bluuebunny/crossref_metadata_2025 huggingface dataset:
P18.47.A THE PROGNOSTIC IMPACT OF CDKN2A/B HETEROZYGOUS DELETIONS IN IDH-MUTANT GLIOMA
Authors: Ippen F M , Hielscher T , Göbel K , Friedel D , Reuss D , von Deimling A , Wick W , Sahm F , Suwala A
Published: October 2024

BACKGROUND

Homozygous deletions of CDKN2A/B confer unfavorable prognosis in IDH-mutant gliomas and are a criterion for CNS WHO grade 4 in IDH-mutant astrocytomas, but the role of heterozygous CDKN2A/B deletions remains less well understood. The aim of this study was to assess the prognostic impact of CDKN2A/B heterozygous deletions in IDH-mutant low-grade astrocytoma and oligodendroglioma.

MATERIAL AND METHODS

Tissue samples diagnosed as astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant, 1p/19q co-deleted CNS WHO grade 2 and 3 were collected from the archive of the Institute of Neuropathology in Heidelberg. DNA methylation analysis was performed on formalin-fixed paraffin-embedded (FFPE) samples. Evaluation of the CDKN2A/B locus was performed by visual inspection of copy-number plots derived from methylation-array data for each case. Heterozygous and homozygous losses were assessed in relation to whole chromosomal or larger segmental losses and gains in the chromosomal profile. Survival was assessed using the Kaplan-Meier method.

RESULTS

A total of 334 low-grade glioma cases were identified. Those cases included 173 astrocytomas and 161 oligodendrogliomas. Heterozygous deletions in CDKN2A/B (37/173 in astrocytomas, 15/161 in oligodendrogliomas) did not confer worse survival outcomes compared to CDKN2A/B wildtype cases in neither low grade astrocytoma (p= 0.2458) nor oligodendroglioma (p= 0.2779), regardless of CNS WHO grade, which was further demonstrated on a subgroup of astrocytoma, IDH mutant CNS WHO 4 cases (p= 0.1143).

CONCLUSION

Our study suggests that heterozygous CDKN2A/B deletions do not confer worse survival rates with respect to OS and PFS in astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant, 1p/19q co-deleted CNS WHO grade 2 and 3.
P18.52.B UNVEILING THE IMPACT OF CANCER-IGG ON GLIOMA: INSIGHTS FROM BIOLOGICAL BEHAVIOR AND TUMOR MICROENVIRONMENT
Authors: Han X , Li H , Su L , Tian L , Wang W , Xiao Z , Guo H , Li X , Fan T , Zhou H , Xue X
Published: October 2024

BACKGROUND

Gliomas are the most common malignant brain tumor in the central nervous system, with high invasiveness and heterogeneity. In recent years, cancer derived immunoglobulin G (Cancer-IgG) has been drawing attention of researchers. Cancer-IgG was identified in tumors and could promote tumorigenesis and progression.

MATERIAL AND METHODS

In this study, we explored the expression pattern of Cancer-IgG using available datasets and validated with our own patient samples. A serious of loss- and gain-of function assays were performed to investigate the role of Cancer-IgG. Possible mechanisms were unveiled by co-immunoprecipitation and RNA sequencing.

RESULTS

Our result demonstrated that Cancer-IgG expresses in glioma. And the expression pattern is associated with poor prognosis and malignant molecular characterization. Functional assays confirmed that Cancer-IgG could promote glioma cells proliferation, migration, invasion and resistant to apoptosis. The cGMP/PKG/VASP pathway could be the underlying mechanisms by which Cancer-IgG has an effect. Evidence from co-culture assay suggest that Cancer-IgG could induce macrophages M2 polarization.

CONCLUSION

Collectively, Cancer-IgG could be identified in glioma cells and it could facilitate the malignant biological phenotype in vivo and in vitro. In glioma microenvironment, Cancer-IgG could induce M2 macrophages polarization.
P19.06.B EXPLORING FIBROBLAST ACTIVATING PROTEIN (FAP) EXPRESSION AS THERANOSTIC TARGET IN HIGH-GRADE MENINGIOMA
Authors: Mair M J , Hartenbach S , Tomasich E , Maas S L N , Bosch S A , Widhalm G , Eckert F , Sahm F , Hainfellner J A , Hartenbach M , Berghoff A S , Preusser M , Albert N L
Published: October 2024

BACKGROUND

The therapeutic management of higher-grade meningiomas is challenging given their high recurrence rates and limited treatment options after exhaustion of local modalities. Radioligand therapies such as [177Lu]Lu-DOTATATE targeting somatostatin receptors (SSTR) have shown promising results in small clinical trials and retrospective case series. Further studies on theranostic approaches targeting fibroblast activating protein (FAP) are ongoing in a variety of extracranial solid tumors.

MATERIAL AND METHODS

Formalin-fixed, paraffin-embedded tumor samples of atypical (WHO grade 2) and anaplastic (WHO grade 3) meningioma were immunohistochemically stained for FAP and SSTR2a. Antibodies used were monoclonal rabbit anti-FAP (clone JA56-11, Thermo Fisher Scientific) and monoclonal rabbit anti-SSTR2a (clone EP149, Cell Marque). Panel sequencing for frequently altered genes in meningioma (NF2, TRAF7, KLF4, SMO, AKT1, TERT-promotor, ARID, SUFU, PIK3CA) was performed using Illumina NextSeq, and DNA methylation analysis was done using Illumina 850k chips.

RESULTS

In total, samples of 58 patients were used for analysis, of whom 35/58 (60.3%) were female and median age was 60 years (range: 19-83). Included specimen were from first resection in 39 cases (67.2%). Original histological diagnoses were atypical meningioma in 30/58 (51.7%), chordoid meningioma in 9/58 (15.5%), anaplastic meningioma in 18/58 (31.0%) and rhabdoid meningioma in 1/58 (1.7%). Reclassification according to WHO 2021 identified CNS WHO grade 2 in 39/58 (67.2%), CNS WHO grade 3 in 18/58 (31.0%) and CNS WHO grade 1 in 1/58 (1.7%) patients. FAP expression was observed in 15/58 (25.9%) included samples, most markedly at tumor borders and in stroma-rich areas. Of these, 12 (80.0%) also showed membranous staining for SSTR2a, of whom 6 showed strong, 3 medium and 3 weak positivity. FAP expression was associated with malignant biological behavior, as 12/18 (66.7%) of CNS WHO grade 3 tumors (compared to 3/39, 7.7% of CNS WHO 2, p < 0.001) and 4/5 (80.0%) samples with homozygous deletion in CDKN2A/B were FAP-positive (p = 0.013). In addition, FAP expression was more frequently observed in patients with NF2 mutations (10/25, 40.0%) than in those with wild-type NF2 (5/33, 15.2%, p = 0.032). FAP-positive samples were numerically more common among tumors of malignant (4/8, 50.0%) than intermediate (int-A/int-B: 7/27, 25.9%) or benign (ben-1/2/3: 4/23, 17.4%, p = 0.069) methylation classes.

CONCLUSION

FAP is expressed in a subset of higher-grade meningioma samples, and further investigation of FAP-targeted radioligands is warranted. Given that SSTR2a and FAP are frequently co-expressed, potential synergistic effects of combination treatments can be investigated.
P19.11.B PRELIMINARY DATA FROM THE REGION ÖREBRO COUNTY MENINGIOMA PROJECT
Authors: Löfgren D , Olivecrona M
Published: October 2024

BACKGROUND

Meningioma is typically benign and is occasionally detected during examinations due to other reasons (e.g. suspected stroke, trauma). Reported incidence figures usually come from various registers, and most reported prevalence figures are estimations derived from incidence figures and survival data. The Region Örebro County meningioma project aims to gain a better understanding of the incidence and prevalence of meningioma in the population. With these preliminary data, we seek to ascertain the practical feasibility of our proposed search method.

MATERIAL AND METHODS

In the Swedish county of Örebro with 302,252 inhabitants (2019), all radiology departments are within the public healthcare system. The electronic radiology archive (ERA) includes all patients who have undergone any type of radiological examination in the region since its introduction in 1996. To determine the number of individuals with meningioma in the region and when they were diagnosed, we conducted free-text searches for the word “meningioma” with various spelling variations in ERA and included all patients where the word appears in ERA referrals or responses. Subsequently, using data from the region’s electronic medical records (EMR), we excluded all patients not residing within the region. We then manually reviewed these patients’ referrals, written reports and radiology examinations, to determine whether they have meningioma, the date of diagnosis, whether it was an incidental finding, and presence of multiple meningioma.

RESULTS

We identified 3,428 patients, of which 3,064 have been included in this study (being residents of the region). In a preliminary review, we have been able to identify 1,663 (55 %) patients with likely meningioma. Of the 1,663 patients, 5 % had a diagnosis date before the introduction of ERA. The median age was 73 (IQR 61-82) years. There were 24 % males and 76 % females. Multiple meningioma were found in 9 % of the patients. In the preliminary review 64 % were incidental findings, while 21 % and 15 % were classified as non-incidental and indeterminate, respectively.

CONCLUSION

Performing free-text ERA/EMR searches is a potential avenue to achieve better coverage when investigating incidence and prevalence of a disease such as meningioma in a public healthcare setting. In our initial review, it is evident that the method identifies and can retrieve meningioma patients from the ERA. Gender distribution, median age and multiple meningioma numbers are comparable to other reported meningioma populations. Based on our experience with this dataset, it is not advisable to rely solely on simple automated searches. Projects akin to this would likely be well suited for future automated image analysis (volumetric measurement, meningioma identification, etc.).
P19.13.A RESULTS FROM THE COSMIC PROJECT: CORE OUTCOME SETS FOR MENINGIOMA IN CLINICAL EFFECTIVENESS STUDIES
Authors: Jenkinson M D , Millward C P , Islim A I , Keshwara S M , Srikandarajah N , Brodbelt A R , Marson A G , Williamson P R
Published: October 2024

BACKGROUND

The minimum outcomes that should be measured and reported in all clinical trials for a specific health condition or health area can be defined by a Core Outcome Sets. The aim was to develop core outcome sets for cranial meningioma; for clinical trials (COSMIC: Intervention) and observational studies (COSMIC: Observation).

MATERIAL AND METHODS

An international study advisory group was formed with representation from charities (IBTA, TBTC, brainstust), neuro-oncology organisations (BNOS, EANO, EORTC, ICOM, RANO-PRO, SNO) and neurosurgery societies (SBNS, BIMS). Systematic literature reviews and trial registry searches were performed to identify outcomes reported in published and ongoing 1) meningioma clinical trials, and 2) studies of incidental/untreated meningioma. Outcomes were deduplicated and categorised. Individuals from stakeholder groups (including meningioma patients and carers, healthcare professionals, researchers) were invited to participate in 2-round, international, modified eDelphi surveys. The final core outcome sets were ratified through online consensus meetings.

RESULTS

The COSMIC: Intervention systematic review identified 660 verbatim outcomes, rationalized into 24 Delphi survey items. Following the consensus meeting, 15 outcomes were included in the final set. For COSMIC: Observation, 267 verbatim outcomes were identified and rationalized into 17 Delphi survey items. 16 outcomes were included in the final set. Eight core outcomes common to both COSMIC: Intervention and COSMIC: Observation COS: tumour growth, physical, emotional, and neurocognitive functioning, overall quality of life, progression-free survival, meningioma specific mortality and overall survival. Role and social functioning were core outcomes in COSMIC Observation but not COSMIC intervention.

CONCLUSION

COSMIC has defined the core outcome sets for use in future meningioma clinical trials and studies. Role and social functioning were important to incidental meningioma patients and likely reflects the anxiety and uncertainty around clinical treatment. The international stakeholder community will adopt and use these core outcome sets in future trials.
P20.02.B ANAPLASTIC ASTROCYTOMA AS A SECOND PRIMARY BRAIN MALIGNANCY IN PATIENT WITH NON-HODGKIN LYMPHOMA
Authors: Ardhini R
Published: October 2024

BACKGROUND

Malignant lymphoma survivor can develop second primary malignancies, but have been rarely reported to occur in central nervous system. Risk factor increasing second primary tumor is not well determined, possibly due to lymphoma subtype, patients demographic, previous chemotherapy or radiation therapy. We report a very rare case of anaplastic astrocytoma in patient with remission of non-Hodgkin’s lymphoma (NHL).

CASE PRESENTATION

43-year-old man presented with progressive weakness on the left extremity for the past two months followed by progressive headache and left pacial palsy. Patient had a history of diffuse large B-cell lymphoma (DLBCL) in the lower leg in the previous 5 years and had received systemic chemotherapy. He was on regular follow-up without any evidence of relapsing disease. Brain MRI showed heterogenous intraaxial lesion in the right periventricular white matter of frontal lobe with large peritumoral edema suggestive secondary central nervous system lymphoma. There were no evidence of reccurence disease in the lower leg or other active disease, and no blast cells were found in CSF examination. Craniotomy was performed and histopathological examination revealed Anaplastic astrocytoma, NOS, WHO grade III (based on the WHO 2016 classification). Then the patient received concomittant chemoradiation and adjuvant Temozolomide.

CONCLUSION

Second primary brain malignancy is extremely rare in patient with treated diffuse large B-cell lymphoma. Surgical management and pathological examination must be performed to obtain a definite diagnosis, and to rule out secondary central nervous system lymphoma.
P20.03.B ASSESSING QUALITY OF LIFE IN SCHWANNOMATOSIS: A SYSTEMATIC REVIEW
Authors: Lawson McLean A , Rosahl S , Lawson McLean A , Freier A , Löschner D , Kamp M , Neumeister A , Senft C , Demetriades A
Published: October 2024

BACKGROUND

The term schwannomatosis refers to rare genetic disorders associated with the development of multiple tumours within the central and/or peripheral nervous system. Recent advancements in our molecular understanding of these disorders have led to a redefined conceptual framework within the field. This revised framework groups nf2-related schwannomatosis with other forms of schwannomatosis resulting from various causative pathogenic variants, highlighting their distinct nature compared to neurofibromatosis 1.

MATERIAL AND METHODS

A comprehensive search of electronic databases, including PubMed, MEDLINE, and Scopus, was performed in August 2023. The search methodology entailed variations of keywords such as “neurofibromatosis 2,” “schwannomatosis,” “quality of life,” and “patient-reported outcomes.” Inclusion criteria encompassed studies evaluating QoL in schwannomatosis patients, utilising validated QoL appraisal tools or patient-reported outcome metrics. Case studies and reviews were excluded.

RESULTS

Initial searches yielded 224 articles after removal of duplicates. Following screening, 37 articles met inclusion criteria. These studies employed diverse assessment instruments, including the SF-36 (n=7), PHQ-9 (n=8), GAD-7 (n=5), and the disease-specific questionnaire NFTI-QOL (n=13). Interestingly, patients with nf2-related schwannomatosis overall had worse physical and emotional well-being than the general population, while non-nf2-schwannomatosis patients mainly reported worse pain than the general population.

CONCLUSION

This systematic review provides a comprehensive synopsis of QoL literature pertinent to patients with schwannomatosis. The findings underscore the imperative of a holistic patient-care paradigm, addressing not only tumour management but also the augmentation of overall well-being and QoL among affected individuals.
P20.24.A THE WIDE HISTOLOGICAL SPECTRUM OF ZFTA FUSED WITHOUT RELA FUSION SUPRATENTORIAL EPENDYMOMAS: FROM SARCOMA-LIKE TO EMBRYONAL TUMOR-LIKE
Authors: Xi S , Chen Z
Published: October 2024

BACKGROUND

According to the 5th World Health Organization (WHO) classification of the central nervous system, supratentorial-ependymomas (ST-EPN) RELA-fusion positive was replaced by ST-EPN, ZFTA-fusion positive. This modification reinforces the importance of the ZFTA gene in ST-EPN. The significant histopathological heterogeneity in supratentorial ZFTA fused without RELA fusion ependymomas (not RELA, ZFTA fused EPN) has raised concern recently, which included varied histological patterns.

MATERIAL AND METHODS

To expand the histological spectrum of not RELA, ZFTA fused EPN, we reported four cases of not RELA, ZFTA fused ST-EPN, and described the histological features of this uncommon entity.

RESULTS

In our cohort, one case showed small round cells with chondromyxoid or fibrous stromal components forming a sarcoma-like pattern. The second case presented a lobular or sheet-like pattern infiltrating with trapped glia. The tumor cells carried reticular cytoplasm, prominent cell membranes, and irregular wrinkle nuclei. They were strongly positive for cytokeratin, which resembled metastatic cancer. The third case showed an embryonal tumor-like pattern with relatively circumscribed but infiltrated cells, hypercellularity and necrosis were seen. Focal differentiation to neurocytes and ganglion cells could be observed. The tumor cells are partially positive for Neu-N. The last case presented the embryonal tumor-like pattern with highly cellular unstructured primitive areas and high-grade classic EPN histology like the rosettes and fibrillar areas with few nuclei. The first case carried ZFTA-MAML2 fusion, and three instances carried ZFTA-NOCA2 fusion. Three cases underwent DNA methylation profiling and were classified as EPN satellite clusters. The clinicopathological features and molecular alterations are summarized, one of the patients died during the follow-up.

CONCLUSION

Compared to the ST-EPN, RELA-fusion positive, not RELA, ZFTA fused ST-EPN often presented uncommon histological features, the adult cases often present morphology resembling sarcoma or metastatic cancer, and the pediatric cases present embryonal tumor-like histology. The subtype may carry a worse outcome.
P21.01.A CEREBELLOPONTINE ANGLE EPIDERMOID CYST WITH MALIGNANT TRANSFORMATION TO SQUAMOUS CELL CARCINOMA: UNUSUAL COMPLICATION OF A BENIGN INTRACRANIAL TUMOR
Authors: Garcilazo-Reyes Y J , Navarro-Fernández J O , Magos-Rodríguez D , Arias-Ruiz L F , Pérez-Díaz M L , Gómez-Apo E , Hernández-Montes de Oca R , Gutiérrez-Aceves G A
Published: October 2024

BACKGROUND

Intracranial epidermoid cysts (EC) account for approximately 0.2%-1.8% of all intracranial tumors. Extremely rare, these benign lesions may undergo malignant transformation into squamous cell carcinoma (SCC). The time frame for transformation can vary greatly, and the ideal management approach remains uncertain.

MATERIAL AND METHODS

55-year-old female patient with history of migraines was diagnosed with an incidental cystic lesion suggestive of EC in right cerebellopontine angle (CPA) since the age of 30. She experienced a sudden onset in March 2023 of auditory decline in her right ear, tinnitus, vertigo, headache, dysgeusia, and gait disturbance. Examination revealed involvement of the VIII right cranial nerve with sensorineural hearing loss and complete right facial nerve palsy. She underwent surgery in June 2023 where the cyst was resected however, the capsule of the tumor was strongly adhered to the brainstem, unable to be removed. It showed positive immunohistochemistry for p63, p40, CK5/6, CK7, D2-40, S100, PD-L1, Ki67 was positive in 20% of neoplastic cells, brachyury was negative, consistent with EC with malignant transformation to SCC. She developed few days after the surgery, dysarthria, diplopia, IV and VI right nerve palsies and right dysmetria. Neuroaxis contrast-enhanced MRI was performed with no evidence of lesion otherwise. Brainstem auditory evoked potentials, blink reflex test and facial nerve conduction tests were completed and abnormal due to axonal right facial nerve neuropathy with side-to-side ≥ 90% difference and profound right hearing loss.

RESULTS

The one-month follow-up brain MRI showed the right CPA lesion with heterogeneous enhancement with increase in diameter and involvement of the auditory canal. 18FDG) PET/CT demonstrated focal hypermetabolism (SUVmax 10.3) in the right CPA indicative of progression. She underwent radiosurgery with a total dose of 30 Gy in 5 sessions (October 2023). The follow-up 18FDG PET/CT (April 19, 2024) showed no distant sites associated with abnormal hypermetabolism but persistent focal hypermetabolism that decreased compared to previous exam (SUVmax 7.2). The patient is currently 11 months apart from her diagnosis without new neurological findings. Chemotherapy or checkpoint inhibitors have not been used yet.

CONCLUSION

We report a case of intracranial SCC derived from an EC, the occurrence this malignant transformation is uncommon and typically indicates a poor prognosis. Small series and case reports are to date available in the literature. After surgery, radiotherapy or radiosurgery should be considered, close follow-up is recommended, chemotherapy or immunotherapy can be used but its effectiveness remains unclear.
P22.10.B LOW-GRADE GLIOMA PATIENTS WITHOUT PROBLEMS IN DAILY FUNCTIONING: A SILENT MINORITY
Authors: Siebenga F F , van der Weide H L , Gelmers F , Rakers S E , Kramer M C A , van der Hoorn A , Enting R E , Bosma I , Groen R J , Jeltema H , Wagemakers M , Spikman J M , Buunk A M
Published: October 2024

BACKGROUND

Low-grade gliomas (LGG) represent a heterogeneous group of primary brain tumors. Although all patients with LGG face similar challenges in coping with an incurable disease, interestingly, a subset of patients reports no (significant) problems in daily functioning and appear to resume their activities without changes. It is crucial to identify the group of patients that seem to cope so well, in order to find possible indications to help patients who do experience problems in daily functioning. Therefore, the present study aims to characterize the LGG patient group without problems in daily functioning.

MATERIAL AND METHODS

144 patients with LGG were included post-surgery and before adjuvant therapy. Patients were divided into two groups: patients with and without problems in daily functioning, based on the Patient Competency Rating Scale (PCRS). Demographic variables, disease characteristics (tumor location, tumor volume), anxiety, depression (HADS), coping (UCL) and general cognition (neuropsychological tests) were analysed to identify characteristics specific to the patient group without problems in daily functioning.

RESULTS

Of the entire LGG cohort (mean age= 43 ± 12), 26.4% of the patients no (significant) problems in daily functioning. No significant differences were found for demographics (gender, age and educational level), disease characteristics and general cognition between patients with and without problems in daily functioning (p>0.05). However, patients without problems had significantly lower scores for anxiety (p<.01), depression (p<.01), avoidant (p=<.01) and passive coping (p<.001), compared to patients with problems in daily functioning.

CONCLUSION

More than a quarter of the patients with LGG experience no (significant) problems in daily functioning, after surgery and before adjuvant therapy. Notably, this subset of patients did not differ from patients with problems in daily functioning considering demographics, disease characteristics and cognitive functioning. However, the cohort of patients with no problems in daily functioning report lower levels of anxiety and depression, and use a more effective coping style, compared to patients who do experience problems in daily functioning. Therefore, it seems to be crucial addressing coping strategies, serving as a potential to help patients who do experience problems in daily functioning. Future research should focus on whether the patient group without problems in daily functioning continues to report zero complaints after adjuvant therapy, i.e. examining if an initial problem-free status serves as a protective factor during and after treatment.
P24.03.B PATIENT AND CAREGIVER VIEWS ON AN INNOVATIVE SURGICALLY IMPLANTABLE MEDICAL DEVICE TO DELIVER ELECTRIC FIELD THERAPY IN GLIOBLASTOMA
Authors: Purdy R , Thomson A , Bulbeck H , Munir N , Venters D , Koh K , Akhtar Q , Bullock C , Price S , Fu R
Published: October 2024

BACKGROUND

Glioblastoma (GBM) is the most common primary brain cancer in adults and carries a poor prognosis, with just 3% of those diagnosed surviving to 5 years. The standard of care (SOC) for glioblastoma has remained the same for the last 20 years: debulking brain surgery, chemotherapy, and radiotherapy. Electric field therapy (EFT), or Tumour Treating Fields (TTFields), is a promising novel treatment option for glioblastoma but there is just one commercially available device, applied to the head externally. It is currently unavailable to GBM patients in the UK through the National Health Service (NHS). QV Bioelectronics is developing an implantable medical device to deliver EFT, called GRACE, and has recently undertaken several patient and public involvement (PPI) studies alongside charity and clinical partners to understand the views of patients and caregivers on glioblastoma treatment and emerging EFT research.

MATERIAL AND METHODS

19 patients living with high grade glioma, of which glioblastoma is a subtype, and 6 caregivers were recruited to the PPI sessions. Four live workshops were conducted virtually in focus groups, each session lasting between 60 and 120 minutes. During the workshops, information was presented to participants with regular intervals for open-ended discussion. Material explored as part of the workshops included current treatment options for GBM, the design of GRACE, its eligibility criteria, and clinical trial design. A survey comprising 10 questions was also sent to a sample of participants prior to the workshops to understand views independent of technology developed by QV Bioelectronics.

RESULTS

The questionnaire was sent to 17 participants prior to the workshops, of whom 14 (82%) responded (8 patients and 6 caregivers). 100% strongly agreed that better treatment options for glioblastoma were needed, and only 21% were aware of TTFields as an approved therapy. 93% would consider an implanted medical device to deliver EFT as part of their or their close person’s treatment plan. During the workshops, the main concern expressed by participants was the impact of current treatment options on activities of daily living (ADLs) and quality of life. Participants felt that GRACE and its components were appropriate and would not hinder ADLs or negatively impact quality of life, and provided advice on patient-facing material. Participants expressed support for clinical trials and associated dissemination methods.

CONCLUSION

UK patients living with high grade glioma and their caregivers clearly outlined the current treatment gap in glioblastoma and the opportunities for improved therapy options.
P26.11.B PIWIL2 AS A POTENTIAL REGULATOR OF STEM-CELL PHENOTYPE IN GLIOBLASTOMA
Authors: Garcia-Borja E , Mateu R , Siegl F , Šána J , Šedo A , Bušek P
Published: October 2024

BACKGROUND

PIWI proteins are highly conserved RNA-binding proteins that constitute a germline-specific subfamily of Argonaute proteins. They bind to short non-coding RNAs known as piRNAs forming a piRISC (piRNA-induced silencing complex). The PIWI/piRNA complexes are pivotal in repressing transposable elements and regulating gene expression in stem cells. Recent findings reveal their implication in the progression of several cancer types, including glioblastoma (GBM). This study analyzed the expression profiles of the four human PIWI proteins (PIWIL1, PIWIL2, PIWIL3 and PIWIL4) in gliomas and in glioblastoma stem-like cells (GSCs), a critical subpopulation of malignant cells involved in GBM progression, treatment resistance, and recurrence.

MATERIAL AND METHODS

A panel of 160 GBMs (grade 4, IDHwt), 20 low-grade gliomas (grade 2 astrocytomas and oligodendrogliomas), and 12 non-tumorous brain tissues (pharmacoresistant epilepsy) was selected to examine the expression of PIWIL1-4 by qRT-PCR. 24 paired GSC and non-GSC cultures were derived from freshly resected human GBMs to analyze the expression of PIWIL1-4 by RT-qPCR.

RESULTS

PIWIL3 expression was not detected in an initial screening of 30 GBM tissues, leading to its exclusion from further analyses. PIWIL1 was detected in only half of the 160 GBM tissues, exhibiting very low expression. In contrast, PIWIL2 and PIWIL4 were present in the majority of tissues, with their expression being lower in GBMs compared to low-grade gliomas and non-tumorous brain tissues. In agreement with our results in tissues, PIWIL1 and PIWIL3 were either undetectable or expressed at very low levels in GSCs and non-GSCs. PIWIL4 was detected in both cell subpopulations displaying similar expression in GSCs and non-GSCs. In contrast, PIWIL2 expression was significantly higher in GSCs compared to non-GSCs and declined in GSCs upon serum-induced differentiation. Moreover, only PIWIL4 and PIWIL2, were detected in GSC-derived orthotopic tumors in immunodeficient mice.

CONCLUSION

Our findings challenge the previously reported upregulation of PIWIL1 in GBMs and its presumed relevance in GSCs. Instead, our data indicate potential contribution of PIWIL2 in maintaining the stem cell characteristics of glioma cells. Experiments aimed at silencing PIWIL2 with siRNAs in GSCs are currently ongoing. This work was supported by the Ministry of Health of the Czech Republic (NV19-03-00501), the National Institute for Cancer Research (Programme EXCELES, LX22NPO5102), the European Union - Next Generation EU, EATRIS-CZ (LM2023053), and Charles University Cooperatio Program, research area”Oncology and Haematology”.
P26.12.A REPURPOSING ITRACONAZOLE AND PYRIMETHAMINE WITH TEMOZOLOMIDE AS A COMBINATORIAL TREATMENT FOR GLIOBLASTOMA
Authors: Lootens T , Vandersteene J , Pinson H , Boterberg T , Vermeirssen V , De Wever O , De Smet F , Raedt R
Published: October 2024

BACKGROUND

Glioblastoma (GB) is marked by a poor median overall survival of 14-16 months despite surgery, radiotherapy and chemotherapy, highlighting the need for improving treatment. Drug repurposing offers the advantage of using commercially available compounds with known safety profiles, while simultaneously addressing the need for more effective and cost-efficient cancer treatments. However, preclinical or clinical evidence of efficacy is often lacking or merely anecdotal. In this in vitro study, we evaluated the therapeutic potential of combining repurposed agents itraconazole (ITR) and pyrimethamine (PYR) with low-dose temozolomide (TMZ) using primary GB patient-derived stem cell lines (PDSCLs).

MATERIAL AND METHODS

CellTiter-Glo cell viability assays were used to assess the effects of single and combination drug treatments in PDSCLs from both primary and recurrent GB. Staining with propidium iodide followed by flow cytometry was performed to investigate changes in cell cycle stages. Western blot and qPCR analysis to confirm the mode of action are ongoing.

RESULTS

Both ITR and PYR, at concentrations within the clinical plasma range, caused marked reductions in cell viability after 120h in a heterogeneous population of eight PDSCLs. Variable response rates were observed between cell lines with lowest IC50 values of 0.5 µM and 2.2 µM for ITR and PYR, respectively. Synergy analysis revealed mainly additive effects between the two drugs (Bliss scores of -4.93, 0.15, 1.79, 1.86, 4.19 and 7.67 in six PDSCLs). These effects were accompanied by an increased fraction of cells in the G1 phase after combinatorial treatment with ITR and PYR. Lastly, combining TMZ with this repurposed combination led to a significant decrease in cell viability across five PDSCLs after nine days of treatment, compared to TMZ monotherapy.

CONCLUSION

Our data shows that combining ITR and PYR with TMZ induces strong anti-cancer effects in PDSCLs, highlighting its potential as a combinatorial treatment for glioblastoma. In vivo validation and mode of action studies are currently ongoing. [This work was funded by a fellowship grant from “Fonds voor Wetenschappelijk Onderzoek” (FWO), grant number 1SH3H24N, and a project grant from the “Cancer Research Institute Ghent” (CRIG).]
P27.03.B BIOPSY VERSUS RESECTION IN GLIOBLASTOMA TREATMENT: A PROPENSITY SCORE-MATCHED ANALYSIS OF A RETROSPECTIVE COHORT
Authors: de Haan Y , Moussa A , Gerritsen J K W , Schnitzler S J P , Dirven C M F , Vincent A J P E
Published: October 2024

BACKGROUND

Overall survival (OS) of glioblastoma patients remains poor, even with surgical treatment and adjuvant therapy. Gross-total resection is preferred whenever possible; when this cannot be achieved due to e.g. age or critical tumour localization, biopsy is often performed. To date, no objective guidelines are available to determine what type of surgery is most appropriate for glioblastoma patients. The choice between resection or biopsy remains a comparative assessment between maximizing survival and preventing postoperative neurological deficits. We aimed to identify which treatment strategy benefits specific subgroups of glioblastoma patients with regards to OS and maintaining neurological function.

MATERIAL AND METHODS

This retrospective cohort consists of patients recruited in a tertiary hospital in The Netherlands. Eligible patients were 18 years or older and had undergone either biopsy or resection. Secondary glioblastomas or patients with a Karnofsky Performance Status (KPS) of 50 or lower were excluded. Nearest-neighbor propensity score matching was utilized to create comparable biopsy versus resection cohorts based on sex, age, hemisphere, location, ASA score, year of presentation, pre-operative NIHSS, pre-operative KPS, tumour volume, tumour crossing of the midline and undergoing of adjuvant treatment. Survival outcomes were analyzed using the log-rank test, while NIHSS deterioration (increase of at least 1 point) was assessed using a Chi-squared test.

RESULTS

Between January 1st 2018 and December 31st 2022, 317 patients were recruited, with 98 undergoing biopsy and 219 undergoing resection. Matching resulted in equal cohorts of 86 patients each. The median OS of the unmatched cohort was 9.4 months. However, in the matched cohort, median OS significantly favored resection over biopsy, with 8.8 months versus 3.2 months respectively (p=.004). Regarding NIHSS deterioration at 6 weeks postoperative, we found a possible favoring of resection with 38.5% deterioration in the biopsy group (n=20 of 52 who had follow-up data) and 25.9% in the resection group (n=21 of 81 who had follow-up data). Non-significance of this finding (p=.182) might possibly be due to unequal missingness in follow-up data. We are currently expanding our recruitment to include patients from 2010 onwards to allow for predictive regression analysis and subgroup analysis with regards to age, pre-operative NIHSS score, pre-operative KPS score, midline location and multifocality.

CONCLUSION

Analysis of this matched cohort of glioblastoma patients undergoing biopsy and resection, favors resection with regards to both OS and preserving neurological functioning. Subgroup analysis will follow to better inform physicians and patients in their clinical decision-making.
P27.13.B INSIGHTS INTO PARANEOPLASTIC NEUROLOGICAL SYNDROMES IN THE ERA OF MODERN ONCOLOGICAL TREATMENTS
Authors: Taliansky A , Zohar D N
Published: October 2024

BACKGROUND

The paraneoplastic neurological syndromes (PNS) are an uncommon phenomenon with diverse clinical manifestations. The diagnosis of PNS is often challenging because of the broad range of clinical manifestations and the difficulties in the detection of antibodies (AB) that are confirmatory for the diagnosis. Recently published Updated Diagnostic Criteria for PNS improved the efficacy and accuracy of clinical practice but leaves a “gray zone”. The utilization of immunotherapy is rapidly expanding, but the safety and the efficacy of the immunotherapy in PNS patients are unclear as well. Managing PNS is challenging, as there is no consensus on the type of immunomodulatory therapy and the indications for advanced treatment lines.

MATERIAL AND METHODS

We retrospectively evaluated the data about the case of PNS treated in the neurology department and Neuro-oncology unit at Sheba MC Israel.

RESULTS

68 years old male was hospitalized at July 2022 with C7-T3 myelopathy syndrome. The evaluation was negative excluding protein 75 mg/dl and mild pleocytosis, but negative cytology. There was clinical improvement after Methylprednisolon treatment. At March 2023 the patient admitted with acute onset of Lt. hemiparesis and Lt. hemihypoesthesia that developed three weeks after COVID-19 infection. PNS panels of high-risk and low-risk AB in serum and CSF were negative. The Brain MRI showed Rt. thalamic and internal capsule lesion that was hyperintense in FLAIR sequence and homogeneously enhanced by contrast in T1 sequence. The lesion was diagnosed as TUMEFACTIVE demyelinating lesion. Transient clinical and radiological response on steroids treatment was reached. The systemic evaluation revealed the Rt. axillary mass that was diagnosed as BRAF V600E mutated melanoma and case was diagnose as probable PNS. The treatment by BRAF and MEK inhibitors was started and sustained clinical and radiological neurological improvement and oncological complete response were reached.

CONCLUSION

Many questions arise while making therapeutic decisions that relate to PNS. One of those is the question of if cancer therapy alone is sufficient and if it is possible to skip the advanced immunomodulatory treatment lines, because immunosuppression constitutes an aggravating prognostic factor for oncological outcome. New targeted oncological therapies have a short time to response which makes this therapeutic approach possible and our case illustrates the concept.
P27.18.A RADIOGRAPHIC AND CLINICAL RESPONSE OF SACRAL WHO GRADE 2 MYXOPAPILLARY EPENDYMOMA WITH PROTON BEAM RADIATION AND TEMOZOLOMIDE WITHOUT SURGICAL RESECTION
Authors: Valerius A , Sener U , Rose P , Breen W , Lehrer E , Thomsen A , Baykal D
Published: October 2024

BACKGROUND

Myxopapillary ependymomas (MPE) are slow-growing tumors of the spine typically involving the medullary conus and cauda equina. MPE is regularly managed with surgical resection with radiation therapy reserved for cases where gross total resection cannot be achieved. Management of inoperable cases represents a clinical challenge. No systemic therapy is approved for treatment of MPE. Addition of chemotherapy may improve outcomes for cases not amenable to resection.

MATERIAL AND METHODS

We report feasibility and preliminary efficacy of combination treatment with proton beam radiation therapy and temozolomide chemotherapy for a patient with large, unresectable MPE.

RESULTS

A 19-year-old female presented with one year of gradually worsening hip and back pain despite treatment with physical therapy. MRI Lumbar spine identified a destructive and expansile T2-heterogenous and hyperintense intraosseous mass (14 x 12 x 13 cm) with extraosseous expansion involving the sacrum, coccyx, and left SI joint with abnormal soft tissue enhancement extending along the posterior spine. No additional lesions were identified on neuro-axis imaging. Biopsy of the mass was consistent with a WHO grade 2 myxopapillary ependymoma. Standard treatment of care would include complete surgical resection. Unfortunately, this would require a morbid procedure in an en block fashion with immediate and permanent loss of bowel, bladder, sexual, and ambulatory function in a young patient whose primary symptom was pain and mild weakness. It was therefore elected to treat the patient in an unconventional approach and begin with proton beam radiation therapy (59.4 Gy in 33 fractions) with concurrent temozolomide followed by 6 cycles of adjuvant temozolomide. Mild clinical improvement and significant radiographic response were achieved (size reduced to 8 x 7 x 11 cm).

CONCLUSION

This case suggests a potential role for use of proton radiation therapy with concurrent and adjuvant temozolomide for management of myxopapillary ependymoma not amenable to surgical resection.
Exposure to procedural ionizing radiation and cancer risk among physicians
Authors: Simpson A N , Sutradhar R , McArthur E , Tanuseputro P , Bharatha A , Ray J G
Published: October 2024

Background

Physicians in certain specialities are routinely exposed to procedural ionizing radiation. Their risk of cancer is unknown, including by cancer sub-types.

Aims

To assess cancer risk among exposed physicians.

Methods

This population-based case–control study was completed in Ontario, Canada, where healthcare is universal, using linkage of physician billing claims to a province-wide cancer registry. Up to five cancer-free physician controls were matched to each cancer-affected physician, by sex, and both age at and year of, entry into practice. Cumulative exposure to procedural ionizing radiation was captured by physician billing claims. Conditional logistic regression generated an odds ratio (OR) of cancer per 1000 procedures performed and as a binary exposure comparing physicians above the upper 95th percentile cumulative number of procedures (≥200) to those below this cut point.

Results

Mean (standard deviation) age of the 1265 cases and 5772 non-cancer controls was 39.7 (10.7) and 37.7 (9.0) years, and 45% and 49% were female, respectively. After a median (interquartile ranges) of 13.0 (6.9–20.4) and 12.5 (6.5–20.1) years of lookback among cases and controls, the OR of cancer was 1.02 (95% confidence interval 0.99–1.05; P = NS) per 1000 additional procedures performed. Modelling the cumulative exposure to procedures nonlinearly did not change the observed association (P > 0.40 for each). Comparing physicians above versus below the upper 95th percentile cumulative number of procedures, the OR of cancer was 1.23 (95% confidence interval 0.75–2.01, P = NS).

Conclusions

Physician exposure to procedural ionizing radiation was not associated with a higher risk of cancer. Measures that minimize radiation exposure should continue.
Optimizing Lumefantrine Dosing for Young Children in High-Malaria-Burden Countries Using Pharmacokinetic-Pharmacodynamic Simulations
Authors: Simeon Segolene , Hughes Emma , Wallender Erika , P. Solans Belén , Savic Rada
Published: October 2024

Background

Artemether-lumefantrine is the most widely used treatment for uncomplicated malaria and it is dosed based on weight bands according to World Health Organization (WHO) guidelines. However, children are vulnerable to underdosing. Inadequate dosing can lead to treatment failure and drug resistance.

Methods

Nutritional parameters for 372 363 children <5 years old in 25 high-malaria-burden countries were acquired from the Demographic and Health Surveys program. Prevalence of attaining day 7 lumefantrine concentrations ≥200 ng/mL and remaining reinfection free for 42 days were evaluated using a simulation-based approach with a population pharmacokinetic-pharmacodynamic model. Besides the WHO-recommended lumefantrine dosing regimen (twice daily for 3 days), we explored 3 adjusted regimens: extended (2 extra days of dosing), increased (1 extra 120-mg tablet per dose), and intensified (thrice daily for 3 days). We also explored an alternative method dosing malnourished children based on expected weight for age.

Results

We estimated that 75% of children reached the 200 ng/mL lumefantrine threshold and 77% were malaria free for 42 days when using WHO treatment guidelines. By switching to the alternative dosing method, 5% more children achieved target lumefantrine levels; 22% more achieved the target using the alternative dosing and the extended regimen. With combined alternative plus extended dosing, 97% of children reached 200 ng/mL lumefantrine and 88% were malaria free for 42 days.

Conclusions

This study highlights the inadequacies of weight-based lumefantrine dosing for young and underweight children and supports the need of clinical trials using extended dosing based on expected weight in malnourished children.
Revisiting immunity vs. exposure in schistosomiasis: A mathematical modeling study of delayed concomitant immunity
Authors: Milne Gregory C , Oettle Rebecca C , Whittaker Charles , Kabatereine Narcis B , Basáñez Maria-Gloria , Webster Joanne P , Walker Martin , Wilson Shona
Published: October 2024

The relative contributions of exposure vs. acquired immunity to the epidemiology of human schistosomiasis has been long debated. While there is considerable evidence that humans acquire partial immunity to infection, age- and sex-related contact patterns with water bodies contaminated with infectious cercarial schistosome larvae also contribute to typical epidemiological profiles of infection. Here, we develop a novel schistosome transmission model that incorporates both partially protective “delayed concomitant” acquired immunity—stimulated by dying worms—and host age- and sex-dependent patterns of exposure. We use a contemporary Bayesian approach to fit the model to historical individual data on exposure to infectious cercaria, eggs per gram of feces, and immunoglobulin E antibodies specific to Schistosoma mansoni Tegumental-Allergen-Like protein 1 collected from a highly endemic community in Uganda, estimating the relative contributions of exposure and acquired immunity. We find that model variants incorporating or omitting delayed concomitant immunity describe equally well the age- and sex-specific immunoepidemiological patterns observed before intervention and 18 months after treatment. Over longer time horizons, we find that acquired immunity creates subtle differences in immunoepidemiological profiles during routine mass drug administration that may confer resilience against elimination. We discuss our findings in the broader context of the immunoepidemiology of schistosomiasis.
Pre-emptive pharmacogenetic testing in the acute hospital setting: a cross-sectional study
Authors: McDermott John H , Burke Kerry , Fullerton Neil , O’Sullivan James , Alex Aleina , Ingham Amy , Sharma Videha , Godfrey Nicola , Odudu Aghogho , Syed Tania , Stevens Andrew , Beynon Rhys , Greaves Nicholas , Akam Daniel , Mirza Selman , Wilson Paul , Wright Stuart , Payne Katherine , Newman William G
Published: October 2024

Background

Pharmacogenetic-guided prescribing can be used to improve the safety and effectiveness of medicines. There are several approaches by which this intervention might be implemented in clinical practice, which will vary depending on the health system and clinical context.

Aim

To understand the clinical utility of panel-based pharmacogenetic testing in patients admitted acutely to hospital and to establish variables that predict if an individual might benefit from the intervention.

Design

A cross-sectional study recruiting patients admitted acutely to hospital.

Methods

Participants underwent panel-based pharmacogenetic testing, and their genetic results were analysed in their context of the medicines they had been exposed to as an inpatient. The primary outcome was the proportion of patients with clinically actionable gene–drug interactions. Individual variables that predict the clinical utility of pharmacogenetic testing were established via logistic regression.

Results

Genetic and prescribing data were available for 482 inpatients (55% male; median age 61.2 years; range: 18–96), 97.9% of whom carried a pharmacogenetic result of interest. During their admission, 79.5% of patients were exposed to a medicine for which there is pharmacogenetic prescribing guidance available. Just under one in seven individuals (13.7%) had a clinically actionable gene–drug interaction. Increasing age (>50 years) was positively correlated with the likelihood (2.7-fold increased risk) of having a clinically actionable interaction.

Conclusions

These findings demonstrate the potential scale, and potential clinical utility, of pharmacogenetic testing as an intervention, highlighting the need to develop infrastructure to support healthcare professionals make use of this emerging tool.