bluuebunny/crossref_metadata_2025 huggingface dataset:
P17.07.A DIRECT COMPARISON OF LUNG-GPA AND LABBM PROGNOSTIC SCORES FOR PATIENTS WITH LUNG CANCER BRAIN METASTASES
Authors: Furman O , Keret S , Limon D , Waissengrin B , Bittan A , Blumenthal D T , Bokstein F , Wolf I , Zach L
Published: October 2024

BACKGROUND

Brain metastases (BM) are the most common malignant CNS tumors in adults, associated with decreased survival and severe impairment to quality of life. The majority of BM originate from lung cancer (40-50%), where availability of new drug therapies calls for personalized risk-benefit calculations. While several prognostic tools were developed to support therapeutic decision-making in the specific context of BM detection, our experience in the clinic suggests none is currently used routinely.

MATERIAL AND METHODS

We compared the predictive capabilities of two different prognostic scores on a retrospective cohort of 90 lung cancer patients treated for BM at the Tel Aviv Sourasky Medical Center. Both scores were computed for each patient. Lung-GPA score is based on age, Karnofsy performance status (KPS), number of BM, number of extra-cranial metastases and molecular features when relevant (for NSCLC patients, EGFR/ALK mutations, PD-L1 expression). LabBM score is based on levels of hemoglobin, albumin, CRP, LDH and platelets in blood tests taken at BM diagnosis.

RESULTS

Median age at diagnosis was 67.1 (range 36-88), 43 patients were female, mean number of BM was four (range 1-10), 79 patients had NSCLC, of which 15 (18.9%) had confirmed EGFR/ALK mutations, and 11 had SCLC. Median survival was 6.8 mo (range 0.5mo-103mo). Survival rates at 3mo, 6mo, and 12mo were 73%, 51%, and 40%, respectively. Both scores were significantly predictive of OS at these times, and direct comparison between them using ROC analysis revealed no differences in predictive ability for survival at 3mo (0.7 for LabBM and 0.67 for Lung-GPA); at 6mo (0.7 for LabBM and 0.74 for Lung-GPA) and at 12mo (0.61 for LabBM and 0.71 for Lung-GPA).

CONCLUSION

In a real-world cohort of patients with lung cancer BM we find that Lung-GPA score and LabBM score both show a similar prognostic ability. Future studies should examine whether predictive scores could improve by use of patient data currently not captured by either score, such as treatment response or neuroimaging-based features.
P17.13.B NANO-LM: AN UPDATED SCORECARD FOR THE CLINICAL ASSESSMENT OF PATIENTS WITH LEPTOMENINGEAL METASTASES
Authors: Le Rhun E , Nayak L , Lim-Fat M , Rudà R , Pentsova E , Forsyth P , O’Brien B J , Preusser M , Kumthekar P , Brandsma D , Weller M
Published: October 2024

BACKGROUND

There are no validated tools for the clinical neurological assessment of patients with leptomeningeal metastases. However, clinical examination during the course of the disease guides medical management and is part of response assessment in clinical trials. Standardization of clinical neurological assessment in LM is therefore essential, also because MRI may not always be obtained owing to rapid clinical deterioration and itself subject to rater disagreement.

MATERIAL AND METHODS

The RANO-LM group launched a 2-steps process, aiming at improving and homogenizing the clinical assessment in patients with leptomeningeal metastasis. We report here on the first step: the establishment of a consensus scorecard. The RANO-LM group had 9 virtual meetings to define general recommendations on neurological assessment and selected domains of interest that should be tested. Domains of interest were selected from the Neurological Assessment in Neuro-Oncology (NANO) scale and from the first RANO-LM proposal.

RESULTS

Fourteen domains in neurological assessment were selected: level of consciousness, cognition, nausea and vomiting, vision, eye movement, facial strength, hearing, swallowing, dysarthria, limb strength, ataxia, walking, cauda equina symptoms-bowels and cauda equina symptoms-bladder). For each item, a clear instruction on how to perform the assessment is provided with scoring criteria between 0 and 2. The general status of the patient and use of steroids, pain medications, and anti-emetics should be considered when assessing the patient. Neurological sequelae from previous brain metastases or treatment (neuropathy, post-radiotherapy toxicities) should be rated at the baseline evaluation; it should be specified in the comments when symptoms or signs may be related to a condition other than leptomeningeal metastasis. The evaluation should be declared as non-evaluable when neurological symptoms or signs that develop during the follow-up are related or suspected to be related to comorbidities or any other medical event. In these situations, specific details should be included in the comments. If these signs and symptoms are retrospectively interpreted as related to leptomeningeal metastasis and not to any comorbidity, the date of symptoms or signs appearance should be retrospectively back-dated to assess the response.

CONCLUSION

A NANO-LM consensus scorecard has been established. A prospective validation of the proposal is currently ongoing at various medical centers.
P17.14.A OPTIMISATION OF THE STEREOTACTIC RADIOSURGERY (SRS) SERVICE AT THE BEATSON, WEST OF SCOTLAND CANCER CENTRE (BWOSCC)
Authors: Walker S , Nowicki S , James A , Williamson A
Published: October 2024

BACKGROUND

Since 2017 HyperArc™ VMAT SRS has been offered at BWOSCC as a treatment option for patients with brain metastases. During this period, WBRT (whole brain radiotherapy) or PB(Partial Brain)RT for the treatment of brain metastases has correspondingly reduced. Given the reduction in side effects, improved local control and reduced visits with SRS over WB/PBRT, the dedicated neuro-oncology team want to ensure all patients eligible for SRS treatment are being offered it, identify barriers to referral and ways to optimise the service.

MATERIAL AND METHODS

57 patients treated with WB/PBRT for brain metastases were identified via the RT database from August 2022-September 2023. Patients with primary small cell lung cancer, post-neurosurgical resection site or leptomeningeal disease were excluded. Patient demographics; primary site; number of brain metastases; diagnostic imaging; geographical location; RT dose and fractionation and survival post-treatment were documented and analysed. Diagnostic imaging for each patient was peer-reviewed by two consultant clinical oncologists, a SABR clinical research fellow and consultant neuro-oncology radiographer to determine whether SRS treatment was technically deliverable. Where it was felt SRS treatment was an option, the patient’s electronic record was interrogated to identify reasoning as to why SRS was not offered.

RESULTS

The majority of patients had either primary breast(26) or lung(22) cancer: gynaecological(3); colorectal(2); oesophageal(2); CUP(1); urothelial(1). All patients except 2 were treated with 20gy/5# (otherwise 30Gy/10#). Most were treated with WBRT(43). 14 had single brain metastasis; 20: 2-4 metastases; 9: 5-10 metastases; 14 patients had ≥11 brain metastases. 27 had MRI imaging in addition to CT. Most patients’ geographical location was outside of Glasgow(35). In 16 of the 57 patients identified(28%), SRS was technically deliverable. Median survival was 145 days(4.8months): within the technically deliverable SRS group, median survival was also 145days(4.8months).In these 16 patients, 7 were not offered SRS due to widespread systemic disease (not necessarily a barrier to SRS). There was no identifiable rationale in the remaining 9.

CONCLUSION

From this work we have identified up to 16 potential patients (28%) who could have been offered SRS treatment. As an innovative and committed centre, we want to optimise this service further. Moving forward, we will survey the consultant body to ask what they believe the potential barriers to SRS referral are, and deliver tumour-site-specific and hospital-wide education sessions on SRS treatment and delivery. After these educational interventions, we will review a further 6 months of patient data and compare to this work.
P17.20.A REVERSAL OF EPIGENETIC DYSREGULATION IN BREAST CANCER BRAIN METASTASIS VIA HDAC1/2 INHIBITION
Authors: Luzietti L , Gomez G , Zwart W , Prekovic S , Young L , Damir Vareslija D
Published: October 2024

BACKGROUND

Breast cancer metastasising to the brain poses significant clinical challenges due to its severe prognosis and limited treatment options. Investigating the molecular mechanisms behind breast cancer brain metastasis (BCBM) is crucial for the development of targeted therapies. The adaptability of cancer cells in the brain, likely driven by epigenetic modifications, highlights the potential for targeted epigenetic interventions.

MATERIAL AND METHODS

We analysed a clinically characterised cohort of primary breast tumours and brain metastases using RNA sequencing for pathway enrichment. This was complemented by integrating Chromatin-Immunoprecipitation (ChIP)-seq data with brain metastasis transcriptomes and conducting pharmacological screening across various cell line models to pinpoint vulnerabilities.

RESULTS

Our research identified a pivotal role for the co-REST transcriptional network and its associated histone deacetylases (HDACs) in managing brain metastasis. Elevated REST levels were linked to poorer outcomes in brain metastasis cases. Pharmacological assessments pointed to the HDAC pathway as a viable therapeutic target, corroborated by in vitro and ex vivo validations using patient-derived organoids. Crucially, targeting HDAC1/2 with quisinostat effectively hindered metastatic progression—a notable improvement over outcomes from singular HDAC targeting, as seen in glioblastoma studies. Further mechanistic investigations highlighted the involvement of the HER/AKT/mTOR and TGF-β pathways in BCBM.

CONCLUSION

Our findings establish the REST/HDAC axis as a key promoter of BCBM. Quisinostat, by specifically inhibiting HDAC1/HDAC2, demonstrated significant effectiveness, indicating its potential as a management strategy for brain metastases. This approach underscores the promise of HDAC inhibitors with enhanced selectivity and brain penetration as emerging tools in neuro-oncology.
P17.27.B TOWARDS IMPROVED PROGNOSTICATION: A LOOK AT SURVIVAL SCORE ACCURACY IN ELDERLY PATIENTS WITH SURGICALLY TREATED BRAIN METASTASES
Authors: Gubian A , Sulejmani A , Rinkel G , Etminan N , Brehmer S
Published: October 2024

BACKGROUND

Because of demographic changes in highly developed countries, the number of elderly patients requiring surgery for brain metastasis is increasing. However, concerns for risk-benefit ratio, ability to tolerate invasive treatment, and limited healthcare resources may explain why intracranial surgery is often declined in elderly patients. Although prognostic scores have been implemented to predict survival of patients with intracranial metastasis, no evaluation of those scores for the elderly population exist. We aimed to address the lack of data on the accuracy of prognostic scores in this specific population.

MATERIAL AND METHODS

Patients over the age of 65 who underwent surgery for intracranial metastases between 2015 and 2022 at the Department of Neurosurgery, University Hospital Mannheim (Germany) were retrospectively analysed. The evaluated prognostic scores included the recursive partitioning analysis (RPA) and the disease-specific grade prognostic assessment (ds-GPA). A log-rank analysis was conducted to assess differences in predicted versus observed survival. To further define the different model’s performance metrics, survival was classified into four classes (<6 months, 6-12 months, 12-24 months and < 24 months), and a confusion matrix was generated. The primary endpoint was the accuracy of prediction of survival in elderly patients with surgically treated intracranial metastases.

RESULTS

A total of 83 patients who underwent surgery for intracranial metastases between 2015 and 2022 were analysed. RPA and ds-GPA scores could be attributed for 83 and 77 patients, respectively. The mean age was 73.2 years. The 0.5-, 1-, 2- and 3-year probabilities of overall survival were 47%, 36%, 24% and 18% in the studied population, respectively. These probabilities were predicted to be 3%, 0%, 0% and 0% by the RPA model and 25%, 6%, 1% and 0% by the ds-GPA model. A statistically significant difference was observed between the predicted and actual survival rates in the studied population (p-value < 0.005). Using the categorised survival and a confusion matrix, the accuracy, recall, precision, and F1-score for the RPA model were 0.41, 0.17 and 0.24, respectively. The recall, precision, and F1 score for the DS-GPA model were 0.39, 0.36 and 0.31, respectively. Conclusion: Our analysis revealed a statistically significant discrepancy between predicted and actual survival in elderly patients with surgically treated intracranial metastases. These findings underscore the critical need for developing updated prognostic scoring systems specifically tailored to this population.
P17.29.B UNVEILING MEMORY DECLINE POST-SRS: DIFFERENTIAL EFFECTS OF HIPPOCAMPAL DOSE ON COGNITIVE FUNCTION IN PATIENTS WITH BRAIN METASTASES
Authors: van Grinsven E E , Cialdella F , David S , Verhoeff J J C , Philippens M E P , van Zandvoort M J E
Published: October 2024

BACKGROUND

Brain metastases (BMs) occur in ten to thirty percent of the adult cancer population and are often treated with stereotactic radiosurgery (SRS). Even with high dose fall-off at tumor borders, such as in SRS, some radiotherapy dose gradient will fall outside the BMs to ensure adequate tumor coverage. This may include radiation to the neural stem cell regions, like the subventricular zone (SVZ) and the hippocampus (HPC), which can possibly play a role in neurocognitive functioning (NCF). Patients with BMs commonly experience radiation-induced cognitive decline, yet the underlying mechanisms remain incompletely understood. In this retrospective study, we aimed to elucidate the impact of radiotherapy dose on the SVZ and HPC and subsequent cognitive changes three months post-SRS, focusing on memory and information processing speed (IPS).

MATERIAL AND METHODS

The study population consisted of 36 adult patients with BMs that were referred for SRS. Neurocognitive assessments were performed before and three months post-SRS and reliable change indices were calculated to asses cognitive changes. The SVZ and HPC regions were acquired via nonlinear registration of brain atlases (COBRA and SVZ atlas) on pre-SRS T1 MRI images using CAT12 and median radiotherapy dose per region was calculated.

RESULTS

Multivariable linear regression analyses corrected for age, previous radiotherapy, number of brain metastases, and previous systemic therapy indicated a significant association between higher radiotherapy dose to the HPC and decline in memory performance, specifically in HVLT-R immediate recall (β = -0.787, p =.011) and delayed recall (β = -0.587, p =.036), and ROCFT delayed copy (β = -0.700, p =.046). Conversely, no significant association was found between radiation dose to the SVZ and memory, nor between dose to either region and IPS (p >.05).

CONCLUSION

These results suggest potential benefits of minimizing radiation exposure to the HPC, even with SRS, to help preserve memory function in patients with BMs. Further prospective evaluation is warranted to validate these findings and inform clinical decision-making regarding radiation therapy protocols for preserving NCF in this patient population.
P18.10.B CLINICAL AND NEUROPATHOLOGICAL MARKERS FOR DISTINGUISHING BETWEEN IDH-MUTANT ASTROCYTOMAS OF WHO GRADE 2 AND 3
Authors: Blobner J , Harter P N , Weller J , Teske N , Ruf V , Schönecker S , Forbrig R , Albert N L , von Baumgarten L , Tonn J , Thon N , Karschnia P
Published: October 2024

BACKGROUND

The neuropathological criteria of anaplasia to distinguish between IDH-mutant astrocytomas of WHO grade 2 and 3 are ill-defined by the WHO 2021 classification. Following the positive phase III trial results and the expected approval of Vorasidenib for astrocytomas grade 2, a salient point of the discussion remains which markers might be of prognostic relevance to distinguish between grade 2 and 3 tumors.

MATERIAL AND METHODS

We retrospectively searched our institutional database for patients meeting the diagnostic criteria for IDH-mutant astrocytomas according to the WHO 2021 classification. Clinical, neuropathological, and molecular data were collected; and outcome was compared using log-rank analysis. Prognostic markers identified on univariate analysis were forwarded into a multivariate model.

RESULTS

We identified 99 patients with IDH-mutant astrocytomas in which detailed neuropathological and clinical information were available for review, including 63 tumors (63.6%) which were assigned to WHO grade 2 and 36 tumors (36.4%) assigned to WHO grade 3. At a median follow-up of 7.5 years, median progression-free survival was 5.7 years for WHO grade 2 tumors and 4.4 years for WHO grade 3 tumors. Median overall survival for WHO grade 2 and WHO grade 3 tumors was not reached. On univariate analysis, higher WHO grade, an increased number of mitoses on histopathology, elevated Ki67 indices on immunohistochemistry, and the presence of contrast enhancement on pre-operative imaging were associated with less favourable outcome. However, only the presence of contrast enhancement retained its prognostic significance when forwarded into a multivariate model (p = 0.034 for overall survival, p = 0.012 for progression-free survival). The findings on the association between contrast enhancement and outcome were confirmed in treatment-based subgroups, including individuals treated with a watch-and-scan approach (n = 30), radiotherapy (n = 25), or chemotherapy (n = 33). Notably, neuropathological measurements of proliferation were generally higher in patients who underwent open resection compared to biopsy.

CONCLUSION

While our findings await confirmation in larger prospective cohorts, neuropathological criteria for anaplasia might need to be accompanied by clinical information including contrast enhancement to prognostically distinguish grade 2 from grade 3 tumors particularly in patients undergoing biopsy given the risk for undersampling. Centralized slide review is currently ongoing to exclude neuropathological inter-rater variability due to the retrospective nature of our study.
P18.11.A CLINICAL OUTCOMES OF GLIOBLASTOMA MULTIFORME TREATED WITH HYPOFRACTIONATED (40GY/15 FRACTIONS) RADIOTHERAPY: THE WESSEX EXPERIENCE
Authors: Khoury E , Clarke E , Ching J , Main S
Published: October 2024

BACKGROUND

IDH wildtype Glioblastoma Multiforme (GBM) is the most common and aggressive form of primary brain malignancy. Hypofractionated cranial irradiation with 40Gy in 15 fractions is commonly used for those over the age of 65 or with a worse performance status. The Perry regimen (2017) provided evidence for the combination of chemotherapy (concurrent + adjuvant) with short course radiotherapy. This study provides a real world experience of short course radiotherapy in a UK tertiary centre.

MATERIAL AND METHODS

A retrospective observational study based on electronic patient records March 2016-May 2022 in a large UK tertiary centre (N=77). All patients received 40Gy in 15 fractions ± concurrent/adjuvant temozolomide chemotherapy. Overall Survival (OS) and Progression Free Survival (PFS) were assessed using Kaplan Meier methodology and Cox proportional hazards modeling with the R language for statistical programming. Subgroup analysis of those >600 days survival was performed using chi squared.

RESULTS

The median age 72 (33-84). Patients were selected due to age >70 years or due to performance status of 2. All completed radiotherapy, 44 (57.1%) were MGMT promoter methylated, 57 (74%) received concurrent chemotherapy, 42 (54.5%) received adjuvant chemotherapy, 33 (42.9%) followed a Perry regimen. Median OS (mOS) for the whole cohort is 11.3 months (95%CI:9-13.7 months) and PFS 8.17 months (95%CI:5.43-12.7). On univariate analysis adjuvant chemotherapy (p=0.0068) predicts survival and MGMT promoter methylation status trends towards this (0.063). Concurrent chemotherapy and extent of resection do not. On Cox proportional hazard modeling, adjuvant chemotherapy independently predicts survival (Hazard ratio 0.55, p=0.019), age, concurrent chemotherapy, performance status, extent of resection and MGMT methylation status do not. In those aged over 65 (N=62), mOS 9.67months (95%CI:8.47-13.37). Only adjuvant chemotherapy predicts survival (p=0.0067) in this cohort. In those with MGMT promoter methylation, mOS 13.4 months (95%CI:9.3-18.47). Use of concurrent and adjuvant chemotherapy has a significant impact on survival: 19.67 months vs 8.5 months (p=0.00078). Over a quarter of patients (25.9%) survive >600 days. The chi-squared test was used to compare differences in groups with OS>600 days (n=20) and OS<600 days (n=57). No significant differences could be identified.

CONCLUSION

This data shows comparable survival outcomes with reference to the Perry regimen (2017). In this cohort, the most important factor in predicting survival was adjuvant chemotherapy rather than: extent of resection, age, performance status, MGMT methylation status and concurrent chemotherapy. Over a quarter of patients survived >600days. In this cohort it has not been possible to delineate factors which may explain this. Further work is needed to investigate this.
P18.14.A DOES WHERE YOU LIVE INFLUENCE GBM SURVIVAL? - A SINGLE CENTRE EXPERIENCE
Authors: Silva I , Choudhury M , Baig A , Stone A , Vaqas B
Published: October 2024

BACKGROUND

Glioblastoma (GBM) is the most common and aggressive form of primary brain tumour in adults. The treatment of these tumours involves biopsy or surgical resection, oncological treatment and/or best supportive care. Patients who undergo maximum resection followed by chemotherapy and radiotherapy still have a dismal survival of only 15.4 months. It is known that deprivation can influence access to cancer services and treatment, but it remains unclear if socio-economic factors influence survival in GBM when compared with other factors in a National Health Service. Aim was to investigate the influence of socio-economic factors, on the survival of patients diagnosed with GBM in a major neurosurgical centre in the UK serving a population of 2.5 million in a mix of urban and rural areas.

MATERIAL AND METHODS

A retrospective analysis was performed of all patients operated between January 2021 and December 2021 with a diagnosis of GBM. Data collected included post code, age, extent of resection, oncological treatment, survival, ethnic background, referral pathway and social connections. In addition, social information from the UK Census was accessed including the Index of Multiple Deprivation (IMD) which are a series of datasets consisting of multiple components of deprivation used to classify relative deprivation. Survival analysis was performed using Kaplan-Meier plots, Cox proportional hazards models and stratified Cox models.

RESULTS

The median overall survival (OS) was 7 months. Age was a significant predictor of survival, with each additional year increasing the hazard of death by 3.38% (HR = 1.0338, 95% CI: 1.016 to 1.052, p < 0.001). The extent of surgical resection was significantly associated with survival. Patients who underwent GTR had a median OS of 11 months, compared to 7 months for STR and 5 months for biopsy (HR = 0.5943, 95% CI: 0.4563 to 0.7739, p = 0.000113). Receipt of further treatment was associated with a 76.1% reduction in mortality risk (HR = 0.239, 95% CI: 0.1549 to 0.3687, p < 0.00001). Extent of surgical resection was associated with increased likelihood to receive treatment post-operatively. No significant association was found between IMD decile and OS when stratified by the type of resection (HR = 0.9796, 95% CI: 0.9116 to 1.053, p = 0.575)

CONCLUSION

Our data confirms that age, extent of surgical resection and further treatment are significant predictors of survival in GBM patients. More extensive surgical resection was also associated with a higher likelihood of further treatment, particularly CRT. Socio-economic status, as measured by IMD, did not significantly impact survival outcomes in this cohort. This study did not measure the impact of socioeconomic status on the quality of patient experience. A further qualitative study is being designed to ascertain this. Further studies are needed to see if socioeconomic factors influence outcomes in low grade gliomas.
P18.17.B EFFECTIVENESS OF DABRAFENIB-TRAMETINIB AND LAROTRECTINIB IN ADULT RECURRENT GLIOBLASTOMA PATIENTS: A REAL-LIFE COHORT ANALYSIS FROM 3 ITALIAN CENTERS
Authors: Padovan M , Cella E , Bosio A , Maccari M , Cerretti G , Caccese M , Corrà M , Giordano P , Bennicelli E , Lombardi G
Published: October 2024

BACKGROUND

Although less than 5% and 1.5% of glioblastomas (GBM) exhibit the BRAFV600E mutation and NRTK fusion, respectively, these cases are significant because some of these patients (pts) may respond well to BRAF/MEK and NTRK inhibitors. Given limited literature, this study aims to evaluate the efficacy of dabrafenib-trametinib and larotrectinib in treating adults with recurrent GBM.

MATERIAL AND METHODS

We retrospectively analyzed a cohort of adult pts with recurrent GBM (WHO 2021) treated in 3 italian centers: Veneto Institute of Oncology (Padua), Ospedale Policlinico San Martino (Genoa), Ospedale del Mare (Naples). Molecular analysis was obtained on formalin-fixed paraffin-embedded tissue samples with next-generation sequencing analysis, PCR or immunohistochemistry. Dabrafenib-trametinib was given as part of compassionate use program or off-label, while larotrectinib has an agnostic approval. Response assessment was based on RANO (Response Assessment in Neuro-Oncology) criteria.

RESULTS

Between March 2020 and November 2023, 17 recurrent GBM pts (12 males, 5 females, median age 52) received target therapy: 13 pts with dabrafenib-trametinib, 4 with larotrectinib. 12 pts had ECOG PS 0-1. All had prior radiotherapy and temozolomide. Median line of therapy with target therapy was 2 (range 2-4), with a median of 6 cycles (range 1-48) of treatment. As of April 2024, median follow-up was 7.6 months. In the entire cohort, median overall survival and progression-free survival (PFS) after starting target therapy were 8.8 and 2.8 months, respectively. Dabrafenib-trametinib subgroup showcased the most prolonged median PFS (5.09 m), alongside a notable disease control rate (DCR) of 77% and an objective response rate (ORR) of 30.7%. Among the 13 pts included, 9 had died while 3 pts are presently undergoing active treatment. Pts treated with larotrectinib exhibited a shorter median PFS (2.5 m), with a DCR of 50%; no patient reported a response (ORR 0%). 3/4 pts had passed away, one pt is currently continuing larotrectinib.No grade 3-4 drug-related adverse events were observed in either subgroups; in any case target therapy was interrupted for toxicity.

CONCLUSIONS

Our results confirm the activity of dabrafenib-trametinib in BRAFV600E mutant GBM pts. Larotrectinib appears to have less activity than data reported in the literature for the pediatric population. However, additional investigations on largest cohorts are needed to elucitate correlations among patient outcomes, molecular characteristics, other prognostic factors, and the timing of target therapy.
P18.19.A EVOLVING STANDARDS: THE INTEGRATION OF NEW THERAPIES INTO NEUROONCOLOGY GUIDELINES
Authors: Lawson McLean A , Lawson McLean A C , Walter J , Senft C
Published: October 2024

BACKGROUND

In the swiftly progressing domain of neurooncology, continuously updated clinical guidelines are essential to integrate emerging therapeutic developments effectively. This study investigates the perspectives and challenges faced by neurooncology professionals regarding these guidelines, with an emphasis on their responsiveness to innovative treatments such as Tumor Treating Fields (TTFields).

MATERIAL AND METHODS

An electronic survey was distributed via the mailing list of the German Neuro-Oncological Working Group, encompassing demographic queries, attitudes towards clinical guidelines, and the assimilation of novel therapies like TTFields. The survey featured Likert-scale items, direct questions concerning the utility and adaptability of guidelines, and specific inquiries regarding the incorporation of TTFields into guidelines. Statistical validation was performed using chi-squared tests, Pearson’s correlations, and Fisher’s exact test.

RESULTS

Out of 87 valid responses, primarily from neurosurgeons (66.7%), a substantial majority (81.6%) affirmed that guidelines enhance the quality of treatment. Nevertheless, 32.2% expressed that these guidelines limit therapeutic freedom. With regard to TTFields, 78.2% were aware of its exclusion from the current DGN glioblastoma guidelines. Analysis indicated a positive correlation between the perception that guidelines enhance treatment quality and the advocacy for their regular revision. The survey also exposed variations in guideline perceptions across different demographic groups, illustrating diverse attitudes towards their utility and progressive adaptation.

CONCLUSION

Clinical guidelines in neurooncology are vital but must be frequently revised to accommodate the latest therapeutic advancements. The findings underscore the necessity for guidelines to adapt dynamically, maintaining their validity and applicability in clinical practice. This study highlights the critical balance between adhering to evidence-based standards and incorporating timely updates, particularly with the integration of innovative treatments such as TTFields.
P18.33.A PROGNOSTIC FACTORS OF MALIGNANT TRANSFORMATION IN LOW GRADE GLIOMA: A RETROSPECTIVE STUDY
Authors: Joanta-Gomez A , Furnari J , Chang R , Diaz M , Bagri-Manjrekar K , Ng C , Iwamoto F
Published: October 2024

BACKGROUND

Malignant transformation (MT) of low-grade gliomas (LGGs) represents a critical event in disease progression, requiring early identification of at-risk patients and the development of preventive strategies. This retrospective cohort study aimed to assess clinical, molecular, and radiological markers predictive of MT in LGG patients.

MATERIAL AND METHODS

Institutional database medical records of adult LGG patients (n=175) diagnosed between 1994-2018 were analyzed. MT was defined as histological confirmation of grade 3-4 after the 1st recurrence or new/increased post-progression enhancement (PPE) consistent with MT by multidisciplinary consensus. Patients were categorized into groups based on MT pattern: group 2-2 (no MT), group 2-3 (MT to grade 3), and group 2-4 (MT to grade 4). Risk factors from the EORTC adapted prognostic index were assessed and logistic regression examined their association with MT. Survival was evaluated using Kaplan-Meier analysis, and PPE’s predictive value for MT was calculated.

RESULTS

Among 55 patients with recurrent LGG, MT occurred in 35 (63.64%), primarily in males (57.20%) with a median age of 39.75 years. Astrocytoma (68.57%) and oligodendroglioma (31.43%) were common initial diagnoses. Majority of the MT patients (62.86%) were allocated to group 2-3. Multivariate analysis revealed 1p19q codeletion negative (OR=3.75, p<0.05), high-risk status (OR=3.71, p<0.05), and resection extent/biopsy (OR=2.38, p<0.05) as prognostic factors for MT. Survival analysis demonstrated longer post-recurrence survival in group 2-2 versus 2-3 and 2-4 (log rank p<0.05). A similar trend was observed in 1p19q codeletion positive versus negative and low-risk versus high-risk groups. PPE exhibited 72% sensitivity, 75% specificity, 83% positive predictivity, and 60% negative predictivity for MT.

CONCLUSION

MT in LGG patients was associated with unfavorable molecular characteristics (1p19q codeletion negative) and high-risk status. Further research is warranted to elucidate preventive strategies against MT occurrence.
P18.39.A SEIZURE PROPHYLAXIS IN GLIOMA SURGERY (SPRING): A MULTI-CENTRE, UNBLINDED, RANDOMISED TRIAL
Authors: Jenkinson M D , Bulbeck H , Rooney A , Thompson G , Burns J , Robinson T , Vale L , Erridge S , Watts C , Grant R ,   SPRING trial investigators
Published: October 2024

BACKGROUND

50-80% of all glioma patients will suffer from seizures during their lifetime. Over half of these patients will have drug resistant seizures. Seizure risk is increased peri-operatively, at tumour progression, and shortly before death. Current guidelines do not support routine use of prophylactic peri-operative anti-epileptic drugs (AED) in seizure naïve patients; despite this, levetiracetam is frequently prescribed for this indication. The aim of this trial was to determine the clinical and cost effectiveness of prophylactic levetiracetam in seizure naïve patients undergoing surgery for a glioma at reducing the risk of seizures.

MATERIAL AND METHODS

Seizure naïve patients with newly diagnosed glioma undergoing surgery (biopsy or resection) were randomised (1:1) to receive 12 months prophylactic levetiracetam or no prophylaxis at 14 neurosurgery and neuro-oncology units in the UK. Participants received standard of care neurosurgery and neuro-oncology treatment and were followed until death or for a maximum of one year. The primary outcome was one year risk of first seizure analyzed using a logistic regression model and intention to treat analysis. Outcomes were analyzed by intention-to-treat. The target accrual was 804 participants. This trial was registered with ISRCTN 49474281.

RESULTS

Between Oct 10, 2019 and Aug 30, 2022, we randomised 96 patients, from 24 to 79 years of age, to levetiracetam (n=49) or no prophylaxis (n=47). Due to slow accrual during the Covid-19 pandemic the trial closed early. In the levetiracetam group there were 43 high grade glioma (HGG) and 6 low grade glioma (LGG), and in the no prophylaxis group there were 43 HGG and 4 LGG. Seventeen (35%) of 49 patients randomised to levetiracetam had a seizure, compared to 15 (32%) of 47 patients randomised to no prophylaxis (OR 1.25, 95%CI 0.49-3.21, p=0.64). Median time to first seizure was 4.8 months in the levetiracetam group and 3.0 months in the no prophylaxis group. In the levetiracetam group 20 (41%) of 49 patients died within 12 months (median overall survival 6.8 months; range 0.2-11.9), and in the no prophylaxis group 15 (32%) of 47 patients died within 12 months (median 4.7 months; range 0.1-12.0). There were no serious adverse events or suspected unexpected serious adverse events related to levetiracetam.

CONCLUSION

Due to poor accrual caused by the Covid-19 pandemic the SPRING trial closed early and is therefore underpowered. Based on the limited data there was no difference in the 12 month seizure risk in the prophylaxis and no prophylaxis patients undergoing surgery for newly diagnosed glioma. The role of prophylactic anti-epileptic drugs remains undefined.
P18.40.B SET UP AND RECRUITMENT TO A RANDOMISED CONTROLLED TRIAL OF MEDICINAL CANNABINOIDS IN RECURRENT GLIOBLASTOMA - THE ARISTOCRAT TRIAL
Authors: Savage J , Mant R , Kirkham A , Buckle P , Banks E , Meade S , Boele F , Williams M , Collinson F , Billingham C , Short S C
Published: October 2024

BACKGROUND

ARISTOCRAT is a unique, randomised, double-blind, placebo-controlled phase II trial of cannabinoids (nabixomols) alongside temozolomide in patients with MGMT-methylated recurrent GBM.

MATERIAL AND METHODS

This UK based trial was funded through a crowdfunding campaign run by The Brain Tumour Charity in 2020 and a multi-disciplinary team of co-applicants including PPI representatives designed the protocol, which randomises patients with first recurrence of IDH wild-type GBM patients in a 2:1 ratio between nabiximols or matched placebo with standard dose temozolomide. Unique aspects include self-titration of nabiximols based on individual tolerance, and fully blinded randomisation with matched placebo. The primary outcome measure is overall survival time with key secondary outcomes including survival at 6, 12 and 24 months, progression-free survival time, health-related QoL and adverse events. The trial initially aimed to recruit a total of 234 patients over 18 months. Intermediate assessment of feasibility to confirm safety, compliance and achievability of recruitment was planned after 40 patients are randomised.

RESULTS

The trial opened in February 2023 and has promoted a high level of patient and public interest, including national press coverage. Despite this, recruitment has been slower than anticipated due to factors including slow site activation complicated by the blinding of a controlled drug, and low numbers of patients screened. We have not identified specific issues in our screening data but did, on request of local PIs broaden inclusion criteria to include patients who received short course (40Gy in 15 fractions) radiotherapy first line. To further address this we have highlighted the use of genomics data from Tessa Jowell BRAIN MATRIX, to identify eligible patients at first diagnosis who can then be flagged for study consideration at relapse. We have also initiated a unique collaboration to use real-world data [the GlioCova data set] to re-test our estimates for potential patient recruitment in the UK, which may suggest specific remedies to ensure the study can deliver definitive data in a realistic time frame.

CONCLUSION

ARISTOCRAT will provide unique, robust clinical data on the role of nabiximols (combined with temozolomide) in improving overall survival and the impact on QoL for patients with recurrent GBM and is the first of its kind in cancer patients. Challenges to set up and recruitment are being addressed using national support through the BRAIN MATRIX genomics platform and real-world modelling approaches.
P18.42.B TAU AND AMYLOID BETA PATHOLOGY IN IDH-MUTANT GLIOMA
Authors: Greutter L , Klotz S , Schnitzenlehner L , Kiesel B , Miller-Michlits Y , Makoli J , Krause E , Widhalm G , Baumann B , Woehrer A
Published: October 2024

BACKGROUND

With an aging population the incidence of brain tumors and neurodegenerative diseases is increasing. Although biological associations between glioma and Alzheimer’s disease (AD) have been suggested, the frequency of comorbidity is insufficiently defined. We here screen tumor-adjacent cortex of a representative cohort of patients with low grade glioma for AD neuropathological changes (ADNC) specifically for phosphorylated tau (pTau) and amyloid beta (Abeta) deposition, microglial activation, amyloid precursor protein (APP) expression, diffuse axonal injury, and cortical tumor cell infiltration.

MATERIAL AND METHODS

A total of 85 patients with astrocytoma, IDH mutant, CNS-WHO grade 2-3, (N=37, median age: 39) and oligodendroglioma, IDH mutant and 1p-19q co-deleted, CNS-WHO grades 2-3 (N=48 median age: 50) were included. 2µm sections were immunohistochemically stained for the markers b-A4, t-AT8, NeuN, APP and Iba1. Whole slide quantification was performed using Matlab and QuPath codes. For a subset of 15 patients, longitudinal samples were available for analysis of post-treatment effects.

RESULTS

The median cell density in the tumor-adjacent cortex was 1355/mm2 for astrocytoma and 1392/mm2 for oligodendroglioma, which was significantly higher than in non-tumor infiltrated cortex (median: 1030 cells/mm², p-value<0.0001). A total of 32 patients (38%) showed Abeta (14%, n=12/85) and/or pTau pathology (36%, n=31/85) in the tumor-adjacent cortex. No difference between astrocytoma and oligodendroglioma was reported. ADNC was mostly frequently observed in older patients but was also present in young individuals (median: 34 years, range: 17 to 77 years). pTau was significantly positively correlated with tumor cell infiltration (Kendall´s tau=0.13, p=0.002). Both Abeta and pTau deposits were frequently observed in the frontal cortex (30%, N=18/60). The tumor infiltration into the cortical regions was associated with neuronal loss (Kendall´s tau=-0.29, p<0.0001). Microglial activation depended on the degree of tumor infiltration (R=0.29), followed by increasing patient age (R=0.12). Diffuse axonal injury was associated with ADNC (Chi²=19.6, p<0.05). APP expression of tumor cells was highest in patients of old age (R=0.35). Longitudinal samples showed stable ANDC pathology in 15/15 subjects.

CONCLUSION

Our preliminary findings suggest presence of ADNC in roughly a third of patients with low-grade glioma, which increases with tumor cell infiltration into the cortex, microglial activation and patient age. Notably, isolated pTau pathology was more pronounced than Abeta pathology suggesting the acquisition of a secondary tauopathy.
P19.08.B MENINGIOMA: A CHALLENGE FOR RADIOLIGAND THERAPY. THE INITIAL EXPERIENCE OF TWO EUROPEAN CENTRES
Authors: Asadurova S , Flaus A , García-Burillo A , Lorenzo-Bosquet C , Lachachi B , Al Mansour L , Gonzalez M , Vieito M , Gamez-Cenzano C
Published: October 2024

BACKGROUND

Evaluation of the treatment with [177Lu}Lu-DOTA-TATE in patients with recurrent meningioma.

MATERIAL AND METHODS

International bicenter retrospective study including 6 patients with recurrent meningiomas treated with [177Lu}Lu-DOTA-TATE between 12/02/2019 and 11/03/2022. Prior to the treatment, the expression of somatostatin receptors has been confirmed by [68Ga]Ga-DOTA-TOC PET/CT. Patients received between two and four cycles of 7400 MBq of [177Lu}Lu-DOTA-TATE. To mitigate potential complications, 50% (3/6) received corticosteroids. We calculated the progression-free survival (PFS), the progression-free survival at 6 months (PFS-6) and the overall survival at 12 months (OS-12). As a secondary objective we assessed the somatostatin receptor expressing tumor volume (SSTR-TV), the total lesion somatostatin receptor expression (TL-SSTR), the SUVmax of the tumor, the pituitary gland and the liver on the [68Ga]Ga-DOTA-TOC PET/CT using Syngo.via software.

RESULTS

The mean age is 61±11.5 years, men:women 1:1. All patients were diagnosed with WHO grade II meningioma, 83% (5/6) with multifocal involvement, 83% (5/6) with intracranial location and 17% (1/6) had a spinal meningioma. One patient had the NF2 mutation. All patients have previously been treated with surgery and radiotherapy as first line treatment, achieving total resection (Simpson grade II) in 50%. 33.3% (2/6) of the patients received [177Lu}Lu-DOTA-TATE as a first line treatment post-recurrence, 33.3% (2/6) as a second line after proton therapy or [177Lu}Lu-DOTA-TATE (retreatment) and 33% (2/6) as a fourth line after somatostatin analogues, mTOR and angiogenesis inhibitors or others. The treatment has been well tolerated, showing asthenia in 50% (3/6), alopecia in 33% (2/6) and mild haematological toxicity in 50% (3/6) of the patients, two of them with multiple previous lines of systemic therapy. The PFS is 14.5 months, PFS-6 was achieved by 83%, and OS-12 is 100%. The patient with the lowest lesion SUVmax (5.2) and the lowest TL-SSTR (23.6 SUV-lbm x cm3) had the shortest PFS (6 months) and the patient with the highest SSTR-TV (68.2 cm3) and TL-SSTR (4206.78 SUV-lbm x cm3) had PFS of 7 months, significantly less than the cohort average. The best responder (17 months) had a small SSTR-TV (12 cm3) with a high TL-SSTR (165 SUV-lbm x cm3).

CONCLUSION

The treatment with [177Lu]Lu-DOTA-TATE in recurrent meningiomas is safe, well tolerated and demonstrates comparable PFS, PFS-6 and OS-12 with other systemic therapies. The total tumor burden (SSTR-TV) and the total lesion somatostatin receptor expression (TL-SSTR) might have an important role in patient selection and therapeutic outcome prediction.
P19.10.A POST-OPERATIVE HYPOFRACTIONATED RADIOSURGERY FOR INTERMEDIATE RISK MENINGIOMA
Authors: Ghosh D , Conger R , Choudhury A , Nguyen M P , Sethi I , Viner J , Oberheim Bush N , Morshed R A , Goldschmidt E , Braunstein S E , Raleigh D R , Chen W C
Published: October 2024

BACKGROUND

Conventional post-operative radiotherapy (RT) after resection of intermediate risk meningioma requires daily outpatient treatment for 6 weeks or more, which impose logistic and financial burdens on patients and the healthcare system. Although shortened course hypofractionated radiosurgery (hypoSRS) over 3 to 5 days has been applied for intact WHO grade 1 or imaging-defined meningiomas, no studies report on post-operative hypoSRS targeting the resection cavity after gross total resection (GTR) of intermediate risk meningiomas. To address this limitation in treatment for patients with the most common primary intracranial tumor, this retrospective case series investigated preliminary safety and efficacy data for patients undergoing hypoSRS after GTR of intermediate risk meningiomas.

MATERIAL AND METHODS

Seven patients (median age 62.2, interquartile range [IQR] 53.9-71.2, 57.1% female) who underwent GTR of intermediate risk meningioma, defined as primary WHO grade 2 (5 of 7, 71.4%), recurrent WHO grade 1 (1 of 7, 14.3%), or WHO grade 1 with a high risk molecular feature (1 of 7, 14.3%, BAP1 deletion), followed by post-operative hypoSRS, were identified. Meningiomas had a median of 4 mitoses/10 hpf (IQR 3-5) and MIB1 labeling index of 6.5% (IQR 4-8.5%) and were located at the convexity (4 of 7, 57.1%) or parasagittal regions (2 of 7, 28.6%). An institutional targeted DNA sequencing panel was performed on 4 of 7 meningiomas (57.1%). Of these, 3 were intermediate molecular risk (integrated grade 2) and 1 was high molecular risk (integrated grade 3). The hypoSRS target was comprised of at-risk dura and the resection bed without any expansion into brain parenchyma.

RESULTS

Patients were treated with a median dose of 30Gy in 5 daily fractions (range 25-30Gy, prescribed to a median 87% [IQR 68-89%] isodose line) to a median target volume of 13.6cc (range 7.4-49.9). Four patients were treated with linear accelerator based hypoSRS and 3 with frameless Gamma Knife Icon. Median volume of brain receiving at least 24Gy (V24Gy) was 7.8cc (IQR 3.0-18.0). At a median of 2.4 years of follow up (IQR 1.0-3.7), there were no recurrences, no occurrences of radionecrosis, and no CTCAEv5 G3+ toxicities.

CONCLUSION

As an alternative to 6 weeks of conventional post-operative RT, this case series suggests that hypoSRS is a safe and convenient treatment for patients with favorable anatomy after resection of intermediate risk meningioma. Larger studies with longer follow up are needed, and a future prospective trial of this approach is planned.