bluuebunny/crossref_metadata_2025 huggingface dataset:
P03.06.A FRAMELESS FRACTIONATED STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: AN INSTITUTIONAL SERIES OF 145 CASES
Authors: Kilic S S , Halima A , Chao S T , Neyman G , Guo B , Magnelli A , Kolar M D , Cho Y , Qi P , Barnett G H , Angelov L , Mohammadi A , Woody N M , Chan T , Yu J S , Murphy E S , Suh J H , Stevens G H
Published: September 2023

BACKGROUND

Cobalt-60 stereotactic radiosurgery (SRS) typically involves single fraction treatment with frame immobilization. However, large tumor size, proximity to critical structures, and prior radiation treatment sometimes necessitate fractionated SRS with mask immobilization. We present a large institutional experience with fractionated mask-based SRS for brain metastases.

MATERIAL AND METHODS

In this single-institution, IRB-approved study, all patients treated with mask-based fractionated SRS for brain metastases from March 2017 to January 2023 were identified. The primary outcomes were 1- and 2-year local control (LC) by Kaplan-Meier method.

RESULTS

118 patients with a total of 145 metastases were treated. The median follow-up time was seven months. The median age at treatment was 64.1 years (range: 26-95 years). 55.9% of patients were female. The most common primary tumors were breast (25.5%), non-small cell lung (23.4%), small-cell lung (8.3%), and melanoma (8.3%). For most cases (59.3%), the indication for fractionation was retreatment. Large size (28.3%), critical location (9.7%), and medical comorbidity (2.1%) were other indications. For all cases, the mean maximal linear size was 34.9 mm and mean target volume was 15.6 cc. For cases fractionated due to size, the mean size was 43.9 mm and mean target volume was 23.8 cc. Median total dose was 2,700 cGy (range: 1,620-3,000), and median dose per fraction (fx) was 600 cGy (range: 405-900). The most common prescriptions were 3,000 cGy/5 fx (40.0% of patients) and 2500 cGy in 500 cGy per fraction (37.2% of patients). Mean maximum dose was 4,833 cGy (range: 2,920-7,500). For 75.2% of treatments, the prescription isodose line was 50 to 59% (mean, 56.9%). Target coverage was 100% in all but one case (99%). For lesions near the brainstem, mean brainstem maximum point dose (MPD) was 9.3 Gy ± 9.8 Gy and brainstem mean dose was 3.3 Gy ± 3.3 Gy. For lesions near the optic pathway, mean optic nerve MPD was 14.4 Gy ± 9.2, optic nerve mean dose was 6.4 Gy ± 5.4 Gy, mean optic chiasm MPD was 11.7 Gy ± 7.9 Gy, and optic chiasm mean dose was 5.4 Gy ± 4.7 Gy. 1-year LC was 88.2% and 2-year LC was 80.4%. When retreatments were excluded, 1-year LC was 98.0% and 2-year LC was 98.0%. 18% of patients had acute grade 1-2 toxicities (fatigue, headache, nausea, and/or alopecia), and one patient had acute grade 3 fatigue. There were no other grade 3+ acute toxicities. 14% of patients had grade 1-2 radiation necrosis (RN); there were no cases of grade 3+ RN.

CONCLUSION

Cobalt-60 frameless fractionated SRS for brain metastases offers excellent local control, rigorous sparing of critical structures, and minimal toxicity. Frameless fractionated SRS should be considered for large, retreated, or critically located metastases.
P03.11.B MITOTIC ENRICHMENT AS AN EFFICIENT RADIOSENSITIZATION STRATEGY FOR INTRACRANIAL TUMORS
Authors: de Gooijer M C , Çolakoğlu H , Çitirikkaya C H , Fedorushkova D M , El Ouazani A , Shah R , Meel M H , Hulleman E , Borst G R , van Tellingen O
Published: September 2023

BACKGROUND

Radiotherapy remains one of the most effective modalities for anticancer treatment and part of standard of care for many primary and metastatic brain tumors. Boosting the efficacy of radiotherapy is therefore a logical avenue to improve patient survival. We have developed a radiosensitization strategy called ‘induction of mitotic enrichment’. It has long been known that the radiosensitivity of a cell depends on the phase of the cell cycle and that mitotic cells are especially vulnerable. Enriching the tumor for mitotic cells by arresting them during division prior to each radiotherapy fraction should therefore render the tumor population more sensitive to irradiation. Ideally, induction of mitotic enrichment should be reversible and non-cytotoxic to prevent healthy tissue toxicity and be compatible with clinically applied fractionated radiotherapy regimens.

MATERIAL AND METHODS

Mitotic enrichment in vitro is established using flow cytometry and radiosensitization is assessed using colony formation assays. In vivo, several independent luciferase-tagged orthotopic brain tumor models are used to investigate mitotic enrichment (phospho-histone 3 immunohistochemistry), tumor growth, survival and healthy tissue toxicity (body weight, blood liver enzymes, γH2AX and cleaved-caspase 3 immunohistochemistry). Pharmacokinetic studies are quantified using LC-MS/MS. All experiments on primary brain tumors included serum-free neurosphere culture models.

RESULTS

We have now identified an orally available targeted tubulin polymerization inhibitor that can achieve repeated and reversible mitotic enrichment for up to 10 hours prior to radiotherapy, without causing cytotoxicity in vitro or healthy tissue toxicity in vivo. This tubulin inhibitor (ABT-751) efficiently radiosensitizes a range of preclinical tumor models representing adult and pediatric, primary and metastatic brain tumors. Importantly, ABT-751 also improves survival in mouse models of adult glioblastoma (GBM), but only in a mitotic enrichment setup when given several hours prior to radiotherapy to allow accumulation in mitosis. Of note, induction of mitotic enrichment does not exacerbate healthy tissue toxicity.

CONCLUSION

Induction of mitotic enrichment by ABT-751 radiosensitizes adult GBM to fractionated radiotherapy. We are currently expanding our preclinical development of mitotic enrichment as a radiosensitization strategy to other targets and cancers and have designed a phase 0/I trial for adult GBM to demonstrate induction of mitotic enrichment and tolerability when combined with radiotherapy. We expect to start enrollment in this trial soon.
P04.03.B VENOUS THROMBOEMBOLISM AND OTHER VASCULAR COMPLICATIONS IN PAEDIATRIC PATIENTS FOLLOWING CRANIOPHARYNGIOMA SURGERY: A SINGLE-CENTER, RETROSPECTIVE STUDY
Authors: Castelli B , Scagnet M , Mussa F , Fonte C , Di Nicola M , Guidi M , Tellini M , Genitori L , Sardi I , Stagi S
Published: September 2023

BACKGROUND

Craniopharyngioma (CP), although slow growing and histologically benign, carries considerable morbidity, particularly in the postoperative period: hypothalamus-pituitary dysfunction and electrolyte disorders represent common complications. Moreover, in these patients, the increased risk of deep venous thrombosis (DVT) and the possible development of fusiform intracranial aneurysms are well known. However, data are still poor, especially in the pediatric population. The aim of our study was to describe the occurrence and timing of DVT and other vascular alterations in neurosurgical operated CP patients and to evaluate the role of predisposing factors in the development of post-surgical and late vascular events.

MATERIAL AND METHODS

This was a single-center, retrospective study. We investigated 19 patients (11 males, 8 females, mean age 10.47±4.29) diagnosed with CP, who had been subjected to neurosurgery between December 2016 and August 2022 in Meyer Children’s Hospital IRCCS in Florence. Demographic and clinical characteristics and surgical data were recorded for each participant.

RESULTS

Five patients (26.3%, 3 females, 2 males, median age 15 years) presented vascular events, all during sodium imbalance. Calcium at lower limits was detected in four of them. Three DVT (two with associated pulmonary embolism, including one female patient’s death) developed after surgery, more frequently at 7-10 days (two patients were central catheter carriers, one obese patient showed hypercholesterolemia and hypertriglyceridemia). In a patient in hyponatraemic state a vascular parietal alteration compatible with pseudoaneurysm was described soon after neurosurgery, requiring vascular stenting and prolonged intensive care. Superficial vein thrombophlebitis was a late complication in an overweight female patient on estrogenic replacement therapy.

CONCLUSION

Patients with CP undergoing neurosurgical brain tumor resection are at a higher risk of developing DVT and vascular alterations, thus careful follow-up should be done in these patients. In our study, we found that the phase of transition from central diabetes insipidus (CDI) to syndrome of inappropriate antidiuretic hormone secretion (SIADH) is probably a significative time for developing this complication; so, we recommend careful monitoring of symptoms suggestive of vascular events in CP operated patients. However, we suggest the execution of a deep vein ultrasound examination in the post-neurosurgical two-four weeks for an early diagnosis of this problem for reducing the risk of severe complications.
P04.09.B UNCOVERING GROUP 4 MEDULLOBLASTOMA THROUGH HUMAN CEREBELLARORGANOIDS
Authors: Leva G , Lago C , Ballabio C , Anderle M , Miele E , Tiberi L
Published: September 2023

BACKGROUND

Central nervous system tumors are the second most prevalent cancers in the pediatric population and among them, medulloblastoma (MB) is the most common and malignant one. MB is divided in four major subgroups: WNT, SHH, group 3 and group 4. Despite this classification, recent studies have highlighted many genetic features shared between the last two subgroups making the patients’ stratification less distinct. Particularly, group 4 MB is the most common subtype, but the least understood. Single-cell transcriptomics studies identified Unipolar Brush Cells (UBCs) as putative cell of origin of group 4 MB subtype. Despite G4 MB being the most common subtype, there is still a paucity of models. In this scenario, my aim is to implement and adapt the cerebellar organoids experimental design already established by Ballabio et al. for G3 MB towards G4 MB modeling.

MATERIAL AND METHODS

We generated cerebellar organoids starting from human pluripotent stem cells. Thanks to the PiggyBac/transposon system and the CRISPR/CAS9 technology we electroporated organoids achieving putative genes’ overexpression and downregulation. Organoids were live-imaged weekly checking for proliferative cells clusters formation and, after having reached the tumorigenic phenotype, they were engrafted in nude mice. The classification of the tumor obtained is based on DNA methylation analysis. Immunostainings were performed on mice cerebella and organoids to identify their cell types.

RESULTS

Because of the aggressiveness and the lack of knowledge of G4 MB, we focused on the development of a cerebellar organoids-based model genetically modified to achieve the tumorigenic phenotype. We studied the best time window in which Tbr2+ (UBCs marker) cells are most present in organoids, deciding to electroporate them at day 70 of differentiation. Based on RNA-seq data of G4 MB patients, organoids were modified with different combinations of genetic alterations. Interestingly, some of them showed the appearance of hyperproliferating engineered cells forming clusters. However, only the co-overexpression of MYCN and Otx2 developed a tumor when engrafted in nude mice. The following DNA methylation analysis attributed the tumor to G3 MB. Hence the need to clone the hTbr2 promoter to guide the expression of oncogenes through a Cre-LoxP system in the UBCs neural progenitors. We confirmed the new promoter specificity through an immunofluorescent quantitative analysis and then performed the genetic screening mentioned above to compare the outcome with our previous results.

CONCLUSION

Despite the timing, the mutational screening performed did not show the expected outcome: since G3 and G4 have common genetic features, we can’t rely on the strong ubiquitous non-specific promoter (CAG). Hence, we suppose that the hTbr2 promoter-guided gene expression could be the promising way toward G4 MB modeling.
P06.05.A INTRACEREBROVENTRICULAR TCR-TRANSGENIC T CELL THERAPY TO TREAT GLIOBLASTOMA (INVENT4GB)
Authors: Bunse L , Kratzmann M , Chih Y , Sanghvi K , de Roia A , Harbottle R , Eichmüller S , Benner A , Green E , Poschke I , Schmidt P , Steinbach J , Vajkoczy P , Bullinger L , Tabatabai G , Stenzinger M , Bönig H , Wick W , Platten M
Published: September 2023

BACKGROUND

Novel concepts in immunotherapy have evolved with the identification of potential (neo)epitopes and/or combinations with immune checkpoint inhibitors (ICI). In contrast to many other solid tumors, ICI have not improved outcome for patients with glioblastoma (GB) in phase 3 studies. However, antigen-specific T cells induced by vaccines or adoptively transferred as chimeric antigen receptor (CAR) T cells produced encouraging responses in early clinical trials and case series. From one of these trials, the Actively Personalized Vaccine Consortium (GAPVAC) European Clinical Trial 101, we have identified a human leukocyte antigen (HLA)-A2-restricted T cell receptor (TCR) targeting protein tyrosine phosphatase receptor type zeta 1 (PTPRZ1). PTPRZ1 is strongly overexpressed in malignant gliomas, especially GB, and analyses of intratumoral heterogeneity revealed that the level of PTPRZ1 overexpression is strongly associated with cancer stemness. The PTPRZ1 epitope is naturally presented on HLA-A2.

MATERIAL AND METHODS

INVENT4GB is a German, multicenter, phase 1, first-in-human, first-of-kind dose-escalation window-of-opportunity investigator-initiated trial in recurrent GB, eligible for re-resection, assessing safety and feasibility of therapy with intravenously (iv) and intraventricularly (icv) infused TCR-engineered T cells (TCR-T). FPI is scheduled for 2024. HLA-A*02:01 positive patients will receive one neoadjuvant iv followed by up to three adjuvant icv infusions of PTPRZ1-specific TCR-transgenic autologous T cell therapy (TCR-T-001) with cyclophosphamide- and fludarabine-based lymphodepletion prior to iv infusion. Patient autologous T cells will be engineered by non-integrating nano scaffold matrix attachment region (SMAR) TCR DNA vectors. Icv infusions will be performed via intraventricular catheter implanted during re-resection. Biomarker discovery includes magnetic resonance imaging (MRI) and longitudinal flow cytometry-based immune monitoring of blood and cerebrospinal fluid. Primary endpoints are feasibility and safety (determination of maximum tolerated dose/ MTD), key secondary endpoints are progression-free survival according to the Immunotherapy Response Assessment in Neurooncology (iRANO) criteria.

RESULTS

TCR-T-001 robustly recognizes target-expressing cells in vitro and is efficacious in preclinical tumor models. Preclinical data and the trial concept will be presented.

CONCLUSION

INVENT4GB is a first-of-kind TCR-engineered T cell therapy for GB patients.
P06.06.B PD-1 CHECKPOINT INHIBITION IN CONJUNCTION WITH NK-92/5.28.Z CELLS IS EFFECTIVE IN AN ADVANCED-STAGE GLIOBLASTOMA MOUSE MODEL AND INDUCES A CD4-ENRICHED T CELL RESPONSE
Authors: Strassheimer F , Roller B , Mildenberger I C , Macas J , Alekseeva T , Tonn T , Sevenich L , Reiss Y , Weber K J , Plate K H , Weigert A , Wels W S , Steinbach J P , Burger M C
Published: September 2023

INTRODUCTION

Checkpoint inhibition in combination with adoptive cell therapy holds promise for cancer immunotherapy, and encouraging treatment responses have already been demonstrated for certain tumor types. Glioblastoma (GB) is the most common and aggressive primary brain tumor with limited efficacy of standard therapy. Analysis of the GB tumor immune microenvironment (TIME) has shown prominent immunosuppressive features, including upregulation of exhaustion markers on tumor and infiltrating immune cells. While the surrounding brain is HER2-negative, GB tumors are frequently HER2-positive, suggesting HER2 as a promising target for adoptive immunotherapy. Previous results from mouse glioma models showed efficacy of off-the-shelf NK-92/5.28.z CAR-NK cells targeted against HER2 as monotherapy in early stage tumors.

RESULTS

Combined treatment with NK-92/5.28.z cells and anti-PD-1 checkpoint blockade resulted in strong synergistic effects, with tumor regression and long-term survival observed even in advanced-stage tumor bearing mice. Analysis of tumor tissues using highplex methods (highplex multicolor flow cytometry, bulk RNAseq and multicolor IHC) revealed changes in lymphocyte infiltration and an altered TIME upon combination treatment with NK-92/5.28.z and anti-PD-1 checkpoint therapy. Specifically, infiltrating lymphocytes displayed an activated phenotype with predominance of CD4 cells and reduction of regulatory T cells.

CONCLUSION

Our data demonstrate that efficacy of HER2-specific NK-92/5.28.z cells can be enhanced by combination with checkpoint blockade. The combination therapy reverted the immunosuppressive TIME, resulting in successful treatment even of advanced othotopic tumors refractory to CAR-NK monotherapy. We are currently translating this concept into early clinical testing by including a respective patient cohort in our ongoing CAR2BRAIN phase I clinical trial (NCT03383978).
P06.14.A DIAGNOSIS AND MANAGEMENT OF NEUROPATHIES RELATED TO IMMUNE CHECKPOINT INHIBITORS: A CASE SERIES
Authors: Cuzzubbo S , Lozeron P , Baroudjian B , D’Oria F , Tétu P , Ursu R , Gounant V , Meppiel E , Lambert T , Ng Wing Tin S , Duchemann B , Belin C , Lebbé C , Carpentier A F
Published: September 2023

BACKGROUND

Immune checkpoint inhibitors (ICIs) are associated with a wide range of neurotoxicities. Several types of neuropathies have been associated to immune checkpoint inhibitors (ICIs), from length-dependent sensory neuropathies to radiculoneuropathies similar to Guillain-Barré syndromes, with an overall incidence estimated to be between 0.1-1.2% of patients. Guidelines recommend prompt ICI discontinuation and the

INTRODUCTION

of steroids depending on the severity of the adverse event. However, the usage of IVIG or plasmapheresis (alternatively or in addition to steroids) has been reported in cases of Guillain-Barré-like syndromes.

MATERIAL AND METHODS

In this study, we report a retrospective consecutive series of patients with an ICI-related neuropathy referred to our department between 2016 and 2021, with the intent to describe their clinical and para-clinical features and the outcome after ICI discontinuation and steroids.

RESULTS

We identified 12 cases of acute peripheral nervous system involvement, with a predominant sensory pattern. The median onset of symptoms from ICI initiation was 18 weeks, and the median number of ICIs doses was 3. Electrophysiological studies, done in 11 patients, showed a radiculopathy in 9 cases, associated with an axonal neuropathy in 3, and a demyelinating neuropathy in 2 cases. Altogether, these findings are consistent with Guillain-Barré-like syndrome. ICIs were stopped in all patients and steroids started in 7 patients, leading to a favourable outcome (complete recovery =7, partial recovery =4, stability =1).

CONCLUSION

This consecutive retrospective series identifies Guillain-Barré-like syndrome as the main clinical pattern of immune related neuropathies. We did not observe any case of length-dependent axonal neuropathy without an associated root involvement. Our systematic management, consisting of ICI discontinuation in all patients and steroids in more severe cases, seems a valid strategy. On the other hand, our results do not support the use of IVIG or other treatments.
P06.20.B LONG-TERM CLINICAL RESULTS OF 493 CASES OF NEWLY DIAGNOSED GLIOBLASTOMA AND SURVIVAL BENEFIT BY COMBINATION WITH PDT AND AFTV, AIMING TO ESTABLISH NEW STANDARD TREATMENT
Authors: Nitta M , Muragaki Y , Saito T , Tsuzuki S , Koriyama S , Kuwano A , Kawamata T
Published: September 2023

BACKGROUND

Glioblastoma has the worst prognosis of brain tumors. Evidence for improving prognosis by maximal tumor removal is being established, and in recent years, new treatments such as photodynamic therapy (PDT, 2014 in Japan), and TTF therapy (2018) have been approved, the treatment results are improving. In principle, our facility performs maximum tumor removal using intraoperative MRI (iMRI) follow by the standard chemoradiation. Intraoperative PDT and autologous tumor vaccine (AFTV) will be given to desired patients. We retrospectively analyzed the long-term clinical results of the patients with newly diagnosed glioblastoma who underwent surgical treatment at our facility, and the treatment results by era and treatment method.

MATERIAL AND METHODS

The clinical features, extent of removal (EOR), OS and PFS of the adult patients with newly diagnosed glioblastoma treated from 2001 to 2021 were analyzed retrospectively. Clinical results of those patients who received PDT and AFTV treatment was also investigated.

RESULTS

The number of cases was 493, median age 58 years (18-85 years), 293 males, 200 females. The median and average EOR of contrast-enhanced lesions were 98% and 96.6%, respectively. The median PFS and OS of all cases (including biopsy) were 9.4 months and 22.7 months, respectively. When the cases were analyzed separately for 2001-2006 (before TMZ), 2007-2010, 2011-2015, and 2016-2021, the median OS for each age group was 12.9 months, 22.9 months, 23 months, and 31.1 months. The treatment results improved with age (p <0.0001). In particular, the median OS of 23 cases treated with PDT and AFTV was 63.1 months. The efficacy of AFTV for newly diagnosed glioblastoma is currently being verified in a multicenter Physician-led clinical trial.

CONCLUSION

The treatment results for glioblastoma have improved over the years. The combination of maximal tumor removal using iMRI, PDT and AFTV may aim for a 5-year survival rate of 50%.
P07.01.A MR-GUIDED LITT THERAPY IN PATIENTS WITH PRIMARY IRRESECTABLE GLIOBLASTOMA: A CONTROLLED, PROSPECTIVE PILOT STUDY (EMITT PILOT-STUDY)
Authors: Viozzi I , Neutel C , Overduin C G , Rijpma A , Rovers M M , ter Laan M
Published: September 2023

BACKGROUND

Laser interstitial thermal therapy (LITT) is growing as a minimally invasive procedure in the treatment of brain tumours, even if high-quality evidence is lacking. We aimed to assess practical feasibility of a randomized controlled trial (RCT) in patients with primary irresectable glioblastoma (nGBM) and to collect pilot data on technical feasibility and safety of LITT.

METHODS

Adult patients with radiologically suspected glioblastoma where the multidisciplinary tumour board advised biopsy-only with KPS ≥70 and feasible trajectories to reach ≥70% ablation were prospectively included. Patients were randomized to receive either biopsy combined with LITT or biopsy alone, followed by chemoradiation (CRT). Main endpoints were practical feasibility of RCT (inclusion rate, willingness to be randomized and ability to complete the follow-up procedures), technical feasibility (time from indication to procedure, time from procedure to CRT, duration of procedure) and safety (complications reported following the Clavien Dindo classification (CD).

RESULTS

A total of 15 patients with an irresectable nGBM were included in the study (5 in the control and 10 in the LITT arm). Patients were highly motivated to participate to the study and all patients completed the follow-up procedure. After including 9 patients randomization was stopped. All patients were planned within 2 weeks after indication and no delay was observed in referring patients for adjuvant CRT. One, two or three laser probes were used to reach ≥70% expected ablation. Total procedure time varied between 200-540 minutes. Two CD≥3 complications occurred in the LITT arm.

CONCLUSION

Our pilot data suggest an RCT investigating LITT in patients with an irresectable nGBM is feasible, with initial safety data appearing in line with that of tumour resection. As a next step, we have designed a national multicenter RCT in order to evaluate survival benefit, quality of life and cost-effectiveness of LITT in this population.
P07.09.B A RANDOMIZED PHASE 2B STUDY OF SURVIVIN VACCINE SURVAXM PLUS ADJUVANT TEMOZOLOMIDE FOR NEWLY-DIAGNOSED GLIOBLASTOMA (SURVIVE)
Authors: Ahluwalia M S , Ciesielski M , Abad A , Reardon D , Aiken R , Barbaro M , Sinicrope K , Peereboom D M , Odia Y , Brenner A , Venur V , Butowski N , Belal A , Qiu J , Ozair A , Khosla A A , Schilero C , Figel S , Casucci D , Mechtler L , Fenstermaker R
Published: September 2023

BACKGROUND

Newly-diagnosed glioblastoma (nGBM) has a dismal prognosis with a median overall survival (OS) of nearly 16 months. nGBM cells have high expression of tumor-associated survivin protein. Survivin, localized to the cell surface through presentation by MHC class I molecules, is recognized by antibodies and cytotoxic T-lymphocytes (CTLs). A Phase 2a trial (NCT02455557) showed that a 15-amino acid-peptide-conjugate vaccine (SurVaxM) stimulates the production of survivin-directed antibodies and anti-tumor CTL in nGBM patients, resulting in a median OS of 25.9 months. This Phase 2b randomized controlled trial (RCT) aims to further investigate the efficacy of SurVaxM and adjuvant temozolomide for nGBM.

METHODS

This multicenter, placebo-controlled, investigator- and patient-blinded, in-progress RCT randomizes nGBM patients receiving standard of care to either SurVaxM (arm A) or saline placebo (arm B) in a 3:2 ratio at 15 sites. Included patients have age ≥18 years, normal organ function, Karnofsky Performance Status (KPS) ≥70, surgical resection, residual MRI contrast enhancement of ≤1 cm3 within 72 hours of resection, and adjuvant temozolomide (TMZ) therapy. Patients with recurrent, multicentric, brainstem- or cerebellar-origin GBM are excluded, as well as patients on tumor-treating fields or other immunotherapies. All patients undergo 3 phases: (1) vaccine priming (VP) phase, starting within 4 weeks after completion of chemoradiation, where 4 doses of SurVaxM or Placebo are administered every 2 weeks; (2) adjuvant TMZ phase, started after ≥1 VP dose; and (3) vaccine maintenance phase, started 8 weeks after VP, with SurVaxM or placebo given every 8 weeks. TMZ phase overlaps with VP and VM phases. The primary endpoint is median OS. Assuming a 1-year survival rate of 75% in the SurVaxM arm, comparable to the median OS in early phase trials, and 60% in the control arm, the study will enroll 265 patients, 159 in arm A and 106 in arm B. A log-rank test stratified by KPS (70-80 and 90-100), MGMT status (methylated and unmethylated), and IDH status (mutant and wild-type) will be used for analysis. Secondary endpoints per study arm are survival at 15, 18, and 24 months, median progression-free survival, toxicity, and progression-free survival at 3, 6, and 12 months. A single sequential OS-driven interim analysis is planned when 50% of OS events (deaths) occur. The study is expected to take 35 months, with ongoing accrual.

RESULTS

69 patients have been enrolled as of April 11, 2023.

CONCLUSION

Findings from this trial will demonstrate the safety and efficacy of survivin vaccine in GBM (Clinical trial information: NCT05163080).
P07.13.B A RANDOMIZED STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION FOR BRAIN METASTASIS FROM NON-SMALL CELL LUNG CANCER (LIMITLESS)
Authors: Ahluwalia M S , McDermott M , Ozair A , Khosla A A , Sahgal A , Mishra M , Achrol A , Woodworth G , Lipsman N
Published: September 2023

BACKGROUND

The blood-brain barrier (BBB) limits the efficacy of systemic therapies for brain metastases (BM), for which non-small cell lung cancer (NSCLC) is the most common etiology. BBB disruption (BBBD) has been demonstrated, in preclinical models, to improve systemic drug delivery for BM. Low-intensity focused ultrasound (LIFU) results in non-invasive BBBD synergistically with intravenously (IV) administered microbubble oscillators. This randomized controlled trial (RCT) aims to determine the safety and efficacy of LIFU-mediated BBBD for NSCLC BM with immunotherapy.

METHODS

LIMITLESS is an ongoing prospective, multicenter, parallel-arm, open-label RCT that randomizes patients with NSCLC BM on pembrolizumab monotherapy prescribed as per standard-of-care to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in 2:1 ratio. Included patients have age ≥18 years, normal organ function, Karnofsky Performance Status ≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM with ≥1 BM meeting measurable disease criteria as per response assessment in neuro-oncology for BM (RANO-BM). Patients on both arms receive standard-of-care therapy, while those on arm 1 also undergo LIFU before each dose of pembrolizumab (200 mg IV every 3 weeks). These patients undergo pre-treatment MRI brain, followed by IV administration of oscillating microbubbles for enhanced sonication. MR-guided BBBD is then performed using a 220 kHz LIFU device with real-time acoustic feedback for maintaining effective cavitation. Pembrolizumab is infused immediately thereafter, and a repeat MRI is done 24-48 hours later to confirm the closure of BBB each cycle. The primary study endpoint is the overall objective response rate (ORR) at 6 months, as assessed using RANO-BM criteria. Using a Bayesian design for power analysis, a superior ORR of 60% is assumed for the LIFU arm versus 30% in the control arm for a total sample size of N=96, 64 subjects in LIFU and 32 in the control arm, for 80% power using a two-sided chi-square test with an alpha of 0.05. For the upper-bound estimate ORR of 45% in the LIFU arm and 30% in the control arm, the study needs N=369 subjects; 246 in the LIFU arm and 123 in the control arm. The secondary outcomes are the best objective response rate and median time-to-response per treatment arm. The exploratory outcomes are median progression-free survival (PFS), overall survival (OS), median intracranial PFS, median extracranial PFS, and quality of life.

RESULTS

Patient enrollment commenced in 2022.

CONCLUSION

Findings from this trial will be critical to liquid biopsy in brain metastases (Clinical trial information: NCT05317858).
P08.05.A A LONGITUDINAL CASE STUDY OF PATIENTS' EXPERIENCES IN THE INITIAL PHASE OF A BRAIN CANCER PATHWAY - AIMING TO IMPROVE PATIENT CARE
Authors: Vedelø T , Sørensen J , Hall E , Delmar C
Published: September 2023

BACKGROUND

A brain cancer diagnosis is life-transforming and involves accelerated diagnostics and treatment and care involving multiple settings and healthcare professionals. Patients are confronted with an uncurable cancer disease but also face progressive neurological and cognitive deficits over time, adding to the uncertain and stressful situation. Knowledge of patients' experiences during their hospital stay in the initial diagnostic phase is sparse. This study aimed to explore patients' experiences at the hospital during the diagnostic workup, the brain surgery, and the post-operative period until discharge and to describe what matters to patients when diagnosed with a malignant brain tumour.

MATERIAL AND METHODS

We used a descriptive longitudinal single-case study design to produce in-depth, context-dependent knowledge and capture real-life situations in patients' day-to-day care experiences from admission to discharge across three different departments throughout the initial diagnostic phase. To explore patients' views directly in the actual situations unfolding in practice, we followed one patient at a time and did 180 hours of field observation and 16 semi-structured interviews. We analyzed field notes and interviews by applying systematic text condensation.

RESULTS

An overarching theme, "A fast transition", was identified, describing the patients' experiences in the two central themes; "From feeling fine to an unknown journey" and "Patient involvement determined by system factors". Within the two themes, six subthemes emerged from the data: Overwhelming uncertainty and fear, Putting life on hold, An unfamiliar dependency and Being unprepared and side-lined, The significance of close relatives, and Managing care needs and demands.

CONCLUSION

The results add to understanding patients' experiences during the initial diagnostic phase. While part of the findings are a fact of life for patients diagnosed with a brain tumour, others point to specific areas for improvement. Small changes in care delivery can enhance patient involvement by proactively informing patients about their care plan, ensuring the presence of relatives during information giving and identifying patients' care needs and preferences. Establishing a patient and public involvement group in 2023 will provide more knowledge gaps for future research.
P08.08.A EXPLORATION OF SURVIVORSHIP ISSUES AND QUALITY OF LIFE IN A COHORT OF IDH MUTATED HIGH GRADE GLIOMA 5 YEARS FOLLOWING DEFINITIVE TREATMENT
Authors: Engel S J , Yim J , Kastelan M , Wheeler H , Back M
Published: September 2023

BACKGROUND

Approximately 2000 people are diagnosed with brain cancer in Australia each year. Compared to glioblastoma patients, the IDH-mutated high-grade glioma (IDHmHGG) is a more favourable diagnosis; better prognosis and survival outcomes. Coupled with improved treatments, the IDHmHGG cohort is living longer which means treatment side effects (eg. fatigue, cognitive deficits, physical limitations etc.) can significantly impact their quality of life in the survivorship years. Hence there is a need to identify and determine the survivorship issues most pertinent for the IDHmHGG cohort.

MATERIAL AND METHODS

A mixed-

METHODS

cross-sectional study was conducted to investigate the relationship between socio-demographic, clinical factors and quality of life in the IDHmHGG cohort. Qualitative data collection consisted of a neuro-oncology clinician focus group (n=11) regarding survivorship issues and was contrasted with semi-structured patient interviews (n=27). Quantitative data collection (n=41) involved socio-demographic questions, the Functional Assessment of Cancer Therapy - Brain (FACT-Br) tool and The Hospital Anxiety and Depression Scale (HADS).

RESULTS

The results indicate that marital status, employment status, and treatment complications are strongly associated with quality of life in IDHmHGG patients. Being single and unemployed is associated with lower quality of life (p<0.05). Similarly, our findings show that psychological distress, specifically the presence of anxiety and depressive symptoms, is a major factor that can negatively impact the QoL in an IDHmHGG cohort. The order of ranking between clinician and patient identified issues only matched for physical limitations (ranked 3rd). Although not matched in ranking, both groups identified cognitive function, employment, social function, isolation and mental health as commonly experienced in the survivorship years.

CONCLUSION

This study highlights the importance of considering socio-demographic and clinical factors in the care and support of brain cancer patients. The most important finding of this study was that being single and unemployed negatively predicted QoL. Additionally, it is notable that our results show a discrepancy between clinician identified issues and patient identified issues. This finding suggests that in order to deliver patient-centred and meaningful care, there is a need to incorporate a more patient focused perspective. Future survivorship models of care for the IDHmHGG cohort should be co-designed with patients.
P08.09.B EFFECTS OF A ONE-WEEK SKIING INTERVENTION ON LOWER LIMB MUSCLE STRENGTH IN BRAIN TUMOR PATIENTS AND THEIR CAREGIVERS
Authors: Jost J , Hansel N , Brandt R , Lemcke L , Stummer W , Wiewrodt R G , Wiewrodt D
Published: September 2023

BACKGROUND

Due to fatigue or feelings of insecurity, many brain tumor patients are not sufficiently active. Among other things, this puts patients at higher risk for sarcopenia predicting overall survival. Exercise interventions of various kinds could effectively counteract this problem. Here, we aim to present the impact of a one-week skiing intervention on leg muscle strength in brain tumor patients and their caregivers as well as feasibility and safety of the intervention.

MATERIAL AND METHODS

Ten brain tumor patients and their families participated in this one-week skiing intervention in a self-catering lodge at 1400m altitude. Daily 4-hour ski sessions (including approx. 1 hour rest) with professional ski instructors were performed in small groups (≤5 participants) divided by proficiency level. Participants could choose between downhill and cross-country skiing. Adverse events were noted daily. Muscle strength was determined 3-10 days pre- and postintervention on 5 different gym machines (knee extension, knee flexion, adductors, abductors, leg press) using Brzycki's equation.

RESULTS

20 adults (10 patients, 10 caregivers) and 7 children participated in the ski-based intervention. All patients were surgically treated at least once and received chemo- and/or radiotherapy (ongoing chemotherapy in 6 patients). No severe adverse events were recorded throughout the week. 15 adults (9 patients, 56% female; 6 caregivers, 67% female) aged 21-69 years (mean 50 years) completed the muscle strength tests. Of those, most patients suffered from grade 4 brain tumors (67%), followed by grade 2 (22%) and grade 1 (11 %) tumors. Mean muscle strength increased in all muscle groups tested (knee extension +13.5%, p=.024, CI 95%: -0.5 - 29.1; knee flexion +7.1%, p=.048 CI 95%: -1.0 - 14.0; adductors +6.6%, p=.039, CI 95%: 1.3 - 13.4; abductors 20.0%, p=.004, CI 95%: 6.9 - 35.7; leg press +19.5%, p=.050, CI 95%: -5.6 - 44.6). Tumor grade, gender, type of ski intervention, and age did not affect the

RESULTS

.

CONCLUSION

During one week of intensive ski training, positive effects on leg muscle strength could be shown in both brain tumor patients and their families regardless of age, gender, downhill/cross-country ski, or WHO grading. Furthermore, this study demonstrates feasibility and safety of ski-based exercises in this patient population. Interventions such as these could help patients overcome (gait) insecurities and motivate them to become more physically active in their daily lives. In the longer term, this may lead to better management of everyday life and improved quality of life.
P08.11.A PREDICTIVE SOCIAL FACTORS ASSOCIATED TO PLACE OF DEATH IN MALIGNANT GLIOMAS
Authors: Benincasa D , Villani V , Focarelli S , Tanzilli A , Cardone F , Biscu A , Alò D , Di Felice S , Pace A
Published: September 2023

BACKGROUND

Malignant gliomas (MG) are tumors affecting central nervous system (CNS) with a poor prognosis. Fast neurological decline (motor, cognitive and behavioural) causes high burden for patients and caregivers and requires specific setting of care (especially palliative care) helping patients to preserve their autonomy and assuring, in the end of life phase, the best care represented by dying at home with dignity that is considered in the literature an indicator of good quality of care in cancer patients.

MATERIAL AND METHODS

The home care program for MG utilized in our Institution is aimed to offer palliative and supportive care during all the trajectory of disease and to facilitate death at home. To identify possible factors related with place of death, we’ve retrospectively investigated social and health data to discover possible factors associated with dying at home in MG patients. Every patient and caregiver/family were analyzed for many factors including sex, work, family relation, presence or absence of caregiver/family, presence of children.

RESULTS

From January 2016 to December 2020, we’ve assisted at home 263 MG patients and collected complete data in 257 patients (6 patients was lost in follow-up). 174 (68%) of them were affected by Glioblastoma Multiforme (GBM) and 83 (32%) were affected by grade 3 anaplastic gliomas; 155 patients (61%) were male and 102 (39%) female. 137 patients (54%) died at home, 88 patients (34%) died in hospice and 32 patients (12%) died in hospital. Male caregivers assisted 178 MG patients of which 141 was male patients (79%); female caregivers assisted 79 MG patients of which 65 was female patients (82%) (p<0.001); presence of social network (family or other type) influenced positively place of death: MG patients who has social network died frequently at home respect on MG patients who didn’t have social network that died frequently in hospital or hospice (p<0.001). No differences were found between age, sex (patient and caregiver), presence of minor children, education level, work, marital status and place of death.

CONCLUSION

In this cohort of MG patients followed with a palliative home care service, place of death and dying with dignity is influenced by presence of social network and reliable caregiver. The evaluation social data in addition to clinical data is an important factor in order to plan timely the end of life phase and the decisions about possible place of death.
P09.06.B GAIT CHARACTERISTICS OF PROGRESSIVE DISEASE IN HIGH GRADE GLIOMA: THE BRAINWEAR STUDY
Authors: Dadhania S , Williams M
Published: September 2023

BACKGROUND

Walking is a useful measure of overall health and walking speed has well-documented predictive value for health-related outcomes such as mortality, quality of life, physical and cognitive functional decline in older people. Wearable technology-based gait analysis is emerging as a powerful tool to detect early disease and monitor progression in areas such as Parkinson’s disease. We present an exploratory analysis of gait characteristics at the time of progressive disease from patients with high grade glioma (HGG) participating in the BrainWear Study which evaluates the use of free-living accelerometers in patients with brain tumours.

MATERIAL AND METHODS

All agreed to wear a wrist-worn Axivity AX3 triaxial accelerometer changed at 14-day intervals. Raw accelerometer data was processed using the UKBiobank OxWearables stepcount model v2.1.2 for Python and inclusion of high-quality wear time selected as ≥72 hours of data in a 7-day data collection and data in each 1-hour period of a 24-hour cycle over multiple days. 12 gait measures were characterised including total daily steps, cadence, cadence peak and minutes walking per day. We analysed variation in gait measures by patient demographics and MRI result. Wilcoxin-signed rank test was used to compare participant gait measures at timepoints of stable disease (SD) or progressive disease (PD). Mixed-effects models were used to evaluate longitudinal changes in gait measures.

RESULTS

17 HGG patients (6 female; 11 male) provided 4654 days of accelerometer data across 49 MRI Head scan

RESULTS

, 32 labelled as PD and 17 as SD. Median age was 62 years (32-79) and mean study participation 273 days (41-550). 8 patients provided accelerometer data at timepoints of both PD and SD allowing for paired analysis. There were no differences in 12 gait measures between age (<60 and >60 years) and gender. In the 6 weeks surrounding an MRI scan, patients with PD walked on average 1856 steps less per day than those with SD, and spent 22 minutes less walking (p=0.0403). Peak 1-minute cadence was 77 steps/min in patients with SD versus 67 steps/min with PD.

CONCLUSION

The complexity of HGG treatment, recovery and survivorship creates a need for novel monitoring approaches. Wearable accelerometry is feasible and acceptable and evaluating gait measures captures objective evidence of significant differences in patients with PD versus SD. Physical activity measures can guide clinicians in optimising quality of life and may act as an alert system prior to events such as disease progression.
P09.07.A SYMPTOM AND DISTRESS IN PATIENTS WITH MALIGNANT BRAIN TUMOR TREATED WITH PROTON BEAM THERAPY. A FIVE-YEAR FOLLOW-UP STUDY
Authors: Kunni K , Langegård U , Fransson P , Proton Care Study Group T
Published: September 2023

BACKGROUND

Due to new treatment regimes, an increasing proportion of patients with malignant brain tumors will likely be long-term survivors. To ensure optimal care for this patient group, it is crucial to conduct further research, including long-term follow-up of treatment-related symptoms, and distress. Patients with malignant brain tumors experiencing distressing symptoms will result in poorer overall survival and decreased quality of life. Despite this, the correlation between symptoms and distress in adults with malignant brain tumors undergoing proton beam therapy remains poorly understood. This study aimed to explore if symptoms and distress change over five years in adults with malignant brain tumors treated with proton beam therapy. An additional aim was to explore if symptoms and distress correlate.

MATERIAL AND METHODS

The study had a quantitative longitudinal multicenter design.Adult (≥18 years) patients (n = 149) with malignant brain tumors treated with proton beam therapy were followed over five years. The degree of symptom and distress were evaluated using the patient-reported Radiotherapy-Related Symptom Assessment Scale. Data from baseline, 1, 12-, and 60 months were analyzed using non-parametric tests. The correlation between symptoms and distress were analyzed using Spearman’s correlation.

RESULTS

Levels of symptoms and distress were generally low. Fatigue had the highest levels at all timepoints. Cognitive impairment increased significantly at 12-months (P=0.002) and was the most distressing symptom at 60-months follow-up. The results showed a significant, moderate to strong, correlation at all time points between symptoms and distress of fatigue, insomnia, pain, cognitive impairment, worry, anxiety, nausea, sadness, and skin reactions.

CONCLUSION

Our study highlights the correlation between symptoms and distress in adults with malignant brain tumors treated with proton beam therapy. Further, this study emphasizes that nursing should focus on what patients experience as the most distressing symptoms. Research should identify effective interventions to alleviate symptoms and reduce patient distress. Given the significant correlation between symptoms and distress in our study, we suggest developing cancer rehabilitation. Reduced levels of distressing symptoms would lead to a better quality of life and increased survival for this vulnerable group of patients.