bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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 (&lt;6 months, 6-12 months, 12-24 months and &lt; 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 &lt; 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

Abstract

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 &gt;.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

Abstract

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

Abstract

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 &gt;600 days survival was performed using chi squared.

RESULTS
The median age 72 (33-84). Patients were selected due to age &gt;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 &gt;600 days. The chi-squared test was used to compare differences in groups with OS&gt;600 days (n=20) and OS&lt;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 &gt;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

Abstract

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 &lt; 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 &lt; 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

Abstract

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

Abstract

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

Abstract

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&lt;0.05), high-risk status (OR=3.71, p&lt;0.05), and resection extent/biopsy (OR=2.38, p&lt;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&lt;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.