bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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 &gt;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

Abstract

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

Abstract

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&lt;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

Abstract

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&lt;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&lt;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&lt;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

Abstract

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

Abstract

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

Abstract

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&gt;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.