bluuebunny/crossref_metadata_2025 huggingface dataset:
P10.29.A FUNCTIONALLY INSTRUCTED COMBINATION-TREATMENTS INVOLVING REGORAFENIB IN EXPERIMENTAL GLIOMA
Authors: Haeusser L A , Kuhlburger L , Walter B , Becker H , Merk D J , Tabatabai G
Published: September 2023

BACKGROUND

Glioblastoma are incurable primary tumors of the central nervous system. The standard of care for newly diagnosed glioblastoma outside clinical trials includes a combination of radiation therapy, alkylating chemotherapy and tumor-treating fields. Yet, for progressive glioblastoma, only lomustine is registered in Europe. The REGOMA trial (Lombardi et al., Lancet Oncol 2019) had investigated regorafenib versus lomustine in a phase 2-trial. Furthermore, the use of regorafenib in a compassionate-use-program was recently reported (Tzaridis et al., Neuro Oncol 2019) Yet, the regorafenib arm in the Glioblastoma Adaptive Global Innovative Learning Environment (GBM Agile) master protocol was stopped after an interim analysis that showed a low probability of improvement of overall survival compared with control (press release 21 September 2022). We investigated here a functional genomics-based approach to discover and validate potential modulators of response to regorafenib treatment in experimental glioma in vitro, in vivo and ex vivo.

MATERIAL AND METHODS

We performed CRISPR/Cas9 activation (Calabrese P65-HSF activation library) and knockout (genome-wide knockout library Brunello) screens during treatment with regorafenib, sequenced and analyzed the genomic DNA of the remaining cells.

RESULTS

We discovered functionally-instructed molecular hits, designed a drug library for further validation by functional assays in vitro and combination treatments in murine glioma models in vivo.

CONCLUSION

Taken together, we discovered and validated functionally-instructed combination treatment options involving regorafenib. Our finalized results will be presented.
P10.32.B SCREENING FOR OPTIMAL MULTI-TARGET DRUG COMBINATIONS TARGETING THREE MAJOR PROLIFERATION PATHWAYS IN GLIOBLASTOMA
Authors: Their A , Baltira C , Rozing K , Beijnen J H , de Gooijer M C , van Tellingen O
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is one of the most malignant adult brain tumors, with a median survival of only 14 months. The lack of efficient therapies so far can be traced back to issues such as resistance to treatments leading to relapses, novel drugs being unable to penetrate the blood-brain barrier (BBB) and focus on monotherapy approaches in a highly heterogeneous disease. Characterization of the genomic landscape of GBM has revealed that three major signaling pathways are co-abrogated in the majority of patients. We have previously shown proof-of-concept that targeting these pathways (PI3K-mTOR-AKT, MAPK and CDK4/6-RB) using a multi-target combination therapy (MTCT) is a promising way to treat GBM. By looking into a panel of drugs, we are screening for alternative MTCT combinations to identify those most suitable for clinical translation.

MATERIAL AND METHODS

From a panel of drugs targeting one these three pathways, we compare each drug's single-agent properties to various combinations. The synergy of the drugs is scored based on proliferation and target inhibition effects. We will establish if candidate drugs are an ABC transporter substrate with transwell assays and how well the drugs can cross the BBB in vivo using ABC transporter knock-out mouse models. Promising MTCT combinations will be further studied using in vivo orthotopic GBM models.

RESULTS

We have identified several MTCT combinations that have synergistic effects on target inhibition and cell proliferation. Transwell assays indicate that multiple drugs are to some degree ABC transporter substrates, which might affect the brain penetration of the compounds. Nonetheless, we could identify several candidate drugs targeting the PI3K or MAPK pathway that are relatively weak substrates and for which brain entry is relatively unimpeded. In contrast, finding a candidate with favorable pharmacological properties among the available CDK4/6-RB pathway inhibitors has proven to be more challenging.

CONCLUSION

Our results indicate that using an MTCT approach might be promising for treating GBM. Further research is being conducted to find the best possible MTCT combination that can access the tumor through the BBB at sufficient levels to exert its pharmacodynamic effects.
P10.34.B ONCOGENIC ASPP2KAPPA(K), A DOMINANT-NEGATIVE ISOFORM OF THE APOPTOSIS STIMULATING PROTEIN OF P53-2 (ASPP2) PROMOTES CLASSICAL HALLMARKS OF CANCER IN GLIOBLASTOMA
Authors: Hafner M , Ruiba A , Kampa L , Sommer I , Ahrens A , Kälin V , Zeitlberger A , Buchauer K , Plasswilm L , Hundsberger T , Neidert M , Schittenhelm M M , Kampa-Schittenhelm K M
Published: September 2023

BACKGROUND

GB is the most common, most aggressive primary brain tumor with a deleterious prognosis. ASPP2 is a tumor suppressor, directly interacting with p53. We recently identified a dominant-negative isoform of ASPP2, named ASPP2κ, lacking the important p53 binding sites and show that ASPP2κ is highly expressed and functionally active in glioblastoma, affecting all classical hallmarks of cancer.

MATERIAL AND METHODS

Grade IV glioma (n=46) were assessed for ASPP2κ expression. Isogenic GB models, stably suppressing or overexpressing ASPP2κ, were established in A-172, U-251 and T98g cell lines and from resected GB tissue. The role of ASPP2κ in induction of apoptosis, cellular proliferation, migration and invasion was assessed in vitro and in vivo. Proteome arrays allowed to study pathways involved in ASPP2κ signaling. Two ASPP2κ knock-down (KD) NOD/SCID xenotransplant mouse models were established to study ASPP2κ in tumor engraftment and progression.

RESULTS

Frequent overexpression of ASPP2κ was confirmed in virtually all patients analyzed compared to tumor-free tissue. Expression thereby varied widely in between patients (2-40 fold). Functional analyses confirm that ASPP2κ directly affects multiple cancer hallmarks in GB, resulting in a more aggressive phenotype with impaired induction of apoptosis (avg. -25 %), higher proliferation (avg. +25%), migration (avg. +65%) and invasion (avg. +70%) rates. Silencing of ASPP2κ rescues the ASPP2 wt tumor suppressor phenotype, rendering cells more susceptible towards temozolomide (TMZ, avg. +25%), γ-irradiation (avg. +40%) or combinational approaches. Upregulation of p53 phosphorylation sites (S15: 2,5x/S46: 1,5x) and cell cycle regulators (p21: 2x, p27: 3x and pRAD: 2,5x) thereby confirms restoration of important p53-mediated pathways. GB mouse models confirm attenuated tumor engraftment and progression of ASPP2κ KD tumors in vivo. Mice carrying ASPP2κ-KD tumors presented with statistically significant increased overall survival in both models (p= 0.03 and p=0.005) and attenuated tumor growth (p=0.0001). Importantly, neo-angiogenesis was strongly regulated in relation to ASPP2κ expression, impairing tumor growth and metastasis in the ASPP2κ KD models. Downregulation of pro-angiogenic (VEGF 20x, angiogenin 4x) and upregulation of anti-angiogenic (endostatin 2x, LAP 2,5x) players in ASPP2κ KD models were confirmed.

CONCLUSION

ASPP2κ is highly expressed in GB, affecting all classical hallmarks of cancer, including regulation of apoptosis, cell cycle, invasion/metastasis and angiogenesis. ASPP2κ contributes to aggressiveness of disease and resistance to therapy and silencing of ASPP2κ re-activates crucial p53-mediated tumorsuppressor pathways. Studies evaluating ASPP2κ as a target for therapy are ongoing.
P11.10.B USEFULNESS OF PHOTODYNAMIC THERAPY (PDT) WITH TALAPORFIN SODIUM FOR GLIOBLASTOMA
Authors: Sasayama T , Tanaka K , Nagashima H , Fujita Y , Yamanishi S
Published: September 2023

BACKGROUND

Photodynamic therapy (PDT) with talaporfin sodium uses the toxicity of singlet oxygen generated by a reaction between a photosensitizer in tumor cells and light with a specific wavelength. PDT was introduced in our hospital in April 2017. We retrospectively analyzed the glioblastoma (GBM) patients treated with PDT and compared with the patients who did not receive PDT.

MATERIAL AND METHODS

From April 2015 to March 2023, total 145 patients with GBM were treated in our hospital. Among them, 90 patients with GBM were performed PDT. Patients of recurrence, IDH mutant, biopsy and no chemo/radiotherapy were excluded. After the tumor had been resected as extensively as possible, the region of probable tumor invasion in the resection cavity were irradiated superficially with a 664-nm diode laser for 180 sec (27 J/cm2) at a power density of 150 mW/cm. The patients’ characteristics, adverse event, changes of the MR image, recurrence pattern, outcome of the patients were analyzed. In addition, survival time of the patients between the PDT group and the non-PDT group was compared.

RESULTS

A total of 80 GBM patients were analyzed. Forty-four patients received PDT. Gross total resection (GTR), Subtotal resection(STR), and partial resection were performed in 56, 16, and 8 patients, respectively. In the PDT group, 4 patients had adverse event; cyst formation, venous infarction, brain swelling, and delirium. In most of the patients, linear high signals of 5-7 mm on DWI were detected at the surface of the resected cavity and matched the PDT-irradiated area from 1 day after PDT. All hyperintense signal on DWI disappeared in about 30 days without any neurological deterioration. Sixty-seven patients had recurrence (PDT group; 33 cases, non-PDT group; 34 cases). Recurrence pattern of distant/dissemination were significantly increased in the PDT group compared with the non-PDT group. The PDT group tended to have longer survival in both OS (p=0.08) and PFS(p=0.07) than the non-PDT group. In multivariate analysis for OS, age and MGMT promotor methylation were significant prognostic factors, but not PDT.

CONCLUSION

PDT was safety and useful for GBM. However, the PDT group had significantly more distant/disseminated recurrences than the non-PDT group. We need to analyze more cases to clarify efficacy and recurrence patterns.
P11.12.B SEIZURES IN PATIENTS WITH BRAIN METASTASES FROM BREAST CANCER: RESULTS FROM A RETROSPECTIVE SINGLE-CENTRE STUDY
Authors: Bruno F , Pellerino A , Borgognone M , Palmiero R , Bertero L , Marchesani E M , Garbossa D , Soffietti R , Rudà R
Published: September 2023

BACKGROUND

Seizures may be a symptom of brain metastases (BrMs) from breast cancer. Gross-total resection (GTR) is known to correlate with a better seizure control, while the impact of radiotherapy (RT) and chemotherapy (CT) still remains uncertain. In this study, we aimed to explore which clinical and molecular factors might affect seizure control in a cohort of patients with BrMs from breast cancer. Patients and

METHODS

We retrospectively included patients ≥18 with surgically resected BrMs from primary breast cancer treated in our Institution from 1991 to 2022.

RESULTS

We included 79 patients in the analysis. Thirty-three (41.7%) had a history of seizures. Seizures prevailed in patients < 50 vs ≥ 50 (59.0% vs 32.0%, p=0.021), and they were not associated with BrMs location, number, or morphology (cystic vs non-cystic; bleeding vs non-bleeding). Patients with low (score 0-1) vs high (score 2-3) STAT3 expression in the peritumoural reactive astrocytes (RAs) had a slightly higher incidence of seizures (50.0% vs 35.0%, p=0.337). Seizure incidence did not differ between HER2+, HR+/HER2- and TNBC patients. Seizures tended to be more common after non-GTR as compared with GTR (21.0% vs 11.0%, p=0.293). RT and CT did not affect seizure control.

CONCLUSION

Younger age was associated with a higher risk of seizures, whereas different molecular subgroups (HER2+, HR+/HER2-, TNBC) or STAT3 expression in the RAs were not. To our knowledge, this is the first real-life study investigating the correlation between seizures and clinical and molecular factors in patients with BrM from breast cancer.
P11.13.A FREQUENCY AND SURVIVAL OUTCOMES OF MOLECULAR GLIOBLASTOMA IN IDH-WILD HISTOLOGICALLY LOWER-GRADE GLIOMAS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Nakasu S , Deguchi S , Nakasu Y
Published: September 2023

BACKGROUND

The WHO 2021 classification defines IDH wild-type (IDHw) histologically lower-grade glioma (hLGG) as molecular glioblastoma (mGBM) if TERT promotor mutation (pTERTm), EGFR amplification or chromosome 7 gain and 10 loss aberrations are indicated. However, majority of studies reported that patients with mGBM were likely to undergo biopsy rather than resection and less likely to receive adjuvant radiochemotherapy. Thus, while most studies have suggested the prognostic correspondence between hGBM and mGBM, the equivalence has not been sufficiently demonstrated. Furthermore, molecular marker frequency in IDHw hLGGs differ extensively between studies (pTERTm rates = 15% to >70%). It is unclear if such differences are caused by methodological or other factors, however, differences may affect tumor classification and prognostication.

MATERIAL AND METHODS

We systematically reviewed articles of IDHw hLGGs studies in PubMed, Ovid MEDLINE, Cochrane library and Scopus, andmeta-analyzed mGBM prevalence and overall survival (OS) according to the PRISMA statement.

RESULTS

We selected 49 studies (N = 3748) for the analyses. mGBM rates in IDHw hLGG were significantly lower in Asian regions (43.7%, 95% confidence interval [CI: 35.8-52.0]) when compared with non-Asian regions (65.0%, [CI: 52.9-75.4]) (P = 0.005). IDHw hLGGs without pTERTm rarely expressed other molecular markers in Asian studies when compared with non-Asian studies. We compared OS rates of IDHw hLGG tumors between Asian and non-Asian studies using individual patients’ data. The median OS rate in Asian mGBM tumors (21.1 months [CI: 16.1-24.7]) was similar to in non-Asian tumors (20.8 months [CI: 17.9-22.7]) (P = 0.45). Patients with mGBM had significantly longer OS times when compared with histological GBM (hGBM) (pooled hazard ratio (pHR) in univariate analyses 0.824, [CI: 0.694-0.98], P = 0.028, I2 = 46%)). Moderate heterogeneity improved in the pooled HR in multivariate analyses, which showed a significantly better OS in mGBM (HR 0.61 [CI: 0.50-0.74], I2 = 0%) (P < 0.0001). In patients with mGBM, histological grade was a significant prognostic factor (P = 0.018), as was age (P = 0.001) and surgical extent (P = 0.018).

CONCLUSION

Patients with mGBM have better OS when compared with patients with hGBM, especially when grade II histology is indicated. We identified differences between Asian and non-Asian regions in terms of molecular marker frequency pattern for mGBM in IDHw hLGG. However, OS rates in patients with mGBM were concordant between Asian and non-Asian cohorts.
P11.15.A IMPACT OF PERIOPERATIVE DEXAMETHASONE IN THE CONTEXT OF NEUROSURGICAL BRAIN METASTASIS RESECTION
Authors: Wasilewski D , Bukatz J , Peukert R , Shaked Z , Poeser P , Karbe A , Trelinska-Finger A , Jelgersma C , Frueh A , Raspe M , Radbruch H , Capper D , Schlaak M , Thuss-Patience P , Bischoff P , Horst D , Krentzke M , Xu R , Ehret F , Kaul D , Misch M , Bullinger L , Frost N , Vajkoczy P , Onken J
Published: September 2023

BACKGROUND

Patients with brain metastases that undergo brain metastasis resection regularly receive perioperative dexamethasone. We sought to evaluate whether perioperative dexamethasone in brain metastases is linked to survival.

MATERIAL AND METHODS

Retrospective data on perioperative dexamethasone dosage in resected brain metastasis patients at three hospital sites of the Charité from 2010-2022 were collected. Cut-off values for cumulative perioperative dexamethasone dose as a continuous predictor variable for survival were determined using maximally selected rank statistics. Patients were dichotomized based on determined cut-offs of cumulative dexamethasone (pre-operative: < 40 mg vs ≥ 40 mg; post-operative: < 180 mg vs ≥ 180 mg) and pre- and postoperative: < 281 mg vs ≥ 281 mg). Medical records included baseline demographic, radiological, histopathological and treatment-related characteristics. Based on cut-off values for dexamethasone downstream statistical analyses included Kaplan-Meier, Cox proportional hazards regression for overall survival with adjustment for potential confounders including age, gender, Karnofsky performance index and presence of extracranial metastasis via propensity score matching.

RESULTS

539 patients were included. Median follow-up time was 58,97 months. After adjusting for age, gender, Karnofsky performance index and presence of extracranial metastasis patients with higher cumulative perioperative dexamethasone (≥281 mg) showed shorter survival (HR: 1.47 (1.20-1.80, p<0.001) as compared to patients with lower cumulative doses (<281 mg). This effect remained significant after correction for patients that died within 3 months after resection and for patients with KPS below 50% and, independently from this approach performing propensity score matched-based analysis of the total cohort of patients, respectively.

CONCLUSION

Cumulative perioperative dexamethasone is associated with decreased survival in the context of brain metastasis resection. Strict dosage, down taper or methods reducing corticosteroid dependency should be regularly evaluated in clinical practice in patients with brain metastases
P11.17.A TEMOZOLOMIDE ONLY FOR GBM MGMT PROMOTER METHYLATEDELDERLY PATIENTS IN REAL CLINICAL SET
Authors: Falah E , Furman O , Haisraely O , Atar is N , Jan E , Zach L , Taliansky A
Published: September 2023

BACKGROUND

The course of glioblastoma (GBM) is worse in elderly and low KPS patients. The NORDIC and NOA08 clinical trials proved the non-inferiority of temozolomide (TMZ) treatment to radiotherapy alone for GBM MGMT promoter methylated (MGMT MET) elderly patients. TMZ alone is thus recommended in guidelines as first line of treatment for this group of patients. The data of real life efficacy of this treatment are sparse.

MATERIAL AND METHODS

We retrospectively evaluated the data of GBM MGMT MET patients, older than 65y that were treated in the Neuro-oncology unit at Sheba MC during 2012-2022. The treatment was adjuvant TMZ 200mg/m2/day 5 days q28 days. We compared treatment outcomes in our patients to the results of the NORDIC and NOA08 RCTs.

RESULTS

36 patients were included in our analysis with stereotactic biopsy for diagnosis in 47% of them: 34 patients had GBM, 1 had WHO grade 3 Astrocytoma and in 1 patient the diagnosis was made by imaging (non diagnostic biopsy). Of this group, 25 were males and 11 females. The mean age was 76y (64-90) and 96% had KPS ≤ 60. Only one patient had IDH 1 mutation and in 9 cases IDH status was unknown. The interval from diagnosis to treatment was 2-19 weeks (median 6 weeks). The number of TMZ cycles was 1-12 (mean of 4 cycles after the exclusion of 11 patients who received less than 3 cycles). Median PFS/OS was 3 /7.5 months and 5/11 months respectively for the whole group and for patients that received ≥3 cycles. The 12/18/24 months survival rate was 33%/13%/8% respectively. 21 patients received second line treatment: 13 radiotherapy, 1 TMZ re-challenge and 7 Bevacizumab. Eight patients received a third line of treatment: 2 radiotherapy, 4 Bevacizumab, 1 Procarbazine and 1 TMZ. Grade 3-4 hematological toxicity was documented in 20% of the patients, with infections in 12.5% and bleeding in 4%. Fatigue was reported in 17% of the patients.

CONCLUSION

While our patients were older and with lower KPS than the patients in the RCTs the efficacy of TMZ only treatment was comparable with the clinical trials results with mOS of 11/11.9/8.3 month in Sheba/NOA08/Nordic patients, PFS of 5/8.4/NA in Sheba/NOA08/Nordic patients respectively. The main toxicity reported in all 3 data sets was hematological 20%/38%/12% in Sheba/NOA08/Nordic patients. We can conclude that TMZ only for GBM MGMT MET elderly patients in real clinical set is a valuable and safe first line treatment. 
P11.20.B ASSOCIATION OF HAND-FOOT SKIN REACTIONS WITH SURVIVAL IN RECURRENT GLIOBLASTOMA PATIENTS TREATED WITH REGORAFENIB
Authors: Werner J , Hau P , Kowalski T , Treiber H , Roth P , Wollring M M , Stetter I , Tscherpel C , Rosen E K , Ceccon G S , Chapuy C I , Schlegel U , Weller M , Fink G R , Galldiks N
Published: September 2023

BACKGROUND

The phase 2 REGOMA trial suggested a survival benefit of the multikinase inhibitor regorafenib for the treatment of patients with glioblastoma at first recurrence. Hand-foot skin reactions (HFSR) following multikinase inhibitor therapy have been reported as a predictor for prolonged survival in patients with solid tumors. Data on the predictive value of HFSR in patients with recurrent glioblastoma undergoing regorafenib therapy remain scarce.

MATERIAL AND METHODS

Fifty-seven patients (age range, 35-77 years) with recurrent IDH-wildtype glioblastomas were retrospectively identified from five centers in Germany and Switzerland. Regorafenib was administered at 160 mg/d for the first three weeks of each 4-week cycle, with individual dose adjustments according to toxicity. Patients were stratified into two groups based on the occurrence of HFSR following regorafenib. Group differences were investigated using the Mann-Whitney rank-sum test and Fisher's exact test. Kaplan-Meier analysis was used for univariate analyses, and the Cox proportional hazards regression model for multivariate analyses.

RESULTS

Patients received a median of two regorafenib cycles (range, 1-14 cycles). Median follow-up after recurrence was 7.0 months (range, 0.6-35.9 months). The median number of previous treatment lines was 2 (range, 1-6 lines). At the time of data analysis, 47 patients (82%) had died. HFSR were observed in 14 of 57 patients (25%) and was associated with a significantly longer OS (10.6 vs. 6.0 months; P=0.040). No significant group differences (HFSR compared to no HFSR) were observed regarding age, the extent of resection, MGMT promoter methylation, Karnofsky performance status, or number of completed regorafenib cycles (all P>0.05). Cox proportional hazards regression analysis confirmed that HFSR were associated with longer OS (P=0.039; HR, 0.438), independent of age, Karnofsky performance status, and the number of previous treatment lines (all P>0.05).

CONCLUSION

Our results suggest that the occurrence of HFSR following regorafenib is associated with longer OS in recurrent glioblastoma patients.
P11.25.A TUMOR TREATING FIELDS (TTFIELDS) REAL-WORLD EXPERIENCE IN NEWLY DIAGNOSED GLIOBLASTOMA: A SYSTEMATIC LITERATURE REVIEW AND META-ANALYSIS OF OVERALL SURVIVAL
Authors: Ballo M T , Conlon P , Lavy-Shahaf G , Kinzel A , Vymazal J , Rulseh A M
Published: September 2023

BACKGROUND

Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability and tumor progression by a multi-modal mechanism of action. TTFields therapy is FDA-approved for newly diagnosed glioblastoma (ndGBM) based on results from the randomized, phase 3 EF-14 study (NCT00916409). We assessed the overall survival (OS) benefit of adding TTFields therapy to standard of care (SOC) for patients with ndGBM treated in clinical practice, as well as the relationship between OS and device usage rate.

MATERIAL AND METHODS

A systematic literature review (PubMed, Embase, and Cochrane Library) identified single-cohort and comparative clinical studies that assessed survival in patients with ndGBM who received TTFields therapy. Inter-study heterogeneity was quantified using the Higgins I2 statistic and Cochran Q test. A distribution-free random-effects method was used to pool survival curves.

RESULTS

Nine studies were identified that evaluated survival with TTFields therapy in ndGBM. Of these, the 7 studies (1430 patients) that compared TTFields therapy with SOC to SOC alone were included in a pooled analysis for OS. The pooled data showed significantly longer OS with TTFields therapy/SOC vs SOC alone (hazard ratio [HR]: 0.63; 95% CI, 0.53-0.75; P<0.001). A sensitivity analysis indicated that the effect was robust and independent of any individual study. In post-approval studies, pooled median OS was 22.2 months (95% CI, 17.3-42.6) for TTFields therapy/SOC and 17.3 months (95% CI, 13.6-22.0) for SOC alone. Gross total resection was generally more prevalent in the real-world setting, irrespective of TTFields use. Among studies evaluating device usage, an average usage rate of ≥75% was associated with prolonged OS vs <75% usage (pooled HR: 0.60; 95% CI, 0.48-0.73; P<0.001).

CONCLUSION

Pooled analysis of comparative TTFields therapy studies suggests a significant survival benefit with TTFields added to SOC for patients with ndGBM, and that a recommended 75% usage rate may be clinically meaningful in the real-world setting.
P11.27.A RADIOTHERAPY-INDUCED CHANGES IN THE BRAIN: A LONGITUDINAL STUDY IN PATIENTS WITH LOW-GRADE GLIOMAS
Authors: Wickborn K , van der Weide H L , Kramer M C A , de Vries E F J , Borra R J H , Spikman J M , Buunk A M , van der Weijden C W J , van der Hoorn A
Published: September 2023

BACKGROUND

Low-grade gliomas (LGG) are brain tumors with a comparably moderate malignancy grade and slow progression. Most patients are young to middle-aged adults with a relatively good prognosis given the advancement of multimodal treatment

METHODS

. Radiotherapy (RT) is an integral component of this treatment. During RT, protons or photons are used to eradicate the tumor while minimizing the damage to surrounding areas. However, healthy brain tissue is inevitably exposed to radiation, which can have adverse effects with a severe impact on the cognition and quality of life of survivors. With the improved survival of patients, understanding RT-induced changes and their consequences becomes more and more important. Here, we investigate the volumetric changes in LGG patients 2.5 years after treatment to gain insights into the neuronal long-term effects of RT.

MATERIAL AND METHODS

To quantify the volumetric changes in the brain of LGG patients over time, LGG patients (N= 17) were scanned before and 2.5 years after proton RT. For both time points, volume parameters per brain structure were extracted using T1w MRI scans and cNeuro® software. The volumes of the structures in the tumor-contralateral hemispheres before RT were compared with the measures 2.5 years after RT using paired samples t-tests or nonparametric alternatives.

RESULTS

Analysis of the total grey matter of the contralateral hemisphere indicated a statistically significant volumetric reduction in our cohort 2.5 years after RT. An analysis targeting volumetric changes in the contralateral hippocampus also indicated a statistically significant decrease. In the following steps, additional structures will be analyzed.

CONCLUSION

Preliminary results suggest a potential RT-induced decrease in the tumor-contralateral grey matter and hippocampal volume 2.5 years after treatment. Volumetric changes will be compared with the received radiation dose per structure using radiation dose distribution maps.
P11.33.B A PATIENT WITH GLIOBLASTOMA AND EXTENSIVE EXTRANEURAL METASTASES - DOES MOLECULAR BIOLOGY PLAY A CRUCIAL ROLE?
Authors: Moen Taule E , Brekke J , Miletic H , Sætran H , Maric S , HogenEsch I , Mahesparan R
Published: September 2023

BACKGROUND

Extraneural metastases of glioblastoma (GBM) are rare, reported incidence in literature is 0.4% to 2%. There is a lack in epidemiological data, and what little exists is outdated. The most commonly reported sites of metastases are bone, lymph node and lung. There is an insufficient understanding of the biological mechanism of metastasis, nevertheless, surgical intervention and peritoneal seeding through a ventriculoperitoneal shunt have been postulated as rational routes for the tumor cells. However, reports show metastasizing GBM in patients where neither of these procedures have been performed and therefore biological aspects should be elucidated. Previously, some few genomic studies have shown high mutational burden and that some mutations are only detected in the metastases, indicating clonal evolution. Commonly TP53, TERT, PTEN and CDKN2A/B have been revealed as shared mutations.

MATERIAL AND METHODS

A 55-year-old man presented with approximately 2 months of progressive headache and behavioral changes. Brain MRI revealed a left temporal lesion suspicious of GBM and no extracranial metastasis was detected. The patient underwent near total surgical resection and completed Stupp protocol. Nine months later, he was admitted to the local hospital with reduced general condition, tachypneic and lower back pain, but subsequent CT of thorax and abdomen revealed multiple pathological lesions in mediastinum, bones, lung, soft tissue, and mesentery. MRI confirmed the findings and a large soft tissue lesion at the level of the 6th thoracic vertebrae, was biopsied and showed metastasis from GBM. There was also local progression of the primary tumor in the brain. Treatment strategy was changed to a combination of lomustine, vincristine and bevacizumab. It was collected blood samples from the patient in respect of circulating tumor cells. A molecular characterization of the tumor samples was performed.

RESULTS

The primary tumor was MGMT promotor methylated, IDH-1/-2 wildtype, had no TERT promotor mutation, TP53 wildtype and ATRX was intact. The biopsy of the paravertebral lesion showed infiltration of a low differentiated, highly cellular tumor. Immunohistochemically the tumor cells were positive for GFAP, OLIG2 and S100. The molecular features revealed no mutation in BRAF or NTRK. Interestingly, PD-L1 was extremely upregulated, may indicating a potential benefit of immune-checkpoint inhibitors for extraneural metastases. A literature survey is done to find out any risk factors for metastasis.

CONCLUSION

We report a rare case of GBM with extensive extraneural metastases. This underlines the importance of comparing molecular biology, localization, and other patient and tumoral factors in order to identify any specific risk factor for metastasis. In turn, helping to stratify the follow up of this subgroup in the future.
P11.44.A THE ROLE OF RADIOTHERAPY IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS: A MULTICENTER COHORT STUDY
Authors: Jansma C Y M N , Coert J H , Grünhagen D J , Verhoef C , Martin E , Taal W
Published: September 2023

BACKGROUND

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are rare and aggressive malignant soft-tissue sarcomas (STS), of which 40% are associated with neurofibromatosis type 1 (NF1). Current treatment in localized disease mainly revolves around surgical excision, yet MPNSTs harbor a high probability of local recurrence (LR). Radiotherapy (RT) is increasingly being used, as it improves local control in STS, yet does not impact survival. Nevertheless, its use is controversial in some cases as major wound complications can be much higher and NF1 patients harbor a potential higher risk for secondary malignancies as MPNST commonly arise within plexiform neurofibromas. This study evaluates the use of RT in these rare tumors and tries to understand its impact in local control, especially in the NF1 setting.

MATERIAL AND METHODS

Surgically treated primary MPNSTs between 1988 to 2019 in the MONACO multicenter cohort were included. Demographic and treatment differences, especially the use of RT, between NF1 and non-NF1 were analyzed. Univariate and multivariable logistic regression analyses were used to identify factors independently associated with the use of radiotherapy. Multivariate Cox regression analyses were performed to identify factors associated with LR in NF1 patients.

RESULTS

A total of 528 patients (31.8% NF1) were included, of which 149 (28.2%) developed a LR. RT was administered in 53.2% of patients (55.6% in NF1). Of these, 26.7% received neoadjuvant RT, and 71.2% adjuvant RT. The use of both treatment modalities was similar between patients with and without NF1. Multivariable regression showed that microscopically positive margins and high-grade tumors were independent factors for the use of RT. The rate of RT use in NF1 did not alter after correcting for tumor-, patient- and surgical factors. RT did not impact overall survival in sporadic and NF1 associated MPNST. In NF1 patients, microscopically positive margins (R1) (HR 3.2; 95% CI, 1.41-7.62), tumor size >5cm (HR 2.2; 95% CI, 1.14-4.3), and a high grade (HR 3.13; 95% CI, 1.23-7.98) were independent risk factors for the development of a LR. Correcting for tumor-, patient- and surgical factors, use of RT was not associated lower rates of LR, in contrast to the sporadic population.

CONCLUSION

Radiotherapy is commonly used in MPNST treatment regardless of its origin in NF1. While it may impact LR rate in sporadic patients, this is less clear in NF1 patients. Further studies are needed to evaluate its role and indications in NF1 associated MPNST.
P11.45.B LOCAL RECURRENCE IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS: A MULTICENTER COHORT STUDY
Authors: Jansma C Y M N , Acem I , Coert J H , Taal W , Grünhagen D J , Verhoef C , Martin E
Published: September 2023

BACKGROUND

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are rare and aggressive malignant soft-tissue sarcomas (STS) and compromise 5-10% of STS. About 40% of MPNST cases are associated with neurofibromatosis type 1 (NF1). High-grade MPNSTs have a high probability rate of a local recurrence (LR). Risk factors vary in current literature due to its rarity, as does the optimal treatment for LRs. Factors include the role of radiotherapy, surgical margins and NF1. This study investigated both gaps in knowledge.

MATERIAL AND METHODS

Surgically treated primary MPNSTs between 1988 to 2019 in the MONACO multicenter cohort were included. Multivariate Cox regression analyses were performed to identify factors associated with LR and overall survival (OS) after a LR diagnosis. Treatment of LR was evaluated.

RESULTS

A total of 507 patients were included in this analysis, of which 142 developed a first LR. A high-grade (HR 3.40; 95% CI, 1.32-8.70) , microscopically positive margins (R1) (HR 3.6; 95% CI, 2.16-6.00), and tumor size (HR 2.14; 95% CI, 1.04-4.42) were independent risk factors for the development of a LR. Radiotherapy (HR 0.43; 95% CI, 0.23-0.79), on the other hand, reduced the risk. Patients with a LR had significantly worse OS. Most LRs (50.7%) were treated surgically without additional therapy. Only a small amount of patients (11.3%) received additional radiotherapy.

CONCLUSION

This analysis provides important insights into clinicopathologic, and treatment factors associated with a LR and outcomes in MPNST patients. NF1 is not associated with an increased risk of developing a LR1 whereas other clinical factors are.
P11.51.B STATUS EPILEPTICUS IN WHO GRADE 2 AND 3 DIFFUSE GLIOMA - PREVALENCE AND PREDICTORS
Authors: Venugopal H , Berendsen S , van Kessel E , Seute T , Leijten F S S , Robe P A , Snijders T J
Published: September 2023

BACKGROUND

Status Epilepticus (SE) is a potentially life-threatening and highly debilitating manifestation of diffuse glioma. Glioma-associated SE has yet been poorly studied; consequently, evidence-based recommendations for clinical management are scarce. Prevalence and predictors of SE might vary across the biomolecular heterogeneity of glioma. We aimed to determine the prevalence of SE in grade 2 and 3 diffuse glioma throughout the disease trajectory, and identify associated baseline determinants (BD) and short-term determinants (STD).

MATERIAL AND METHODS

We conducted a single-center retrospective cohort-study in a consecutive cohort of patients with WHO grade 2 and 3 glioma, diagnosed between 2010 and 2017. Candidate determinant variables included demographic, clinical and tumor-related variables at first surgery (BD) and epilepsy-associated variables immediately preceding the first SE after diagnosis (STD). Occurrence of BD and STD was correlated to (a) all occurrences of SE and (b) SE with in-hospital treatment separately. A within-patient comparison of STD-frequency between a 30-day hazard period and control period, defined relative to the index-SE, was executed. Univariable and multivariable logistic regression analyses were performed for both BD and STD.

RESULTS

SE occurred in one third of the total cohort (n=63/197). Nearly 14% had an in-hospital treated SE. We identified several baseline clinical and tumor-related correlates of SE in the univariable analyses, including central, parietal and occipital tumor localization, tumor grade, extent of resection and acute symptomatic seizure occurrence after first surgery. In the multivariable model for all SE, parietal tumor localization and acute symptomatic seizure occurrence after first surgery were associated with an increased risk of SE, whereas baseline Karnofsky Performance Score (KPS) and cognitive disorders were associated with a decreased risk; for in hospital-treated SE, the model was too underpowered for valid analyses. None of the STD were significant predictors of (in-hospital) SE.

CONCLUSION

One third of patients with grade 2 and 3 diffuse glioma developed a SE at any timepoint after diagnosis. Baseline parietal tumor localization, postsurgical acute symptomatic seizure occurrence, KPS and cognitive status were identified as independent determinants of SE. These explorative findings, if validated, could guide personalized risk stratification, patient counselling and therapeutic decision-making in the clinic.
P11.52.A LONG-TERM SURVIVORS OF GLIOBLASTOMA: A SINGLE-CENTRE RETROSPECTIVE STUDY
Authors: Fortuna A , Luz P , Cordeiro M
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet, despite advancements in understanding its biology, it remains an incurable disease with a high mortality rate. Less than 5% of patients survive beyond 5 years, making identification of factors associated with long-term survival critical in improving outcomes for patients with glioblastoma.

MATERIAL AND METHODS

In this retrospective study, we conducted a descriptive analysis of patients who were diagnosed with glioblastoma and survived for 19 months or longer after their initial diagnosis. We included patients discussed on the multidisciplinary tumour board from September 2020 to June 2022.

RESULTS

We evaluated 43 patients, 9 of these had a survival rate of more than 19 months, with a median survival of 25.53 months. The date of diagnosis ranged from May 2017 to August 2021. The majority were male (n=7). The median age at diagnosis was 58 years (minimum 35, maximum 73). Most had good performance status (PS): 4 had ECOG 0 and 4 had ECOG 1. Concerning tumor characteristics, most presented in the parietal lobe (n=7) and 6 were IDH wild type. Other genetic alterations were not evaluated. Four patients underwent macroscopic total resection, 3 underwent partial resection, 1 partial resection and subsequent total excision and 1 biopsy. All patients completed the STUPP protocol, with half of the patients on corticoids during the protocol. Of the 9 patients, 7 relapsed. After relapse, 2 patients underwent bevacizumab, 2 patients underwent total resection one with adjuvant STUPP protocol and one with adjuvant lomustine, 1 patient had radiotherapy and bevacizumab, 1 patient had bevacizumab and lomustine and 1 patient had temozolamide in monotherapy. Out of these, 6 patients had disease progression and only 4 received a second line of treatment. All 4 patients progressed and received treatment. Of these, 3 progressed and only 1 patient received therapy. At the end of follow-up, early April 2023, 4 patients were still alive.

CONCLUSION

With all these data profiles of long-term survivors of GBM and the pooled evidence from the literature, this extremely favorable prognostic group is still difficult to define. However, clinical and tumour characteristics of long-term survivors may differ from those of shorter-term survivors. In our series, long-term survivors were found to be IDH wild-type in the majority, young male, with good PS at the time of diagnosis and had GBM located in the parietal lobe. Larger series of patients and longer follow-up periods are needed to draw more robust conclusions about prognostic and predictive factors.
P11.57.B OVER ONE YEAR OF SURVIVAL DIFFERENCE BETWEEN DISTINCT COHORTS OF GLIOBLASTOMA PATIENTS
Authors: Poon M T C , Woo P Y M , El Helali A , Brennan P M
Published: September 2023

BACKGROUND

Understanding the differences in outcomes based on study and patient characteristics can inform better research designs and improve the interpretation of translational glioblastoma studies.

MATERIAL AND METHODS

This study compared the clinical features and median overall survival (mOS) of 2,203 patients from two genomic cohorts (The Cancer Genome Atlas [TCGA] and the Chinese Glioma Genome Atlas [CGGA]) and two consecutive regional cohorts (Hong Kong [HK] and Southeast [SE] Scotland) with histologically confirmed glioblastoma.

RESULTS

A total of 2,203 patients with newly diagnosed glioblastoma were identified, including 414 from SE Scotland, 1,033 from HK, 510 from TCGA, and 246 from CGGA. In patients who have available treatment data and received standard chemoradiotherapy, the mOS was 35.2 months (95%CI 27.1-50.2) in SE Scotland, 22.2 (95%CI 19.0-25.5) in HK, and 14.1 months (95%CI 11.8-17.9) in TCGA. Using data from 1,023 patients from SE Scotland (N=414) and HK (N=609) where sufficient data was available, the multivariable Cox regression model did not demonstrate survival differences among patients treated in HK compared to those treated in SE Scotland (hazard ratio 0.93; 95%CI 0.80-1.08; p=0.30).

CONCLUSION

Survival differences between distinct cohorts of glioblastoma patients warrant further investigations into associated determinants to assess reproducibility and generalizability of research.
P11.61.B TUMOR ASSOCIATED EPILEPSY AND RESTRICTION OF DRIVING PRIVILEGES IN THE FIRST YEAR AFTER BRAIN TUMOR SURGERY
Authors: Dimov D D , Lazarov S , Simon M
Published: September 2023

BACKGROUND

In most countries, the risk of postoperative seizures prompts regulations restricting driving privileges at least temporarily following brain tumor operations. The present study investigated the frequency of epileptic seizures and driving habits in the first year after brain tumor operations in a prospective and a retrospective patient cohort.

MATERIAL AND METHODS

The authors studied overall 523 patients undergoing surgery for a brain tumor at the authors’ institution (prospective cohort, 09/2021-09/2022: N=313 and retrospective cohort, 01/2020-12/2020: N=210). Clinical data were obtained by reviewing patient charts and through (telephone) interviews.

RESULTS

The cohort included 160 (30.6%) meningiomas, 135 (25.6%) glioblastomas, 111 (21.2%) metastases and 56 (10.7%) other gliomas. 135/523 (25.8%) presented with seizure(s). At 3 months (excluding early post operative seizures) overall 57 (10.9%; prospective vs. retrospective cohort: 13.2 vs. 8.1%) patients reported seizure(s). The seizure incidence at 1 year was 18.4% (prospective vs. retrospective cohort: 18.7 vs. 18.2%). 22/173 (12.7%) patients reported de-novo seizures at 1 year. Significant predictors of seizures at 1 year included preoperative seizures (p<0.001), an adverse preoperative and postoperative KPI (p=0.038 and p=0.001) as well as postoperative NANO (p<0.001) score and histology (e.g. meningiomas: 7.5%, metastases: 22.0%, glioblastomas: 38.5%, other gliomas: 18.8%; p<0.001). 219/318 (69.9%) assessable patients were not driving in 3 months. Reasons included no driver’s license (6.3%), death (7.9%), neurological deficits (38.4%), epilepsy (9.0%), and personal choice (12.9%). 91.3% of glioblastoma patients did not drive in 3 months (cf. metastases: 77.8%, other gliomas. 72.4%, meningiomas: 43.8%; p<0.001).

CONCLUSION

We documented a high incidence of postoperative seizures and potential risk factors in patients following brain tumor surgery. Our figures support postoperative restriction of driving privileges even in seizure-naive patients (12.7% de-novo seizures at 1 year). Of note, epilepsy was the reason for not driving after surgery for a brain tumor only in 9.0%.
P11.68.A INTRA-ARTERIAL ADMINISTRATION OF [68GA]GA-PSMA-11 IN MALIGNANT PRIMARY AND SECONDARY BRAIN TUMOURS; A NOVEL APPROACH THAT SIGNIFICANTLY INCREASES TUMOUR UPTAKE AND POTENTIAL OF/FOR THERANOSTIC STRATEGIES
Authors: Pruis I J , van Doormaal P , Balvers R K , van den Bent M J , Harteveld A A , de Jong L C , Konijnenberg M , Segbers M , van Dis V , van den Bosch T P , Verburg F A , Smits M , Veldhuijzen van Zanten S E M
Published: September 2023

BACKGROUND

Primary and secondary brain tumours carry a dismal prognosis and require new treatment strategies. First studies into novel radionuclide therapies have thus far yielded little success, potentially because of limitary uptake in tumour upon intravenous (IV) administration. The aim of the present study was to show that intra-arterial (IA) administration of radiopharmaceuticals will lead to much higher uptake and, consequently, to higher delivered dose to the tumour, which convincingly outweighs the systemic non-target uptake.

MATERIAL AND METHODS

Ten patients with malignant brain tumours (n=5 high-grade glioma (HGG), n=5 brain metastasis (BM)) twice received 1.5 MBq/kg [68Ga]Ga-PSMA-11 followed by PET-MRI at 90, 165 and 240 minutes post-administration, first upon IV and subsequently upon selective IA administration, with a median interval time of 5 days. Standardised uptake values (SUVs) were calculated for tumour, and non-target sites (contralateral healthy brain, salivary glands and liver) using volumes of interest (VOIs). Tumour-to-liver (T/L), tumour-to-salivary gland (T/SG) uptake-ratios and simulated achievable tumour doses with either [177Lu]Lu- or [225Ac]Ac-PSMA were calculated for each patient. Paired T-test and Wilcoxon signed rank-test were performed to compare outcomes.

RESULTS

All patients showed significantly higher uptake in tumour following IA administration compared to IV administration, with a median SUVmax of 142.8 (range: 31.3-336.8) versus 10.5 (range: 5.1-17.1, P=0.005). Healthy brain showed no significant uptake, independent of the route of administration (SUVmean range: <0.1-0.1). Uptake at non-target sites was comparable following IA and IV administration, resulting in more favourable T/SG-ratios of 8.4 (median, range: 1.8-18.9) for IA versus 1.8 (0.9-7.0) for IV; P=0.005 and T/L-ratios of 26.5 (7.4-68.7) for IA versus 1.8 (0.9-7.0) for IV; P=0.005. Simulations showed a maximum delivered dose to the tumours for a single treatment cycle to be 68 Gy (median, range: 5-282) for [177Lu]Lu- and 78 Gy (5-174) for [225Ac]Ac-PSMA when administered intra-arterially, versus 10 Gy (1-37) and 18 Gy (1-49), when administered intra-venously.

CONCLUSION

Selective IA administration of radiopharmaceuticals in malignant brain tumours leads to a significant and therapeutically relevant increase in target to non-target uptake ratios. This observation opens new avenues for the development of theranostic strategies for patients with HGG and BM whom we, to date, have no curative treatment to offer.