumors, and as many as 25% of patients will harbor large BMs. Surgical resection followed by postoperative stereotactic radiosurgery has become the standard modality to treat large BMs, given the ability to obtain a satisfactory local control with neurocognitive preservation. Notwithstanding the excellent outcome of a combined treatment approach, one concern is the potential risk of developing leptomeningeal disease (LMD) occurring in up to 30% of patients receiving surgical resection followed by postoperative SRS. We evaluated LMD in patients enrolled in prospective phase 2 study treated with surgery followed by hypofractionated radiosurgery (HSRS) on the tumor bed in oligometastatic patients with single large brain metastases (BMs). Local control (LC), brain distant failure (BDF), overall survival (OS), and prognostic factors related to LMD were analyzed too.

MATERIAL AND METHODS

A retrospective review of patients treated into a prospective phase 2 study with surgery followed by HSRS on the tumor bed from June 2015 and May 2018 has been performed. Patterns of LMD were determined radiographically based on the first MRI at which LMD was diagnosed. Prognostic factors for LMD have been evaluated as well. LC was assessed using Response Assessment in Neuro-Oncology criteria, BDF defined as the appearance of new BMs in other brain sites in respect to the treated ones. OS was calculated from BMs treatments. Cause of death was defined as neurologic in case of diffuse brain or meningeal progression, and systemic in case of diffuse extracranial progression with controlled brain disease.

RESULTS

One hundred and one patients were included in the present analysis. The median follow up time for the whole cohort was 25 months (range 3-109 months) and 79 months (range 67-91 months) for alive patients. LMD has been recorded in 20 (19.8%) patients at a median time of 9 months (range 3-47 months) from surgery. For patients with LMD the median OS time, 6-month, 1-year, and 2-year OS rates were 16 months, 95%, 75%, and 20%, respectively compared to 20 months, 93%, 80.6%, and 38.7%, respectively for those with BDF only without LMD. According to logistic regression analysis, the infratentorial site (p=0.04) and meninges not surgically removed (p=0.01) influenced the development of LMD. At long term follow up the 2, 5 years LC, BDF, and OS rates 87%, 78%; 50.4%, 56.8%; 49.5%, 23.8% respectively. The occurrence of LMD significantly influenced OS (p=0.01).

CONCLUSION

Surgery followed by HSRS on the tumor bed is an effective and safe treatment approach. LMD conditioned a worse outcome. In the future the employ of preoperative HSRS could represent a valid approach to potentially reduce this adverse event.
P17.15.A PATTERNS OF CARE AND OUTCOMES IN BRAIN METASTASES FROM BILIARY TRACT CANCERS IN THE UNITED STATES: A REAL-WORLD ANALYSIS
Authors: Jayram D , Ozair A , Ahmad S , Bellur S , Frias Perez N , Podder V , Ahluwalia M
Published: October 2024

BACKGROUND

Biliary tract cancers (BTC) are frequently diagnosed late in their disease course. Brain metastases (BM)s from BTC, while rare, lack contemporary literature. This study describes patient characteristics, patterns of care, and outcomes of BM from BTCs in the United States (US).

MATERIAL AND METHODS

This retrospective study was conducted following ESMO ‘Guidance for Reporting Real-World Oncology Evidence’ (GROW) guidelines using the National Cancer Database, a nationally representative US database capturing > 70% of oncology outcomes, for BTC BMs from 2010-2020. Patient attributes and patterns of care were analyzed with descriptive statistics. Kaplan-Meier estimation was used for median overall survival (mOS, 95% CI).

RESULTS

Of 88,274 BTC patients, 0.16% had BM (n=138). Median age was 65 years (IQR 58-74). Of patients with BMs, 50.7% were female. 78.26% were White, 13.04% Black, 1.45% Asian. 16.7% were Hispanic. Incidence proportion of patients with BMs increased from 5.8% (n=8) in 2010 to 12.32% (n=17) in 2020. 50.72% (n=70) had Medicare, 13.04% (n=18) Medicaid, 29.7% (n=41) were privately insured, and 4.4% (n=6) were uninsured. 46.4% (n=64) cases originated from the extrahepatic bile duct, 8.7% (n=12) in the ampulla of Vater, 2.9% (n=4) in the overlapping area of biliary tract, and 34.8% (n=58) were not specified. 41.3% (n=57) received no treatment. mOS for the whole cohort was 2.2 months (CI 0.1-16.9). mOS for treated patients was 4.0 months (CI 3.1-6.9). 41.3% (n=57) received chemotherapy, 23.9% (n=33) radiation to the brain, 14.5% (n=20) radiation to other sites, and 2.2% (n=3) surgery. Among chemotherapy recipients (n=57), 78.9% (n=45) received multiagent therapy, 15.8% (n=9) received single-agent therapy, and 5.3% (n=3) lacked specified agent numbers. Of the patients who underwent cranial radiation, 69.7% (n=23) received stereotactic radiosurgery and 30.3% (n=10) received whole brain radiation. 13.7% (n=19) received both cranial radiation and chemotherapy, and 0.7% (n=1) received cranial radiation, surgery, and chemotherapy.

CONCLUSION

Patients with BM from BTCs have a dismal prognosis. Clinical trials on efficacious therapies are urgently warranted for these patients.
P17.18.B RECURRENT PINEOBLASTOMA WITH LEPTOMENINGEAL METASTASES
Authors: White J D , Baykal D , Webb M J , Neth B , Mahajan A , Kowalchuk R , Schwartz J , Sener U
Published: October 2024

BACKGROUND

Pineoblastoma is an aggressive, rare tumor of the pineal gland. Due to rarity of pineoblastoma, no large-scale prospective clinical trial data is available to guide clinical practice. Patients often receive treatment based on approaches to other high-grade embryonal central nervous system (CNS) tumors such as medulloblastoma. Multimodality treatment typically consists of maximal surgical resection followed by radiation therapy and chemotherapy. Despite treatment, recurrence is common and five-year survival rate is 60-70%. Pineoblastoma can disseminate through the leptomeninges, which is associated with poor survival. No therapy is known to confer a survival benefit in the setting of leptomeningeal disease (LMD) related to pineoblastoma.

MATERIAL AND METHODS

We report radiographic response and longer than expected survival for a patient with LMD related to pineoblastoma treated with single-agent temozolomide chemotherapy.

RESULTS

A 22-year-old male with a history of pineoblastoma presented with periodic headaches and leptomeningeal enhancement on surveillance imaging. 5 years prior to presentation (age 17), he was initially diagnosed with pineoblastoma after gross total resection followed by treatment with proton craniospinal radiation and adjuvant carboplatin/vincristine chemotherapy. Surveillance craniospinal MRIs identified diffuse leptomeningeal enhancement involving the posterior fossa and diffusely throughout the spine and lumbosacral nerve roots. While cerebrospinal fluid (CSF) cytology was negative for tumor cells on three separate occasions, CSF cell-free DNA (cfDNA) analysis isolated tumor DNA. He was started on temozolomide chemotherapy with near complete resolution of leptomeningeal enhancement on MRI after 2 cycles and complete resolution after 6 cycles. Treatment was well-tolerated with grade 1 fatigue as the only toxicity. Patient remains alive 20 months after initial diagnosis of LMD with resolution of headaches and durable radiographic response.

CONCLUSION

This case highlights utility of CSF cfDNA as a companion tool for diagnosis of LMD. Durable clinical and radiographic response achieved suggests temozolomide can be considered as a salvage treatment option for recurrent pineoblastoma with LMD.
P17.19.A RESECTION OF BRAIN METASTASES WITH FLUORESCENCE GUIDANCE - COMPARISON BETWEEN SODIUM-FLUORESCEIN AND 5-ALA
Authors: Neumeister A , Meier T , Lawson McLean A C , Andreas N , Senft C
Published: October 2024

BACKGROUND

Complete neurosurgical resection is an integral part of treatment in cancer patients with metastatic brain disease. The distinction between metastatic and healthy brain tissue is of critical importance in this context. Whereas the use of 5-ALA fluorescence has been established for gliomas, reportedly not all metastases enhance with 5-ALA. Therefore, resection using sodium-fluorescein (Na-Fl) may be more helpful to delineate tumors and their margins.

MATERIAL AND METHODS

We performed a retrospective analysis of resected brain metastases (BM) and use of intraoperative fluorescent agents from 2021 to date. The surgical reports were analyzed whether 5-ALA or Na-Fl was used and if fluorescence was visible using the specific microscope filter. The histopathological findings were then documented. Finally, a chi-square independence test was performed.

RESULTS

Of 56 patients with BM, Na-Fl was applied in 30 cases, whereas 26 BMs were resected with use of 5-ALA. Following Na-Fl-administration, in 2 of 30 cases, there was no visible fluorescence in the Yellow 560 nm filter (6.7 %), but fluorescence was positive in the remaining 28 metastases (93.3 %). In contrast, 5-ALA induced fluorescence in the Blue 400 nm filter was negative in 11 (42.3 %), positive in 10 (38.5 %). In 5 cases, the fluorescence pattern was not documented (19.2 %). The difference in positive fluorescence between Na-Fl and 5-ALA was statistically significant (p=0.0007).

CONCLUSION

In intracranial metastases, Na-Fl-induced fluorescence was more frequently observed in contrast to 5-ALA. Na-Fl can therefore be useful in the identification of brain metastases as well as the rapid and cost-effective differentiation of metastatic from healthy brain tissue. Further studies should be carried out to investigate whether use of Na-Fl influences the extent of resection.
P18.03.B ANTIBIOTIC EXPOSURE DURING RADIOTHERAPY FOR GLIOBLASTOMA MULTIFORME IMPACTS SURVIVAL
Authors: Main S , Swampillai A , Lavrador J , Al-Salihi O , Chia K , Brazil L , Manik V , Ching J , Clarke E , Reis Ferreira M
Published: October 2024

BACKGROUND

IDH wildtype Glioblastoma multiforme (GBM) is an aggressive primary brain tumour. Despite treatment with surgical resection, radiotherapy (± chemotherapy) and adjuvant chemotherapy median survival remains poor. Antibiotics influence the human microbiota and alter treatment efficacy in other tumours. This study addresses antibiotic exposure in GBM.

MATERIAL AND METHODS

A retrospective observational study based on electronic patient records March 2016-May 2022 in a large UK tertiary centre (N=234) and replicated for validation purposes in a second UK tertiary centre (N=179) over the same time period. All patients received radiotherapy 54-60Gy/30 fractions or 40Gy/15 fractions ± concurrent/adjuvant temozolomide chemotherapy. Prophylactic antibiotics with co-trimoxazole were used during concurrent chemoradiotherapy as per the Stupp protocol. Peri-operative, prophylactic and antibiotic exposures within 30 days of death were excluded. Additional antibiotic exposures were recorded from 4 weeks prior to radiotherapy to the completion/discontinuation of adjuvant temozolomide chemotherapy. Survival analysis was conducted with Kaplan-Meier methodology and Cox proportional hazard modelling using R language for statistical programming.

RESULTS

99 (42.3%) patients in the principal study cohort and 44 (31.7%) patients in the validation cohort received antibiotics. They were most commonly prescribed for respiratory infections (40.2% and 37.3%) and broad-spectrum penicillin-based (60.5% and 49.3%). There was no clear indication for prescriptions in 15.6% and 9.3% of the principal and validation cohorts respectively. Antibiotic exposure has a negative impact on survival in the principal and validation cohorts: median overall survival (mOS) 12.0 months(mo) vs 15.2 mo (P= 0.0062); mOS 12.5mo vs 19.2mo(P=0.0023). This effect is greater in those with better predictors of prognosis (i.e. MGMT promoter methylation receiving Stupp chemoradiotherapy): mOS 15.2mo vs 33.3mo (P=0.013) and mOS 9.3mo vs 27.7mo (P=0.001) in principal and validation cohorts respectively. The association of antibiotic exposure and survival compromise was resilient in multivariate analysis with established risk factors in both cohorts: hazard ratio 1.52(P=0.017) in principal cohort and 2.81(P=0.023) in validation cohort.

CONCLUSION

Antibiotic exposure reduces treatment efficacy in GBM. The human microbiome (gut/intratumoural) may well underpin the mechanism of this observed effect. Ongoing work will explore the presence and influence of the tumoural and gut microbiome in GBM. These results pose a challenge to the use of prophylactic antibiotics with chemoradiotherapy. We recommend multi-centre validation and that clinicians consider to use prophylactic antibiotics only in those with a high risk of PJP (low lymphocyte count, prolonged high dose corticosteroids).
P18.05.B ASSOCIATION OF CELLULAR DRUG RESPONSES AND METABOLIC PROFILES IN ADULT TYPE DIFFUSE GLIOMAS
Authors: Stanzer S , Bandres-Meriz J , Harbusch N , Franz J , Mahdy-Ali K , Ferreira da Silva Souza Monedeiro F , Magnes C , Zügner E , Pieber T , El-Heliebi A , Urbanic Purkart T , Wöhrer A , Prietl B
Published: October 2024

BACKGROUND

Functional precision medicine is the next step in individualized patient centered medicine, seeking to guide treatment based on ex-vivo drug response of patient-derived tumor cells (PDCs). In this study we aimed to evaluate the drug response (combination of potency and efficacy) to a panel of cytotoxic and targeted agents in PDCs isolated from IDH-mutant (mut) and -wild type (wt) gliomas. Next, we integrated these assessed drug responses with corresponding metabolomic tissue signatures reflecting the in-vivo metabolic profile of IDH-mut and -wt gliomas. To gain further insight into the aggressive behavior of IDH-wt tumors, we aimed to characterize clonal and sub-clonal metabolic heterogeneity within IDH-wt gliomas to uncover potential therapeutic vulnerabilities.

MATERIAL AND METHODS

The tumor tissues of patients with glioma were used for PDC isolation prepared by mechanical and enzymatic tissue dissociation. After short-term cultivation (7-14 days) under standard culture conditions, spheroids (n=50) were dissociated into a single-cell suspension and subjected to drug screening using a high throughput screening platform. The drug panel consisted of 80 chemotherapeutics and targeted drugs. Dose response curve (DRC) fitting per drug was performed and the area under the curve (AUC) was evaluated. Corresponding tumor tissues obtained from surgical resections were analyzed by HILIC-HRMS. We then correlated the metabolomic profiles with the drug response.

RESULTS

First analysis within this cohort (n =18) showed significantly lower AUC values (i.e. enhanced drug response) of panobinostat and vorinostat (HDAC inhibitors), AMG232 and RG7112 (MDM2 inhibitors), selinexor (exportin-1 inhibitor) and temsirolimus (mTOR inhibitor) in IDH-wt gliomas (all p<0.05). Statistical correlation analysis between AUC values and metabolite levels showed substantially more significant correlations (criteria: |r|> 0.5, p<0.05) between drug responses and metabolites in IDH-wt tumors (1329 versus 926).

CONCLUSION

These first analyses showed an association between drug response and metabolism when using a holistic approach. Additionally, these results suggested a connection between metabolic pathways and drug susceptibility. In the next step, we plan to investigate the metabolic heterogeneity of IDH-wt gliomas within the tumor in more detail to find out whether there is an influence on the response to treatment.
P18.06.A AUTOMATED DETECTION OF RESIDUAL GLIOMA TISSUE IN RECEPTION CAVITY USING OF RAMAN SPECTROSCOPY. PRELIMINARY DATE FROM SINGLE INSTITUTION STUDY
Authors: Kalita O , Ranc V , Pavlacka O , Hrabos D , Hrabalek L , Kazda T
Published: October 2024

BACKGROUND

Gliomas are the most common and the deadliest brain tumors. The most aggressive multimodal therapy (maximally radical and safe tumour resection, followed by the Stupp protocol oncotherapy) has yielded the best treatment outcomes. Neurosurgeons, thus, must compete with a considerable challenge to correctly identify the existing margins of the glioma tissue. The residues of the primary tumor or eventually formed small satellites being left aside are one of the main reasons leading to a recurrence of the disease.

MATERIAL AND METHODS

We performed, during the routine glioma resection, the tumor tissue detection on walls of the resection cavity using Raman spectroscopy. For on-site exposure we used fiberoptic probes transmit laser light and collect Raman scattering. The spectral analysis of Raman data consists of removing the spectral background, data smoothing, and a machine-learning-based discrimination model based on the decision tree learning approach. The presence of tumor tissue was confirmed by histology samplings. and/or fluorescence activity using fluorescence-guided resection (ALA). Perioperative, the results were compared with ALA activity (fluorescence-guided resection). Postoperative, the results were evaluated with an early MRI and time-to-recurrency of tumor.

RESULTS

The developed approach was first tested on more than 100 Raman spectra obtained from 15 HGG patients and showed statistically relevant results. According to our current data, Raman-guided resection is reliable and more sensitive technique than ALA-guided resection in HGG patients. To confirm our thesis we are continuously gathering data of HGG. Due to a rare occurrence of LGG patients and much more delicate distinctions in Raman spectra, now, we are in preliminary part of study.

CONCLUSION

Using Raman spectroscopy, we developed a new systematic approach for spectrally characterizing of the glioma and its surrounding tissue in real time during brain surgery. An optical-fiber-equipped instrument allows one to probe the targeted tissue spectrally before its extraction. It correctly discriminates between gliomas and surrounding healthy tissue, allowing surgeons to perform a more precise surgery.
P18.13.A DE-NOVO PURINE METABOLISM CAN BE TARGETED SAFELY IN GLIOBLASTOMA TREATMENT TO OVERCOME CHEMORADIATION RESISTANCE: AN INTERIM RESULT OF PHASE 0/1 CLINICAL TRIAL
Authors: Umemura Y , Clarke N , Al-Holou W , Elaimy A L , Scott A , Leung D , Kim M , Ferris S , Thomas J , Heth J , Schipper M , Suresh K , Lawrence T , Wahl D
Published: October 2024

BACKGROUND

Mycophenolate mofetil (MMF) is a commonly used oral immunosuppressant, which exerts its effect by its antimetabolite mechanism. Contrary to normal brain preferring to salvage purines, which is resource-efficient, glioblastoma tumor cells prefer to make new purine via de-novo purine pathway. The de-novo purine metabolism can be disrupted using MMF which inhibits IMPDH, a key enzyme in this pathway. There are pre-clinical evidence of MMF improving radiation and temozolomide efficacy in glioblastoma mouse models, which led to this first-in-human phase 0/1 trial (NCT04477200) to assess the tolerability of MMF with chemoradiation in glioblastoma, MPA accumulation, and purine synthesis inhibition in tumor.

MATERIAL AND METHODS

In the phase 0 study, eight recurrent glioblastoma patients received MMF at doses ranging 500-2000mg BID for one-week before planned surgery. The tissues were analyzed using mass spectrometry for drug accumulation and purine synthesis inhibition. In the phase 1 study, adult patients were given MMF starting at 1000mg PO BID, with the possible dose ranging 500-2000 PO BID using TITE-CRM. Nineteen recurrent glioblastoma patients (target N=30) received MMF one-week prior to and concurrently with re-irradiation (40.5 Gy). Thirty newly diagnosed glioblastoma patients received MMF one-week prior to and concurrently with chemoradiation, followed by MMF one-day before and during 5 days of each adjuvant temozolomide cycles.

RESULTS

Both enhancing and non-enhancing tumor from phase 0 subjects yielded >1µM active drug metabolite, and the GTP/IMP ratio was decreased by 75% in enhancing tumor in MMF-treated patients compared to untreated controls (p=0.009), indicating effective target engagement and inhibition of purine synthesis. In the Phase 1 study, no dose limiting toxicities (DLTs) have been observed at the interim analysis at MMF 1000-1500mg BID combined with chemoradiation. At 2000mg BID, there was no DLT combined with temozolomide alone, however, there were four DLTs noted (hemiparesis, cognitive disturbance, fatigue, thrombocytopenia) when combined with radiotherapy and temozolomide together, though all were reversible. Interim median overall survival in recurrent phase 1 is 15.6 months, and not reached yet in newly diagnosed phase 1.

CONCLUSION

MMF combined with chemoradiation has been reasonably well tolerated in glioblastoma patients with promising evidence of brain tumor target engagement and drug accumulation in glioblastoma. This study yielded the recommended phase 2 dose of MMF 1500mg BID and will provide preliminary efficacy estimate for a randomized phase 2/3 trial.
P18.24.A GLIOBLASTOMA INVASION OF NEURAL STEM CELL REGIONS; MOLECULAR PATTERNS AND SURVIVAL RATES
Authors: Chaudhary A , Lammy S , Grivas A
Published: October 2024

BACKGROUND

Glioblastoma is a very aggressive form of brain cancer and poses a challenge in treatment due to its profound heterogeneity and capacity for extensive infiltration into the brain parenchyma. Research has shown glioblastomas in close proximity to the ependyma have poorer survival rates. Therefore, our aim was to identify distinct molecular features of grade 4 glioma invading ependyma of lateral ventricles and neural stem cell region and the survival prognosis of these patients.

MATERIAL AND METHODS

Retrospective review of 180 patients with a new histologically confirmed diagnosis of grade 4 glioma between 2018 and 2019. Patients excluded if less than 18-years-old, did not have a histological diagnosis, or had missing data. Analysis of anonymised patient data were conducted with ethical consent from NHS GGC Caldicott Guardian. SPSS version-28 used for statistical analysis.

RESULTS

Average age of all patients was 59 +/-12.3 years with 54% male and 46% female. 170 tumours were identified as IDH-wildtype (IDHw), while 10 were IDH-mutant (IDHm). Of the total 180 patients, 77 tumours contacted the ependyma, with 10.4% being IDHm and 89.6% IDHw. 103 tumours were identified as ependymal non-contacting with 2% being IDHm and 98% IDHw. Statistically significance association found between IDH mutations and ependymal contact (p-value 0.02). For both groups, majority of the tumours were unmethylated, with 57% for contacting and 65% for non-contacting tumours. However, no statistically significant associations were observed between MGMT methylation status and ependymal-contact (p-value 0.35). For IDHw glioblastomas, over half of the tumours for ependymal contact and ependymal non-contact were unmethylated (61% and 65% respectively). Mean overall survival (OS) for all patients was 16.6 (CI 19.0, 14.1) months. OS was lower in ependymal-contact tumours compared to non-ependymal contacting tumours (14.9 months compared to 17.5 months respectively, however this was not significant (p-value 0.11). Sub-analysis of IDHw glioblastomas showed reduced survival by ependymal contact with mean OS of 11.9 months compared to 17.4 months for non-contacting IDHw tumours (p-value 0.004). Mean epicentre distance for ependymal contacting MGMT methylated tumours was 17.7mm compared to 15.6mm for MGMT unmethylated contacting tumours. Statistically significant association found between epicentre distance and methylation status of ependymal-contacting tumours (p-value 0.008). No statistically significant associations found between epicentre distance and IDH status of ependymal-contacting tumours (p-value 0.23).

CONCLUSION

We have found that ependymal contacting tumours are more likely to be IDHw and MGMT unmethylated. Adjusted analysis showed ependymal-contact to lower survival rates and IDHw contacting tumours to also have poorer survival outcomes.
P18.26.A IMPROVED OUTCOME PREDICTION AND GRADING OF THE NOVEL TUMOUR TYPE GLIOMATOSIS CEREBRI-LIKE GLIOMA, IDH-WILDTYPE (GCLG, IDH-WT)
Authors: Münzberg M , Muench A , Divé I , Wenger-Alakmeh K , Forster M , Costa F , Dehais C , Bielle F , Kuzman P , Mueller W C , Umathum V , Acker T , Beschorner R , von Baumgarten L , Harter P N , Thomas C , Misch M , Capper D , Wefers A K , Neumann J E , Schüller U , Czabanka M , Steinbach J P , Plate K H , Brandner S , Schweizer L
Published: October 2024

BACKGROUND

Based on a cohort of 16 patients, we recently described a novel tumour type of IDH-wildtype glioma in adult patients, characterised by a gliomatosis cerebri-like growth pattern, frequent TERT promoter mutations, and a distinct epigenetic profile (GCLG, IDH-wildtype; DKFZ brain tumour classifier: adult-type high grade glioma, subtype F, HGG-F).

MATERIAL AND METHODS

We now compiled a larger, multicentric series of 63 patients and conducted an in-depth morphological, molecular and clinical characterisation.

RESULTS

The series consisted of 43 male and 15 female (NA = 5) patients. Median age was 65 years (range 17-88 years). In the initial series, none of the cases demonstrated vascular proliferation or necrosis; in contrast, 6/50 cases in this extended cohort (12%) showed histological features of malignancy (i.e. vascular proliferation and/or necrosis). In addition, 40% demonstrated molecular features of high-grade gliomas (i.e., CDKN2A/B homozygous deletion, chr.+7/-10, high-level amplifications of EGFR, CDK4, PDGFRA). Progression-free and overall survival in GCLG with and without histological and/or molecular signs of malignancy were significantly different (p<0.001). GCLG lacking signs of malignancy (n = 24) demonstrated an intermediate outcome comparable to IDH-mutant astrocytoma (PFS 58 vs. 54 months; OS 73 vs. 89 months) and may be assigned a CNS WHO grade 3 in the future. GCLG with malignant features (n = 14) demonstrated a clinical outcome similar to glioblastoma, IDH-wildtype, corresponding to CNS WHO grade 4 (PFS 11 vs 9 months; OS 16 vs 14 months). In four patients, we were able to compare tumour tissue from the initial and recurrent resection (median interval: 28 months, range: 11-69 months). Two tumours appeared unchanged upon recurrence, whereas two tumours with flat CNV profile and low-grade morphology subsequently acquired a homozygous CDKN2A/B deletion, microvascular proliferation and necrosis compatible with a malignant transformation during the disease course. Only 6/48 (12.5%) tumours had a MGMT promoter hypermethylation.

CONCLUSION

GCLG represents a novel IDH-wildtype glioma type in elderly patients with a distinct disease dynamic compared to glioblastoma, IDH-wildtype, and often extensive involvement of multiple brain regions (gliomatosis pattern at initial diagnosis in 50% of cases). We suggest a classification as either CNS grade 3 or CNS grade 4. Given the potentially large radiation field and unmethylated MGMT promoter in many cases, the optimal therapeutic strategies for GCLG with and without malignant features remain to be determined in the future.
P18.30.B MYCN AMPLIFICATION PREDICTED A WORSE PROGNOSIS IN PATIENTS WITH LOWER-GRADE IDH-MUTANT GLIOMAS AND WAS RELATED TO THE EPITHELIOID HISTOLOGICAL FEATURES
Authors: Xi S , Xie X , Qin Y , Lu J
Published: October 2024

BACKGROUND

In the newest WHO criteria, molecular alterations are increasingly incorporated into the diagnosis and grading of gliomas. MYCN amplification is reported to be significantly associated with poor prognosis in many tumors. However, the prognostic significance of MYCN amplification in IDH mutant gliomas has not yet been well established. This study was performed to explore the role of MYCN gene amplification in the tumor grade and prognosis of IDH-mutant gliomas.

MATERIAL AND METHODS

We evaluated the clinical and pathological features of 190 patients with IDH-mutant gliomas. MYCN amplification was detected by fluorescence in situ hybridization (FISH) using a MYCN probe. Overall survival (OS) was calculated via Kaplan‒Meier analysis and multivariable Cox proportional hazards regression models were used to analyze independent prognostic factors. The morphological features of the patients with MYCN amplification were reviewed and analyzed.

RESULTS

MYCN amplification was detected in 28/190 (14.7%) IDH-mutant glioma patients and was significantly related to a high tumor grade and high Ki-67 index (P<0.05). MYCN amplification was significantly correlated with overall survival in IDH-mutant glioma patients (112.13 ± 6.58 vs. 91.14 ± 14.96 months, p=0.001) and in lower-grade patients (grades 2 and 3) (122.12 ± 6.81 vs. 47.76 ± 6.58 months, p<0.001). Due to the limitations of the current grading system, we refined the grading system by upgrading the lower-grade IDH-mutant astrocytomas with MYCN amplification to high grade and found that the novel MYCN grading system was significantly related to the prognosis of IDH-mutant astrocytoma patients (112.84 ± 10.40 and 77.65 ± 11.15 months, p<0.001). One-half of the patients (14/28) with MYCN amplification exhibited epithelioid histological features, which included abundant eosinophilic cytoplasm and a dislocated nucleus.

CONCLUSION

MYCN amplification should be considered a prognostic factor in IDH-mutant gliomas, especially in lower-grade gliomas. Patients with MYCN amplification often exhibit epithelioid histological features.
P18.32.B OUTCOME OF NIMOTUZUMAB USE ON NEWLY DIAGNOSED AND RECURRENT MALIGNANT GLIOMAS: A PHILIPPINE RETROSPECTIVE STUDY ON TWO TERTIARY INSTITUTIONS
Authors: Imperial M , Batara J , Opinaldo P
Published: October 2024

BACKGROUND

High Grade gliomas have poor overall survival with no standard of care for recurrent disease. Despite treatment, recurrence is inevitable and prognosis remains poor with median survival rate of 12-15 months. EGFR is a membrane bound receptor that is greatly expressed in high grade glioma patients and gene amplification is one of the most frequent alterations of this tumor type. EGFR is present in 60% of GBMs. Nimotuzumab is a humanized monoclonal antibody targeting EGFRV3 with high penetration into the blood brain barrier that has been shown in phase 2 trials to benefit high grade gliomas especially unmethylated gliomas. This study determined if there is an added survival benefit in combining nimotuzumab with the current treatment practices available to our local neuro-oncologists.

METHODS

Chart review was done for all patients with newly diagnosed or recurrent IDH wild type glioblastoma, and recurrent IDH positive malignant gliomas treated with nimotuzumab plus either radiation + chemotherapy with temozolomide followed by adjuvant temozolomide, metronomic temozolomide or bevacizumab alone from 2007-2022 in two institutions in the Philippines. A total of 53 patients were given nimotuzumab, 48 patients were analyzed. Patients included were given Nimotuzumab 200-400 mg intravenously every two weeks for at least four sessions either until recurrence, continuous for six to 12 months or until death. Patients who received less than four sessions of Nimotuzumab and mortality from other causes were excluded from the analysis. Patient’s demographic data, date of surgery and recurrences, histopathologic reports, nimotuzumab doses, and date of death were collected. Primary endpoints were overall survival (OS) and Progression Free Survival (PFS). Side effects and complications were also investigated.

RESULTS

Forty eight patients were analyzed, 21 females and 27 males aged 21-70 with mean age of 48. Median PFS was 13 months (95%, CI 10.2-17.4) and Median Survival 43 months (95%, CI 34-57). Overall Survival Proportion after 1, 2, 3 and 5 years are 93.7%, 72.1%, 63.2 and 34.4% respectively. In the recurrent glioblastoma group, median PFS was 11 months and median OS was 22.11 months. In the recurrent IDH+ high grade gliomas, median PFS was 22 months and median OS was 75 months. Minimal side effects were noted.

CONCLUSION

There is an increased survival benefit in combining nimotuzumab with the current treatments available for malignant gliomas with minimal side effects.
P18.34.A PTEN ALTERATION AS A PREDICTOR OF SECOND-LINE EFFICACY IN PATIENTS WITH RECURRENT IDHWT-GLIOBLASTOMA
Authors: Cella E , Polano M , Padovan M , Bosio A , Caccese M , Corrà M , Cerretti G , Bennicelli E , Toffoli G , Lombardi G
Published: October 2024

BACKGROUND

Patients with rGBM have a dismal prognosis. Nitrosoureas (NS) such as lomustine and fotemustine and antiangiogenic drugs such as regorafenib(Reg) and bevacizumab (Bev) are all treatment options for rGBM. No clinical or molecular factors have been validated as predictors of efficacy to second-line therapy. PTEN mutations are common in GBM, but their potential predictive role has been understudied. We aim to investigate the impact of pathogenic PTEN alterations on the efficacy of different second-line therapies in rGBM patients.

MATERIAL AND METHODS

We conducted a retrospective single-institution study to assess the combination of pathogenic PTEN alterations (FoundationOne®CDx on tissue), and clinical data (molecular and histological characteristics, treatment details and outcomes) in a cohort of consecutive patients with first rGBM treated with Reg, NS or Bev alone at Veneto Institute of Oncology (Padua, Italy) from Oct 2019 to Jan 2023. WHO2021 classification was used for pathological diagnosis, and RANO criteria for neuroradiologic response evaluation.

RESULTS

153 patients were enrolled, treated with Reg (n=95), Bev (n=19), NS (n=39). The mOS from the start of treatment was, respectively: 12m (95% CI 9.1-14), 7.0m (95% CI 6.0-11) and 8.0 months (95% CI 5.0-13) PTEN was altered in 58 pts (61%) treated with Reg, 8 pts (57%) with Bev, in 23 pts (58%) with NS. In univariate analysis PTEN alteration was associated with short survival in Reg cohort (mOS of 10.4 m VS 16.8 m alterated versus wt PTEN, respectively; HR 1.68, p=0.043) and Lomustine cohort (mOS of 6.0m VS 16m in alterated versus wild-type PTEN, respectively; HR 1.27, p=0.01). In contrast, in Bev cohort PTEN alteration did not reach a statistical significance in univariate analysis. Of note, in multivariate analysis adjusted for categorical age (threshold,65 yrs), second surgery, ECOG score (0-1 vs. 2) and steroid use. PTEN alteration maintained a significant impact as predictor of short survival after treatment for both regorafenib and lomustine cohort (HR 1.67, p=0.043 and HR=3.17, p=0.003, respectively) together with MGMT methylation status (HR 0.44, p=0.002 and HR=0.33, p=0.006, respectively).

CONCLUSION

We concluded that pathogenic PTEN alteration may be a predictor of poor efficacy of regorafenib and lomustine in rGBM patients. However, a prospective study with a larger population is needed to better define the role of PTEN.
P18.37.B REPEATED CONVECTION-ENHANCED DELIVERY (CED) INFUSION OF A POLIO/RHINOVIRUS RECOMBINANT (LERAPOLTUREV; LERA) IN RECURRENT GLIOBLASTOMA (RGBM) PATIENTS, FOLLOWED BY CERVICAL PERILYMPHATIC INJECTIONS OF LERA (LERA-CPLI)
Authors: Desjardins A , Brown M , Shoaf M , Herndon II J E , Johnson M O , Khasraw M , Low J , Peters K B , Batich-Vaios K , Friedman A H , Friedman H S , Ashley D M , Bigner D D , Gromeier M
Published: October 2024

BACKGROUND

Phase 1 and 2 clinical trials of a single intratumoral injection of LERA (previously PVSRIPO) via CED into enhancing disease of rGBM has been shown safe and prolonged survival was observed in a subgroup of patients. We are now proposing a clinical trial investigating repeated infusions of LERA via CED into the residual infiltrative disease following maximal safe resection of the enhancing component, followed by LERA-CPLI. In animal models, repeated intratumoral LERA infusions enable infection of dendritic cells (DCs) recruited by LERA, maximizes engagement of tumor-associated and CNS-resident myeloid compartments, and thus optimizes the conditions for LERA-induced tumor immune surveillance. Furthermore, preclinical data in two established cancer models support the use of LERA-CPLI to augment intratumoral therapy.

MATERIAL AND METHODS

Eligibility includes adult patients with a solitary supratentorial rGBM amenable to resection followed by CED infusion of LERA; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS>70%. Patients undergo maximal safe resection of the enhancing component, followed three weeks later by two, 4-day apart, CED infusions of LERA in the residual non-enhancing disease. One week later, patients initiate four weekly injections of LERA-CPLI, followed by LERA-CPLI every 3 weeks for one year.

RESULTS

As of 5/01/2024, three pilot patients have been treated under expanded access protocols and have completed 6, 11, and 17 LERA-CPLI, respectively, following two intracerebral LERA injections via CED. Study related adverse events include grade 1 fatigue (n=2) and grade 1 headache (n=1).

CONCLUSION

Repeated CED infusions of LERA followed by LERA-CPLI in three pilot rGBM patients has been shown safe and feasible. Updates on the formal trial proposed to enroll up to 86 patients will be provided.
P18.44.B THE IMMUNE CELL INﬁLTRATION IN PERIVASCULAR AND INTRATUMORAL OF EPITHELIOID GLIOBLASTOMA
Authors: jiang s , yan q , wu y , zeng j , xi s
Published: October 2024

BACKGROUND

Epithelioid glioblastoma (eGBM) is a rare subtype of adult glioblastoma(GBM)and was proven to portend an extremely poor prognosis. Perivascular lymphocyte proliferation was commonly observed in eGBM. To disclose the relationship between the tumor’s microenvironment and survival and clinical implications in eGBM, we collected the eGBM cases and conducted a study on the tumor microenvironment of eGBM.

MATERIAL AND METHODS

We collected 38 cases of eGBM, 36 cases of typical adult glioblastoma with IDH and H3 wildtype (typical GBM), and 7 cases of inflammatory tumor-like demyelinating diseases (ITDD) from the Sun Yat-sen University Cancer Center, as well as 4 cases of ITDD from Guangzhou Sanjiu brain Hospital. Tumor-infiltrating immune cells including CD4, CD8, Foxp3, and CD20 positive cells, and tumor-associated macrophages (TAMs), including CD68, CD80, and CD163 positive cells, were performed by immunohistochemical staining (IHC). Under the high-power microscope, two hot spots were selected to quantify the positive immune cells of the tumor center and perivascular lymphocytes, respectively. PD-L1 was also detected by IHC and analyzed by combined positive score (CPS) in eGBM. Nonparametric and chi-square tests were used for intra-group and inter-group comparisons. Overall survival was calculated via Kaplan-Meier estimation using the log-rank test.

RESULTS

Compared with typical adult GBM, perivascular lymphocyte proliferation was more common in eGBM (23/38 vs 4/36, p < 0.001). The counts of CD68+ and CD163+ macrophages in the intratumoral zone were significantly higher than in the perivascular zone in eGBM (Median(cells /HPF):29 vs 7.25, p=0.002, 184.75 vs 78, p<0.001, respectively), while CD20+ lymphocytes were lower (Median(cells /HPF): 3.75 vs 27, P=0.03). Overall, the most common type of immune cells is CD163+ macrophages in both the perivascular zone and intratumoral zone of eGBM (Median=184.75 cells/HPF, P < 0.001), and the higher intratumoral CD163 count is an unfavorable prognostic factor for eGBM (OS:11.1 months vs 15.09 months, p=0.023). We also found that the high CD4/CD8 ratio of perivascular lymphocytes predicted a worse prognosis of eGBM (OS:8.77 months vs 15.66 months, p=0.02). The incidence of PD-L1 expression in eGBM patients is frequent, with 16/38 cases showing a CPS score ≥1. Compared with typical GBM and IDD, the count of intratumoral CD163+ macrophages in eGBM was significantly higher than that in typical GBM (Median(cells /HPF):184.75 vs 141, p =0.048), and the number of perivascular Foxp3+ lymphocytes of eGBM was less than that of tumor-like IDD (Median(cells /HPF):0 vs 2, p =0.044).

CONCLUSION

The immune microenvironment of eGBM consisted of the immune cell inﬁltration in the perivascular and intratumoral zones, and significantly differed from that of typical GBM and tumor-like IDD, which may contribute to the poor prognosis of eGBM.
P18.46.B THE INVERSE PARADIGM OF IDH-WILDTYPE GLIOBLASTOMA EXPLAINS THE TWO DISTINCT MODALITIES OF MICRO-INFILTRATION AND PINPOINTS THE ANCESTRAL FOUNDER CELL AS THE KEY THERAPEUTIC TARGET
Authors: Brognaro E
Published: October 2024

BACKGROUND

The IDH-wildtype glioblastoma is the only brain tumor that originates from the ribbon layer of the SVZ and can spread quiescently across the supratentorial brain parenchyma before starting to grow. Moreover, due to indirect and direct experimental evidence, it is finally unquestionably clear that two diffuse micro-infiltrations occur in IDH-wildtype glioblastoma, the first long before the primary bulk growth (the only one able to originate the primary bulk and distant relapses) and the second during bulk growth and evolution. The recognition that the latter is ineffective in giving rise to distant recurrences is a fundamental and very recent breakthrough. As a crucial consequence, there are two causes of therapeutic resistance, and the second one has yet to be identified and challenged therapeutically.

MATERIAL AND METHODS

By collecting multiple spatially separate samples in the tumor mass, we can reconstruct the phylogenetic tree of the primary tumor bulk. However, the therapeutic solution cannot be found in the tumor bulk (where the primordial cells are invariably extinct) but instead in the micro-infiltrated brain, where the ancestral founder CSCs lie quiescently in the perivascular niches. The codified ethical methods (as part of normal glioblastoma surgery) to sample the micro-infiltrated brain parenchyma are enabling us (and our research group is close to achieving this result) to isolate, identify and reproduce the dormant ancestral founder CSCs.

RESULTS

In the bulk, we can infer and reconstruct the phylogenetic tree of the tumor as well as driver and passenger events and the multitude of CSC variants by using multiple separated samples. The ethical methods for sampling micro-infiltrated brain parenchyma are now enabling us to identify and characterize the ancestral founder CSCs, which hibernate in the perivascular parenchymal niches of the supratentorial brain (their activation being the only cause of distant recurrences).

CONCLUSION

The first cause of therapeutic resistance is due to intratumor heterogeneity, while the second cause is the silent presence in the entire supratentorial brain of dormant ancestral founder CSCs from the pre-growth micro-infiltration. Only the identification and characterization of the ancestral founder CSC will enable us to simultaneously overcome both causes of resistance and provide an innovative therapeutic solution. Precisely, the ancestral founder CSC is identical to the premalignant progenitor of the SVZ and to the cell that activated in a single or multiple brain location, gave rise to the primary tumor bulk(s), and transmitted the ancestral driver genomic alterations to all subsequent evolutionary CSC variants.
P19.02.B CHALLENGES AND OUTCOME OF THE RESECTION OF A LEFT PETROCLIVAL MENINGIOMA IN A LOW INCOME COUNTRY
Authors: Ssembatya J , Tan E , Taremwa B
Published: October 2024

BACKGROUND

Petroclival meningiomas pose a surgical challenge due to their complex regional anatomy, with proximity to vital neurovascular structures and involvement of deep, narrow surgical corridors. Until 1970, they were generally considered unresectable due to high operative morbidity. However since the introduction of advanced microscopic surgery with neuronavigation and intraoperative neurophysiological monitoring, surgical outcomes have improved. Sadly, this technology is not available in most low income countries. We report a case of successful resection of a left petroclival meningioma in Mbarara Regional Referral Hospital in Uganda, despite the lack of advanced technology.

CASE REPORT

A 36 year old female presented with a 1 year history of intermittent vomiting and convulsions, worsening over 2 weeks. Neurological examination was normal except a Grade 2 left facial palsy. CT head was performed locally but a 7 hour journey was required for MRI brain; this confirmed a left petroclival meningioma. She returned for tumour resection 2 weeks later due to theatre capacity; neuronavigation, auditory brainstem response testing, sensory/motor evoked potentials and cranial nerve monitoring were not available. A left frontal EVD was initially inserted to control intracranial pressure, before placement in a right park bench position and head secured in a Mayfield clamp. Left retrosigmoid approach was used, with the meningioma visible on reflection of the dura. Under basic microscopic vision, gross total resection was performed with Simpson Grade 2 outcome. The EVD was replaced with an Ommaya reservoir. Postoperative CT head showed no tumour residual, with resolution of the facial palsy and all symptoms. Complications included CSF leak from the nose and Ommaya site, which resolved with conservative management, and DVT treated with anticoagulation. She was discharged at 3 weeks, is fully functioning and working in the community, with Modified Rankin Score 1. Neuropathology results reported meningothelial meningioma WHO Grade 1.

CONCLUSION

Lack of advanced technology in low income countries results in more difficulty locating lesions, increased risk of injury to neurovascular structures and longer operative time. Reduced availability of MRI delays diagnosis, whilst the low resourced hospital wards, together with reliance on patients’ families to fund medication and investigations, results in a challenging perioperative period. Despite this, we report the successful gross total resection of a petroclival meningioma in Uganda. We rely on an in depth understanding of skull base neuroanatomy, three dimensional mental imagery, detailed clinical examination and thorough review of preoperative imaging. We aspire to adopt more advanced technology and collaborate with higher income countries, but hope this case will inspire other low income countries who face similar challenges.