bluuebunny/crossref_metadata_2025 huggingface dataset:
OS09.2.A REGORAFENIB IN COMBINATION WITH TEMOZOLOMIDE WITH OR WITHOUT RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED MGMT-METHYLATED, IDH WILDTYPE GLIOBLASTOMA: A PHASE I DOSE-FINDING STUDY (REGOMA-2, EUDRA CT N° 2021-001604-15)
Authors: Padovan M , De Salvo G , Cerretti G , Krengli M , Caccese M , Maccari M , Farina M , Bergo E , Zabeo C , Grosso D , Caumo F , Coppola M , D'Avolio A , Zagonel V , Lombardi G
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is associated with the activation of multiple signaling pathways, including the receptor tyrosine kinases, VEGFR, FGFR and PDGFR. The potential response to anti-angiogenic agents makes GBM an attractive target for regorafenib (REG). Antitumor activity of REG in recurrent GBM patients was shown in the phase II REGOMA trial. Interestingly, in “in vivo” studies, beneficial effects were observed with the combination of REG and temozolomide (TMZ) in subcutaneous xenografts.

MATERIAL AND METHODS

This phase I open-label multicentric study in progress is evaluating the addition of REG to standard of care treatment with TMZ as adjuvant therapy (cohort A), and in combination with TMZ + radiotherapy (RT) as concomitant therapy (cohort B), in newly diagnosed MGMT-methylated, IDH wildtype GBM patients. Primary objectives are: to determine the safety and tolerability of REG and to establish the maximum tolerated dose (MTD) of REG in these two cohorts. Secondary objectives are: the assessment of pharmacokinetics of REG, TMZ, and possible pharmacokinetic interactions between TMZ and REG in cohort A; the assessment of preliminary antitumor activity; the evaluation of quality of life during the treatment. The dose escalation is being explored according to a “3 + 3” design, starting from cohort A and following 3 dose levels of REG [80 mg, 120 mg and 160 mg]. After finding the MTD in cohort A, the cohort B dose escalation will start, exploring escalating oral doses of REG in combination with concomitant TMZ + RT (60 Gy/30 fractions). In the adjuvant phase of cohort B, REG will be given with TMZ at MTD shown in the prior adjuvant phase dose escalation.The DLT (dose-limiting toxicity) evaluation period will be two cycles from the start of cycle 1 of adjuvant phase (in cohort A) and from day 1 to the last day of the concomitant phase (in cohort B). Recruitment started in May 2022; Level 1 in cohort A (3 patients) has been completed without DLT. Approximately 36 subjects will be enrolled.
OS09.6.A A MULTICENTER, PHASE I/II, OPEN-LABEL STUDY OF INTRATHECAL PEMETREXED FOR LEPTOMENINGEAL METASTASES FROM SOLID TUMOR (PMLM, NCT 05289908)
Authors: Pan Z , Yang G , Wang Z , Shen L , Pang X , Yuan T , Li S , Dong L
Published: September 2023

BACKGROUND

There has never been a dose-escalation study on intrathecal pemetrexed (IP) with vitamin supplementation. This phase I/II study was to evaluate the maximum-tolerated dosage (MTD) of IP with vitamin supplementation and the antitumor activity for leptomeningeal metastases (LM) from solid tumors.

MATERIAL AND METHODS

Phase I study followed the classic 3 + 3 design, with the dose of IP escalated from 15 mg. Phase II followed the Simon 2-stage design with the recommended dose determined in phase I. IP was administered twice per week for 2 weeks (induction therapy), followed by once per week for 4 weeks (consolidation therapy). Clinically stable or improved patients continued IP once a month (maintenance therapy). Vitamin B12 (1000 μg) and folic acid (400 μg, q.d.) were given at the beginning of treatment. Primary end points were MTD in phase I and clinical response rate (CRR) in phase I/II. All patients were assessed to investigate safety, CRR and overall survival (OS).

RESULTS

Between Feb 2022 and Jan 2023, 34 patients (male: 16; female: 18; age: 45-68 years; median: 56 years) were enrolled, including non-small lung cancer (20), small-cell lung cancer (3), breast cancer (8), others (3). Thirty-three patients had a confirmed LM diagnosis (positive CSF cytology). Remaining one had probable diagnosis (positive neuroimaging with typical clinical signs). Ten patients were enrolled in phase I. Three of 4 patients receiving IP at 15 mg completed induction and consolidation treatment without dose limiting toxicity (DLT). The dose was escalated to 20 mg. Two DLT (1 grade 4 hematologic toxicity and 1 grade 5 arachnoiditis) occurred in 6 patients at 20 mg. The MTD was determined to be 15 mg. Then 24 patients were enrolled in phase II and given 15 mg of IP. 82.4% (28/34) and 58.8% (20/34) patients completed induction and consolidation therapy, respectively. 41.2% (14/34) patients received maintenance therapy. Adverse events (AEs) rate was 73.5% (25/34). 50% (17/34) patients showed grade ≥ 3 AEs, including myelosuppression (11), elevation of hepatic aminotransferases (EHA) (5), elevation of blood bilirubin (EBB) (1), arachnoiditis (1), radiculitis (1), fatigue (1) and nausea (1). The overall CRR was 41.2% (14/34) by neuro-oncology proposal criteria, including 10 (29.4%) with improved neurological dysfunction, 11 (32.4%) with CSF cytological response and 4 (11.8%) with neuroimaging improvement. In a total of 28 patients receiving IP at 15 mg, 50% (14/28) patients showed grade ≥ 3 AEs, including myelosuppression (9), EHA (10), fatigue (1) and nausea (1). The CRR was 46.4% (13/28) in patients at 15 mg IP. Median survival was 7.6 (range 0.3-13.7) months in phase I, while has not yet been achieved in phase II until March 15, 2023.

CONCLUSION

MTD of IP was 15 mg with folic acid and vitamin B12 supplementation. IP is an optimal therapeutic option for LM from solid tumors.
OS12.6.A PRELIMINARY RESULTS FROM COPENHAGEN STUDY ON QUALITY OF LIFE IN YOUNG ADULTS WITH GLIOMAS
Authors: Arnkjær K , Bruun-Pedersen M , Skjøth-Rasmussen J
Published: September 2023

BACKGROUND

Young patients diagnosed with gliomas face a life-changing disease, with a limited life length. They face challenges participating in daily social life and educational/work life. While the therapy for this patient group has the goal of prolonging life-length, little is known of their quality of life (QoL). A potential lower QoL due to diagnosis and the side effects of the treatment needs to be continuously assessed by health professionals. This study aimed to assess the QoL over time in young patients diagnosed with gliomas and to elucidate if these patients may need additional help and support. A second aim was to test the feasibility of repeated use of two validated online questionnaires to guide the clinicians working with this patient group. A third aim was to calculate a clinical cut-off score for the Functional Assessment of Cancer Treatment-Brain (FACT-Br).

MATERIAL AND METHODS

The design was a longitudinal, prospective study with a continuous inclusion during a 3-year period (2020-2023). Patients included were 18-35 years old suspected with a low-grade glioma at their first consultation in the clinic. The QoL was evaluated using FACT-Br and WHO-5 (WHO-5 Well-Being Index). The patients received the online questionnaires at pre-selected time points (pre-operation, 3-month, 6-month, 12-month) followed by a 3-month break and then repeated. The feasibility was evaluated in terms of compliance over time, defined as a completion of the first consecutive four questionnaires. A linear Generalized Estimating Equation (GEE) analysis was used to identify changes in FACT-Br total score.

RESULTS

A total of 33 patients were included in the study (Mdn=26y; 60% men; drop-out/exclusion n=3). At 3-month follow-up (n=30) four patients (13,3%) had a WHO-5 score below cut-off value (50/100 points) and five patients (16,7%) had a FACT-Br score below calculated cut-off (144/200 points) (M=160). The cut off-score for FACT-Br was calculated using a ROC-curve based on the WHO-5 cut-off value (n=30). The quality was deemed good (AUC=0,895). The Fact-Br total score showed no significant change over time (n=30). One subscale regarding functional wellbeing did show a significant change (p=0.021) (180 days change = 0,74; 95%-CI: 0,39-1,09). In March 2023 11 of 13 (84,6%) patients had a complete set of the first four consecutive questionnaires.

CONCLUSION

There was no significant change in the overall QoL (FACT-Br), but one subscale improved significantly. Five patients had a FACT-Br score below the calculated cut-off at 3 month-follow-up which might indicate a need for further support. Our study suggests that online QoL questionnaires are feasible in a clinical setup with this patient group. These results may give health professionals better insight in the need of support thus securing the best quality of life possible in young patients waiting for disease progression.
P01.01.A THE IMPACT OF BRAIN LESIONS ON HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH WHO CNS GRADE 3 OR 4 GLIOMA: A LESION-FUNCTION AND RESTING-STATE FMRI ANALYSIS
Authors: Kocher M , Heinzel A , Mottaghy F M , Filss C , Stoffels G , Lohmann P , Friedrich M , Shah N J , Caspers S , Weiss Lucas C , Ruge M I , Galldiks N , Fink G R , Langen K
Published: September 2023

BACKGROUND

In glioma patients, tumor development and multimodality therapy are associated with changes in health-related quality of life (HRQoL). It is largely unknown how different types and locations of tumor- and treatment-related brain lesions, as well as their relationship to white matter tracts and functional brain networks, affect HRQoL.

MATERIAL AND METHODS

In 121 patients with pretreated gliomas of WHO CNS grades 3 or 4, structural MRI, O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET, resting-state functional MRI (rs-fMRI) and self-reported HRQoL questionnaires (EORTC QLQ-C30/BN20) were obtained. Resection cavities, T1-enhancing lesions, T2/FLAIR hyperintensities, and lesions with pathologically increased FET uptake were delineated. Effects of tumor lateralization, involvement of white matter tracts or resting-state network nodes by different types of lesions and within-network rs-fMRI connectivity were analyzed in terms of their interaction with HRQoL scores.

RESULTS

Right hemisphere gliomas were associated with significantly less favorable outcomes in physical, role, emotional and social functioning, compared with left-sided tumors. Most functional HRQoL scores correlated significantly with right-sided white-matter tracts involvement by T2/FLAIR hyperintensities and with loss of within-network functional connectivity of right-sided nodes. Tumors of the left hemisphere caused significantly more communication deficits.

CONCLUSION

In pretreated high-grade gliomas, right hemisphere lesions are associated with reduced HRQoL scores in most functional domains except communication ability, compared to tumors of the left hemisphere. These relationships are mainly observed for T2/FLAIR lesions involving structural and functional networks in the right hemisphere. The data suggest that sparing the right hemisphere from treatment-related tissue damage may improve HRQoL in glioma patients.
P02.05.A DISSECTING THE DIFFUSE MIDLINE GLIOMA TUMOUR MICROENVIRONMENT COMMUNICATIONS USING MULTI-OMICS APPROACHES
Authors: Collot R , Ruiz Moreno C , Wezenaar A , Zomer A , Johnson H , Stunnenberg H , Rios A
Published: September 2023

BACKGROUND

Diffuse midline glioma (DMG) represents a highly aggressive pediatric brain tumour with no chance of survival. Treatment options are urgently needed, and efforts have been put towards the development of T cell immunotherapy. However, this should consider the unique tumour microenvironment (TME) of DMG, both in terms of anatomical location and developmental stage.

MATERIAL AND METHODS

To gain knowledge on this unique tumour niche, we implemented an immuno-competent, syngeneic mouse model based on in-utero electroporation (IUE) of the key driver-mutations to induce tumour formation at embryonic stage. By combining snRNAseq, Spatial Transcriptomics and state-of-the-art imaging, we characterized the spatial and molecular landscape of DMG.

RESULTS AND CONCLUSION

We observed a high intratumoral heterogeneity with spatially restricted cell populations. Importantly, their molecular profiles correlate with patient data, illustrating the clinical relevance of the IUE model. Analysis of cell-cell communications in the TME revealed a novel signalling between DMG and immunosuppressive myeloid cells, that could impact T-cell response. Using an advanced patient-derived DMG organoid co-culture model with macrophages and engineered T-cells, we are currently investigating the role of this pathway on T-cells mediated killing of DMG organoids. Thus, this project fills a critical need to delineate and overcome the immune-suppressive environment in DMG and potentiate T cell targeting.
P02.11.A INTEGRATED GENOMIC PROﬁLING OF LONG-TERM GLIOBLASTOMA SURVIVORS
Authors: Xu P , Chen Z
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is a fatal brain tumor, and few patients survive beyond 5 years. Therefore, a study of genomic alterations in GBM long-term survivors (LTS) is essential for insights into tumor biology and biomarker identiﬁcation.

MATERIAL AND METHODS

In our study, we reviewed medical records from Sun Yat-sen University Cancer Center for GBM patients received initial surgery between the years 2000 and 2018. Thirty patients with GBM had an overall survival of more than 5 years. In addition to established prognostic factors such as radiochemotherapy and total surgical excision, we sought to identify genomic alterations associated with LTS by collecting surgically resected tumor tissues and normal blood controls from 13 GBM LTS (overall survival > 60 months) and 19 short-term survivors (STS, overall survival < 24 months). We performed whole exome sequencing and transcriptome sequencing on these samples.

RESULTS

Our findings revealed no significant differences in the composition of driver genes between the two groups. However, mutation signature analysis indicated that the proportion of mutation signature 19 was higher in the LTS than in the STS (P=0.059). Analysis of copy number variants showed that the longer survivors group had higher copy number variants at the chromosomal level (P=0.049). At the chromosome arm level, the proportion of 19p amplification and 19q amplification in the longer survivors group was significantly higher than in the short survival group (P=0.001/0.002). And in the TCGA GBM dataset, GBM patients with 19p amplification also had a better prognosis (log-rank P=0.04).

CONCLUSION

In conclusion, our study identified the proportion of mutation signature 19 and amplification of 19p as potential genomic alterations that could be used as prognostic biomarkers for GBM. This study could pave the way for new therapeutic approaches to this challenging disease.
P02.15.A PRONEURAL, CLASSICAL AND MESENCHYMAL PROTEIN SIGNATURES LACK PROGNOSTIC VALUE IN WHO 2021 ADULT TYPE DIFFUSE LOWER-GRADE GLIOMAS
Authors: Dénes A , Olsson Bontell T , Barchéus H , Ferreyra Vega S , Carén H , Lindskog C , Jakola A S , Smits A
Published: September 2023

BACKGROUND

Mesenchymal transformation in glioblastomas is associated with therapy resistance and increased aggressiveness. In WHO 2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition between phenotypic states, has not been studied. Most reports correlating proneural, classical or mesenchymal signatures with outcome in dLGG were made prior to the WHO 2021 classification. Here, we set out to investigate if phenotype as well as the transition of phenotype predicted survival in a clinical cohort of WHO 2021 defined dLGGs.

MATERIAL AND METHODS

We used a TMA-based approach and five immunohistochemical markers (EGFR, p53, MERTK, CD44 and OLIG2) to examine 183 primary and 49 recurrent tumors from patients with previously diagnosed dLGG. Of the 49 recurrent tumors, nine tumors relapsed a second time, and one a third time.

RESULTS

In total, 71.0% of all tumors could be subtyped into proneural, classical or mesenchymal. Proneural was the predominant subtype among IDH-mut tumors (78.5%), while in IDH-wt tumors mesenchymal was more common (63.6%). A significant difference in survival was found between subtypes (proneural, classical and mesenchymal) in the total cohort (p<0.001), but not when molecularly stratified (IDH-mut: p=0.220, IDH-wt: p=0.623). Upon relapse, proneural signature was retained in 66.7% of the proneural IDH-mut dLGGs (n=21), whereas IDH-wt tumors (n=10) mainly retained or gained mesenchymal phenotype. There was no significant difference in survival between IDH-mut gliomas remaining proneural and those switching to mesenchymal signature (p=0.347).

CONCLUSION

Subtyping into proneural, classical and mesenchymal phenotypes by five immunohistochemical markers, was possible for the majority of tumors, but statistical significance between phenotypes and survival was lost after molecular stratification according to the WHO 2021 criteria. IDH-mut tumors mainly remained proneural at recurrence, while IDH-wt tumors mostly retained or gained mesenchymal phenotype. This phenotypic shift, which in glioblastoma is associated with increased aggressiveness, did not affect survival. Sample sizes were, however, too small to draw any firm conclusions on whether this negative finding is due to lack of statistical power or reflects a true biological difference from glioblastomas.
P03.08.A HIGH-DIMENSIONAL CHARACTERISATION OF THE CELLULAR AND MOLECULAR CHANGES IN THE HUMAN BRAIN AFTER RADIOTHERAPY
Authors: Millner T O , Panday P , Pomella N , Badodi S , Marino S
Published: September 2023

BACKGROUND

In the UK ~40,000 intrinsic and metastatic brain tumours are diagnosed each year. Although targeted radiotherapy (RT) is integral to increasing survival of cancer patients, it has significant side-effects, the cellular and molecular mechanisms of which are not fully understood. During RT treatment epigenetic changes occur in the neoplastic tissue, but few studies have assessed these in non-neoplastic brain tissue and results are highly variable.

MATERIAL AND METHODS

To explore the effects of RT on patient-specific methylation, we retrospectively identified 19 samples, mainly metastatic tumours, that had undergone stereotactic-RT followed by resection, and contained peri-lesional brain tissue, as well as 14 controls. Peri-lesional brain was micro-dissected, followed by DNA methylation profiling and RNA-sequencing.

RESULTS

Clustering of DNA methylation data showed distinct patterns between the two groups, whilst RNA-seq revealed 1,887 differentially expressed genes. Pathway analysis with GSEA identified differentially represented pathways, including: innate immune system, trans-synaptic signalling, olfactory signalling, regulation of supramolecular fibre organisation, and pattern specification. Computational deconvolution of cellular composition showed increased activated dendritic cells and B-cells, and reduced smooth muscle cells and several sub-sets of astrocytes in the RT samples.

CONCLUSION

We are currently further investigating these findings using spatial transcriptomics and proteomics to produce the first high-dimensional characterisation of the irradiated human brain. This will also provide the first direct evidence of epigenetic dysregulation after targeted-RT, and assess novel epigenetically-regulated genes, which will be validated with single cell tissue-based imaging techniques. A range of epigenetic-based drugs are undergoing clinical trials and we aim to identify targets for radiomitigation in brain tumour patients.
P03.12.A PHASE III RANDOMIZED TRIAL COMPARING PREOPERATIVE HYPOFRACTIONATED RADIOSURGERY (HSRS) TO POSTOPERATIVE HYPOFRACTIONATED RADIOSURGERY (HSRS) FOR PATIENTS WITH LARGE BRAIN METASTASES SUITABLE FOR SURGICAL RESECTION SUPPORT TRIAL
Authors: Navarria P , Pessina F , Clerici E , Bellu L , Politi S , Marini B , Riva M , Bono B , Reggiori G , Raspagliesi L , Scorsetti M
Published: September 2023

BACKGROUND

Standard of care for patients with large brain metastases (BMs) suitable for surgery is surgical resection followed by radiosurgery in single or multifractions (SRS/HSRS) on tumor bed. Although a satisfactory local control is obtained, an increasing rates of leptomeningeal disease (LMD) related to surgery, and symptomatic radionecrosis related to SRS/HSRS have been observed. In the last years the employ of preoperative SRS/HSRS has been investigated in retrospective studies. Advantages seem to be: better target delineation to intact lesion, reduction of normal brain irradiated considering useless of margins, potential prevention of any cells spilled during resection, greater oxygenation ratio of intact region, sterilization effect, and resection of majority of irradiated tissues. Preoperative HSRS versus postoperative ones will be investigated in multicentric randomized phase III trial. Primary endpoint is rate of leptmeningeal disease secondary endpoints, local control, symptomatic radiation necrosis, surgical morbidity, quality of life (QoL) and neurocognitive functions assessment between the two modalities; brain distant progression (BDP), and overall survival (OS) will be evaluated too.

MATERIAL AND METHODS

Inclusion criteria are: patients aged 18-80 years, diagnosed malignant primary tumor, KPS≥70, oligometastatic disease, limited brain metastases (up to 4), large BM suitable for surgery. Exclusion criteria are: prior WBRT, SCLC, or germinal cell tumour or Lymphoproliferative disease, prior neurosurgery, and incompatibility to perform MRI. Stratification factors will be: histology of primary tumor (Breast, NSCLC, Melanoma, Other) and BMs location (sovra-or infra-tentorial). In Arm A (experimental) patients undergo preoperative HSRS, 27 Gy in 3 fractions, followed by surgery. In Arm B (control): patients undergo surgical resection followed by postoperative HSRS at the same doses. Outcome evaluation will be assess using MRI, total body CT scan and/or CTPET, neuropsychological and Quality of life assessment before and after treatments. For distinguish RN occurrence and disease progression delayed-contrastMRI, and perfusion MRI will be employed. Considering that estimated 1 year LMD is 10% for postoperative HSRS, and ≤ 2% for preoperative enrolment of 146 patients is expected (73 per Arm).

RESULTS

Enrollment started at April 2023 and among first patients included the treatment has proven to be safe.

CONCLUSION

Preoperative HSRS in large BMs suitable for surgical resection need prospective evaluation aiming to improve outcome, and reduced treatments side effects.
P04.02.A CEREBELLAR GLIOMA WITH BRAF ACTIVATION: A MOLECULARY DISTINCT GLIOMA SUBGROUP WITH MAPK ACTIVATION
Authors: Hinz F , Schweizer L , Reinhardt A , Reuss D E , Sill M , Witt O , Pfister S M , Jones D T W , von Deimling A , Sahm F
Published: September 2023

BACKGROUND

Rendering the correct tumor diagnosis is key to optimise cancer therapies and to orient patients and relatives regarding prognosis and general understanding of the disease. With the rising impact of molecular diagnostics more molecular profiles of tumors are being generated and assembled in central institutes. With this critical data assembly in world-wide repositories such as www.molecularneuropathology.org, new tumor groups with differing prognosis and driver alterations can be discerned.

MATERIAL AND METHODS

By analysing the epigenetic profiles from over 125.000 CNS tumor samples a distinct group of cases was identified (n=24). The samples in this group did not match an established reference methylation class in the Heidelberg brain tumor classifier (version 12.5). In a first analysis with the clinical data external suppliers have provided, these tumors are located in the cerebellum and typically in children (mean age = 9 years).

RESULTS

The variable histology ranged from low grade glial/glioneuronal appearances such as pilocytic astrocytoma (n= 12), ganglioglioma (n= 4), gangliocytoma (n= 1) to ependymoma (n= 2) and anaplastic ependymoma (n=1). For some cases just a descriptive histopathological diagnosis could be rendered (n= 6). A prominent feature in radiology and histology were micro- and macrocalifications (n =5). From 24 cases, 17 tumors (89% of all analysed tumors) harboured a BRAF V600E mutation. One case revealed a PRKAR2B:BRAF fusion. 6 cases could not be analysed because no remaining tumor material was available. While clinical follow-up data collection is still maturing, relapses were reported in 2 patients, and stable disease was reported in 12 cases. For 10 cases no follow up data is available, yet.

CONCLUSION

We found an epigenetically distinct group of childhood brain tumors located in the posterior fossa with an enrichment of BRAF V600E mutations. Clinical follow-up is yet to be evaluated, but recurrence was observed in a proportion of patients with available follow-up.
P04.06.A A PHASE II MONOCENTRIC STUDY OF LIMITED USE OF HIGH DOSE OF CHEMOTHERAPY AND PROTON THERAPY IN PEDIATRIC HIGH RISK MEDULLOBLASTOMA AND OTHER EMBRYONAL CANCERS
Authors: Guidi M , Fonte C , Tellini M , Castelli B , Gori C G , Giunti L , Di Nicola M , Buccoliero A M , Caporalini C , Giordano F , Rombi B , Desideri I , Pugi A , Tortora K , Greto D , Genitori L , Leo M , Sardi I
Published: September 2023

BACKGROUND

Despite the multimodal approach, medulloblastoma remains a leading cause of cancer-related death in children. We proposed the preliminary data of an interventional, open-label, phase II study to evaluate the safety and efficacy of standard and high-dose chemotherapy associated with craniospinal proton therapy in patients with metastatic medulloblastoma and other embryonal cancers.

MATERIAL AND METHODS

A total of 19 patients have been enrolled from the beginning of the study from February 2018 to May 2022 . The median age was 7,5 years (range; 13 males and 6 female). The protocol predicted the first phase of induction with 4 cycles of chemotherapy. After induction patients with favorable histology without evidence of disease were enrolled to proton therapy (with concomitant vinorelbine biweekly). The maintenance phase with Lomustine repeated every 9 weeks and vinorelbine every 3 weeks for overall 12-18 months (PR). Conversely LC/A MB, pineoblastoma or other high risk embryonic tumors were subjected to consolidation phase with high dose of chemotherapy with tiothepa followed by autologous HSC transplant and successive maintenance phase of 6 months.

RESULTS

At December 2022, the median follow up was 23 months. 18 patients had high risk medulloblastoma and one had a primary leptomeningeal primitive neuroectodermal tumor. After the induction phase 14 patients showed CR, 3 PR, 1PD, 1SD. At subsequent re-evaluations two of the three patients with PR, showed disease control, one CR and the other SD and the patient with PD showed CR. At the end of proton therapy 18 patients had CR. During the reporting period three patient died for progression of the underlying disease. At 15 months from the start of treatment the PFS and OS were 68.8% (95% CI: 34.1% - 87.6%) and 94.7% (95% CI: 68.1% - 99.2%) respectively. The principal expected side effects of chemotherapy were hematology toxicity (fever and neutropenia prevalent after etoposide and carboplatin plus vinorelbine). Among the unexpected side effect was CMV retinopathy with complete blindness and leukoencephalopathy after high dose of thiotepa and proton irradiation.

CONCLUSION

As the study did not reveal any safety issues, proton therapy combined with intensive chemotherapy, and myeloablative chemotherapy only in selected cases and always before irradiation, proved feasible and successful in treating high-risk medulloblastomas and other embryonal tumors.
P04.07.B CHARACTERIZATION OF ARHGAP36/MYC-INDUCED GROUP 3 MEDULLOBLASTOMA
Authors: Gianesello M , Ballabio C , Badaloni A , Bonanomi D , Tiberi L
Published: September 2023

BACKGROUND

Medulloblastoma (MB) is one of the most common pediatric brain cancers of the central nervous system. It is stratified into 4 molecular subtypes (WNT, SHH, group 3, and group 4), which differ from one to the other for various features, such as cellular morphology, age of onset, set of mutations, and percentage of survival. A common point between the four MB subgroups is the absence of treatments for this disease. The current gold standard treatment has deleterious side effects for the patients, which spans from growth defects to low hormone levels and problems with learning. Analyzing transcriptomic data of group 3 MB patients we found ARHGAP36 as a possible gene involved in tumor formation or propagation. Rho GTPase-Activating Protein 36 (ARHGAP36) is a gene that plays a role in regulating PKA activity. Specifically, the ARHGAP36 protein can inhibit PKA function through two distinct mechanisms. Firstly, it acts as a pseudosubstrate for the catalytic subunit of the PKA protein. Secondly, it can drive protein degradation via a lysosome-mediated process.

MATERIAL AND METHODS

We took advantage of the Piggybac/transposon technology to induce a strong and stable overexpression of our genes of interest to generate two different models, one in-vivo and one in-vitro with induced pluripotent stem cells-derived human cerebellar organoids. We also exploited the cre/LoxP system in transgenic mice to overexpress ARHGAP36 under the control of specific promoters. The analysis was conducted using standard techniques such as RT-qPCR and Western Blot, together with immunofluorescence of the cerebellar section and live imaging of the modified cerebellar organoids. The gene expression profile of the tumors obtained in mice was analyzed by RNA sequencing and compared to known group 3 MB mouse models.

RESULTS

We analyzed RNA-sequencing data from medulloblastoma patients and found that high expression of ARHGAP36 correlated with poor prognosis in patients. Through PKA inhibition, ARHAP36 induces ectopic activation of SHH signaling and cell proliferation leading to abnormal development of the cerebellum in mouse embryos. Notably, despite its inductive activity on the SHH pathway, ARHGAP36 expression is higher in group 3 and group 4 MB, rather than in the SHH subgroup. In this study, we demonstrate that intracranial transfection of P0 mouse pups with plasmids overexpressing MYC and ARHGAP36 can generate group 3 medulloblastoma in-vivo. We studied and then confirmed the involvement of the binding with PKA as a tumorigenic mechanism in the MYC/ARHGAP36 co-overexpression using several mutated forms of the gene. We studied the obtained tumors for the presence of group 3 MB immunophenotypical markers, as well as their gene expression profile by RNA-seq.

CONCLUSION

These findings can become of key interest as possible druggable targets to efficiently treat group 3 medulloblastoma patients in the future.
P06.09.B TRIAL IN PROGRESS: PHASE 1 DOSE-FINDING STUDY TO EVALUATE SAFETY AND TOLERABILITY OF CVGBM IN PATIENTS WITH NEWLY DIAGNOSED AND SURGICALLY RESECTED MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Tabatabai G , von Baumgarten L , van den Bent M , Burger M C , Freres P , Glas M , Hau P , Herrlinger U , Mildenberger I , Neyns B , Schäfer H , Seidel C , de Vos F , Galot R , Whenham N , Wick A , Falk M , de Freitas Chama L , Henze J , Kelemen P , Koch S D , Lutz J , Heidenreich R , Romer Roche P , Rost T , Schönborn-Kellenberger O , Gnad-Vogt U
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is characterized by a low mutational burden limiting the number of neoantigen targets for cancer vaccines. Vaccination against tumor-associated antigens over-presented via MHC class I and II in GBM is an alternative that has shown promise in previous trials. One cancer vaccine containing peptides presented by HLA-A*02-01 (class I) and some DR alleles (class II), showed evidence of peripheral vaccine-induced immune response against these peptides in patients with GBM. Our study will assess the safety and immunogenicity of the messenger ribonucleic acid (mRNA)-based multiepitope vaccine CV-GBM, an investigational therapeutic mRNA vaccine, encoding eight of these peptides that have demonstrated immunogenicity as peptide vaccines. CV-GBM consists of a mRNA with unmodified nucleotides formulated with lipid nanoparticles.

MATERIAL AND METHODS

CV-GBLM-001 is a first-in-human, open-label, international, dose-escalation phase 1 trial. HLA-A*02:01-positive patients with newly diagnosed MGMT-unmethylated GBM (CNS WHO Grade 4), including IDH-wildtype astrocytoma with a molecular signature of unmethylated MGMT-GBM who have had a gross total or partial resection and who completed post-surgery radiotherapy with or without chemotherapy, are eligible to receive CVGBM. The trial comprises a dose-escalation part (Part A) followed by a dose-expansion part (Part B). In Part A, the starting dose is 12 µg mRNA, which may be escalated to 25 µg, 50 µg and 100 µg, with 3 to 6 patients per dose level. Dose escalation will be guided by a Bayesian logistic regression model. Patients will receive 7 doses of CVGBM by intramuscular injection on Days 1, 8, 15, 29, 43, 57, and 71, followed by 6 optional doses at 6-week intervals, up to 1 year after the first dose or until disease progression or intolerable toxicity. An independent Data and Safety Monitoring Board will recommend the dose for expansion in Part B in which about 20 patients will be enrolled. Biomarkers and vaccine-induced innate and adaptive immunogenicity, including, but not limited to, systemically induced cytokines and chemokines and antigen-specific CD4+ and CD8+ T cells, will be monitored in the blood, and optionally in vaccine-draining lymph nodes and relapsed tumor. In addition to the primary safety objectives, secondary objectives of efficacy (progression-free survival, overall survival) and patient-reported quality of life outcomes will be assessed. Trial sponsor: CureVac SE, Germany.
P06.12.A NLGN4X-SPECIFIC TCR T CELLS TARGETING EXPERIMENTAL GLIOMAS
Authors: Krämer C , Kilian M , Chih Y , Kourtesakis A , Boschert T , Sanghvi K , de Roia A , Jung S , Jähne K , Shultz L , Harbottle R , Green E , Will R , Wick W , Platten M , Bunse L
Published: September 2023

BACKGROUND

A human leukocyte antigen (HLA)-A*02-restricted tumor associated antigen in the neuroligin 4 X-linked (NLGN4X) protein was found to be specifically overexpressed in human gliomas. Individualized multipeptide vaccination targeted NLGN4X and induced specific cytotoxic T cells responses in patients with newly diagnosed glioblastoma.

MATERIAL AND METHODS

Post vaccination NLGN4X-tetramer-sorted T cells were subjected to single cell T cell receptor (TCR) sequencing for TCR discovery. The identified TCR was delivered to human T cells (NLGN4X-TCR-T) and functional profiling was performed by flow cytometry and in vitro cytotoxicity assays. NOD scid gamma (NSG) major histocompatibility complex (MHC) I/II knockout (KO) (NSG MHC I/II KO) mice were challenged with NLGN4X-expressing experimental gliomas and treated with intracerebroventricular injection of NLGN4X-TCR-T to assess its therapeutic potential.

RESULTS

We apply for the first time for therapeutic use of an HLA-A*02 restricted vaccine-induced TCR that binds to the NLGN4X antigen. We show the cytotoxic and polyfunctional phenotype of NLGN4X-TCR-T in various cellular models. Intracerebroventricular delivery of NLGN4X-TCR-T prolongs survival and leads to objective radiographic responses in experimental gliomas-bearing NSG MHC I/II KO mice.

CONCLUSION

NLGN4X-TCR-T demonstrates efficacy in a preclinical experimental glioblastoma model. On a global scale, we provide first evidence for the therapeutic retrieval of vaccine-induced human TCRs for the off-the-shelf treatment of glioblastoma patients.
P07.14.A OBSERVATIONS FROM THE FIRST 100 CASES OF INTRAOPERATIVE MRI - EXPERIENCES, TRENDS AND SHORT-TERM OUTCOMES IN PEDIATRIC VERSUS ADULT NEUROSURGICAL POPULATION
Authors: Barchéus H , Peischl C , Björkman-Burtscher I M , Pettersson C , Nilsson D , Farahmand D , Eriksson J , Skoglund T , Corell A
Published: September 2023

BACKGROUND

The intraoperative MRI (iMRI) at Sahlgrenska University Hospital installed in 2017 was the first introduced in Sweden. Herein, we present a single center study with our observations from the first 100 patients undergoing neurosurgery in the dedicated iMRI surgical theater.

METHODS

Patients undergoing surgery in the 3T iMRI hybrid surgical theatre at our neurosurgical department between December 2017 to May 2021 were included after informed consent. Demographic, clinical, surgical, histological, radiological and outcome parameters, as well as variables related to iMRI, were retrospectively collected and analyzed. Patients were subdivided into adult and pediatric cohorts.

RESULTS

A variety of neurosurgical procedures were performed; resection of tumors and epileptic foci, endoscopic skull base procedures including pituitary lesions, deep brain stimulation (DBS), laser interstitial thermal therapy (LITT) and biopsies. Mean age was 32 years (range 0-81 years), 41 patients were pediatric and 42% were female. An iMRI scan was carried out in 96% of cases and led to continuation of surgery in 50 percent of cases, mainly due to visualized remaining pathological tissue. Median time to iMRI from intubation was 280 minutes and median total duration of surgery was 445 minutes. The majority of patients experienced no postoperative complications (70%), 13 patients suffered permanent postoperative deficits, predominantly visual.

CONCLUSION

We demonstrate demographics, clinical, surgical and radiological variables from the first 100 patients planned for surgery in the iMRI surgical theatre after

INTRODUCTION

in 2017. We found that iMRI was performed in almost all cases. In the pediatric cohort, tumors and epileptic focus were main indications for surgery. In adults, indications were intrinsic brain tumors, transsphenoidal pituitary tumor and DBS. Utilization from a resource and patients perspective appears to be most beneficial in tumor surgeries (specially pediatric), epileptic surgery and DBS.
P08.06.B OPTUNE TREATMENT FOR PATIENTS WITH GLIOBLASTOMA: A MIXED METHOD STUDY OF PATIENTS´, NEXT OF KIN´S´, PHYSICIANS´ AND COMPANY STAFFS´ EXPERIENCES
Authors: Letter N , Kastbom L , Wahlberg E , Norrgård J , Degsell E , Karlsson M , Malmström A
Published: September 2023

BACKGROUND

Since the pivotal trial, showing a near 5-month survival advantage with the addition of Optune to standard treatment for glioblastoma (GBM), Optune has been introduced into clinical practice in many countries. In Sweden, the device is prescribed by physicians, while the service of equipment and control of its use occur in the patients’ home by staff from the private company providing the device, this potentially creating a conflict of interest. Also, the daily use of the device necessitates the help of a next of kin. These are unique arrangements for Swedish healthcare, leading to the need of a complex and possibly challenging collaboration, and also raising potential ethical dilemmas.This study investigates Optune treatment for patients with GBM, regarding experiences of those involved in the treatment, namely: patients, next of kin, physicians and staff from the private company providing the device.

MATERIAL AND METHODS

The aim is to include 20 or more participants in each group (patients and next of kin, respectively). They are individually interviewed. The interviews are transcribed and analyzed using quantitative content analysis. Electronic questionnaires were sent during 2021-2022 to all physicians prescribing Optune at Departments of Oncology or Neurology in Sweden. The questionnaires included quantitative as well as open ended questions. Staff working for the company and visiting the patients and next of kin have also received electronic questionnaires focusing on experiences from their work.

RESULTS

Challenges were identified by the physicians, but they had varying opinions on the magnitude of the ethical problems. To date, 10 patients and 9 next of kin have been interviewed. Possible categories already identified are: “Information from the healthcare” and “Patient - company staff collaboration”. The questionnaires to the staff have been answered. The results of the interviews with patients and next of kin, as well as the results of the questionnaires to staff, will be presented.

CONCLUSION

The

INTRODUCTION

of Optune as a treatment of patients with GBM constitutes a new concept and a need for new solutions for tackling medical, practical and ethical issues.

SUPPORT

The Medical Research Council of Southeast Sweden (FORSS), and an ALF grant from Region Östergötland.
P09.08.B UNDERSTANDING THE HOLISTIC NEEDS OF PEOPLE LIVING WITH GLIOMA AND THEIR CAREGIVERS: A THEMATIC ANALYSIS OF THE SEMI-STRUCTURED INTERVIEWS FOR THE COBRA STUDY
Authors: Baddeley E , Sivell S , Retzer A , Nelson A , Bulbeck H , Seddon K , Grant R , Adams R , Watts C , Aiyegbusi O , Kearns P , Rivera S , Dirven L , Calvert M , Byrne A
Published: September 2023

BACKGROUND

The needs of people with brain tumours are unique, particularly in terms of neurocognitive impacts, and their subsequent effects on primary caregivers. Evidence suggests that those with brain tumours and their primary caregivers experience unmet needs in the clinical care setting.

MATERIAL AND METHODS

Semi-structured interviews with people with glioma and their caregivers, in the UK, with the aim to understand their priorities and lived experience of glioma, its treatment and treatment aims. Interviews formed part of a study to identify a core outcome set (COS) for glioma interventional trials (COBra study). The interview data were further analysed to identify concepts of importance to people with glioma and their caregivers within the clinical care setting.

RESULTS

Nineteen people with glioma and seven caregivers were interviewed (n=6 glioblastoma, n=4 astrocytoma, n=4 anaplastic astrocytoma/ oligodendroglioma, n=2 oligodendroglioma n=1 PXA tumour, n=1 ‘oligodendroglioma grade 3’ and n=1 ‘glioma grade 3’). Themes identified related to unmet needs and frustrations around communication, access to/need for support, caregiver impacts, neurocognitive symptoms and impacts to activities of daily living. Our findings also indicate the impact of treatment side effects, and how patients and caregivers negotiated tolerability in terms of trade-offs across the spectrum of glioma. Additionally, it was perceived that glioma grade did not correlate with symptom burden, and for those with longer survival, issues relating to late side effects were prominent - highlighting significant unmet needs across the spectrum of disease. Most described the lack of support and being left to deal with many of the unique burdens of the disease alone. Caregivers needs corresponded to the particular challenges experienced by their loved one, including late and longer-term effects of the disease, particularly neurocognitive impacts and the subsequent effects to patients’ activities of daily living as a result. Psychosocial impacts on caregivers were prevalent, reported by caregivers and also reported by patients interviewed with no caregiver present.

CONCLUSION

The qualitative data highlights the unmet needs of people with glioma and their caregivers, which are complex, unique and affect all those across the spectrum of glioma. As such, there is a need for a consistent and appropriate assessment of needs for patients and their caregivers in clinical practice, which need to incorporate the key concepts, such as communication, tolerability and support. These findings support further investigation into a holistic needs assessment for those with glioma.
P10.09.A TARGETING NITROSATIVE STRESS TO PREVENT NEUROBLASTOMA MALIGNANCY: INSIGHTS INTO THE MTOR SIGNALING PATHWAY
Authors: Ojha S K , Tripathi M K , Hamoudi W , Khaliulin I , Amal H
Published: September 2023

BACKGROUND

Neuroblastoma (NB) represents the most common pediatric tumor and its mechanisms remain elusive. Nitric oxide (NO) is one of the essential regulators of carcinogenesis of different tumors including NB. The mechanistic target of the rapamycin (mTOR) signaling pathway is another important regulator of tumorigenesis. In this study, we investigated the possibility to attenuate NB malignancy by inhibiting nitrosative stress and examined the interplay between NOS and mTOR signalling.

MATERIAL AND METHODS

NOD.CB17-Prkdc-scid/NCrHsd mouse were used for xenograft subcutaneous tumor model to evaluate the ability of HU-53 treatment regimens. Tumor weight and volume were measured during the study. The experiments were also carried out on the human-derived SH-SY5Y cells. Nitrite content was measured biochemically by griess assay. Immunoblotting and immunofluorescence assessed nitrosative stress and its effect on mTOR signaling. Genetic knockdown of nNOS was done in SH-SY5Y with siRNA to check effect of NO on neuroblastoma growth.

RESULTS

Treatment with HU-53 resulted in a significant decrease in tumor weight (p < 0.0005) and volume (p < 0.0002) as compared to mice treated with vehicle. Furthermore, we observed that the HU-53 treatment resulted in decreased levels of nitric oxide and nitrosative stress as confirmed by checking the level of nitrite content and 3-Nitrotyrosine which are important mediators of neuroblastoma growth. Genetic nNOS knock-down also prevented cell proliferation, reduced nitrosative stress (p < 0.0002), and the level of synaptophysin, the marker of NB carcinogenesis. Interestingly, NO inhibition elevated the levels of the core negative regulator of mTOR signaling, TSC2 and decreased the phosphorylation of the components of the mTOR signaling pathway, AKT, mTOR, and RPS6, indicating the reduced activity of this pathway. Thus, these results show inhibition of NO production help in reduced activation of mTOR pathway and prevent tumor growth.

CONCLUSION

Our results indicate that nitric oxide inhibition prevents neuroblastoma tumor growth and suggest that the NO-mTOR axis could serve as a novel potential target for NB treatment.
P10.12.B MOLECULAR MECHANISMS INVOLVED IN THE DEVELOPMENT OF BRAIN METASTASIS FROM THE MATCHED PAIRED LUNG ADENOCARCINOMA AND BREAST CANCER
Authors: Najjary S , Kros J M , de Koning W , Mustafa D A M
Published: September 2023

BACKGROUND

Up to 50% of patients with common cancers will develop brain metastases and incidences of this devastating complication are still rising. In our recent work, we found that the immune response in the brain is significantly stronger when the metastasis develops from lung adenocarcinoma (LUAD) compared to breast cancer (BC). Importantly, we discovered the higher expression of the drug target, VISTA, only in the brain metastasis of the LUAD. The aim of the current study was to investigate the molecular mechanisms driving the formation of brain metastasis from the two different lineages of cancer. In addition, we aimed to examine the expression level of the drugable molecules between primary tumors and their brain metastasis.

MATERIAL AND METHODS

Primary tumor and their matched brain metastasis samples of 11 LUAD and 11 breast cancer (total = 44 samples) were included in this study. RNA was extracted from the FFPE samples and the targeted gene expression profiles were measured using the PanCancer IO360™ Panel that includes 770 cancer-related genes (NanoString technology). Data were analysed using the nSolver software.

RESULTS

A first comparison was made between the primary tumors with their brain metastases for LUAD and BC separately. The second comparison was made between the common genes of both lineages. Pathway analysis indicated that there is higher metabolic stress in breast cancer-brain metastasis compared to that in the lung. In addition, we identified 12 common up-regulated genes in brain metastasis, despite the origin of the primary tumor. Importantly, by comparing the primary tumors of BC and LUAD with their brain metastasis, we found that VISTA is predominantly highly expressed in the primary tumors of LUAD and their matched brain metastasis.

CONCLUSION

Although the general mechanisms of metastasis have been described, our study demonstrates that different cancer lineages utilize various genes/pathways to metastasize to the brain. Moreover, primary LUAD and their brain metastasis express high levels of VISTA highlighting the possibilities for targeted therapy.