bluuebunny/crossref_metadata_2025_split huggingface dataset:
P12.01.B ANTI-VEGF TREATMENT EFFECT AGAINST GLIOMA IS IMMUNE DEPENDENT AND MEDIATED BY ENHANCED T CELL ACTIVITY
Authors: Maire C , Mohme M , Fita K , Reetz M , Heinemann S , Tolosa E , Alawi M , Casar C , Spohn M , Gempt J , Westphal M , Lamszus K 
Published: October 2024

Abstract

BACKGROUND
The majority of glioblastoma patients receive corticosteroids at some point during the course of disease to treat brain edema. Since steroids are immunosuppressive, immunotherapy trials increasingly avoid the use of steroids and consider bevacizumab as alternative. Targeting VEGF in the context of immunotherapy may additionally have immune stimulatory effects, as VEGF is a potent immunosuppressive factor. We explored whether anti-VEGF treatment has immune-mediated components and which mechanisms are involved.

MATERIALS AND METHODS
Murine glioma cells were injected intracerebrally into C57BL/6 wild-type mice or immunodeficient Pfp/Rag2 knockout (KO) mice. Animals were treated with B20 (anti-murine VEGF) or dexamethasone. Tumor-infiltrating and peripheral immune cells were profiled by flow cytometry, and RNAseq analyses were performed on sorted tumor and immune cells at different timepoints. T cells and NK cells were depleted using specific antibodies.

RESULTS
B20 prolonged the survival of immunocompetent mice (p &lt; 0.0001) but not of Pfp/Rag2 KO mice, indicating that the immune system is important for the effect of anti-VEGF treatment. At an early timepoint when controls became symptomatic, B20 “early” tumors (B20-ea) showed increased infiltration with T cells and myeloid cells, and decreased vessel density, while B20 tumors at the survival endpoint resembled IgG-controls. Gene expression in B20-ea tumor cells was dominated by hypoxia, neural development, invasion, TGF-β, Notch and Wnt signatures as well as concerted upregulation of Kmt2 H3K4 methyltransferases. In CD11b+ myeloid cells from B20-ea tumors, M1 hallmark genes and T cell activation genes were upregulated, while M2 genes were downregulated. Bioinformatic deconvolution revealed a transient shift towards pro-immune microglia/macrophages as well as increased NK cells and DCs. In CD8+ and CD4+ T cells, B20 increased the expression of S1pr1 and of α/β TCR genes, indicating oligoclonal expansion. Further, the proportion of progenitor-like exhausted CD8+ cells, which can be reinvigorated by PD-1 blockade, was increased in B20-ea. Among CD4+ T cells, B20 caused skewing towards the CD4+ TFH cell lineage, while dexamethasone increased expression of TH2 cytokines. Immune cell depletion in B20-treated animals demonstrated that CD8+ and CD4+ T cells but not NK cells were necessary for the survival-prolonging effect of anti-VEGF treatment.

CONCLUSION
Anti-VEGF therapy has significant immunostimulatory effects, mediated by CD8+ and CD4+ T cells as well as pro-immune modulation of the myeloid compartment. However, pro-immune effects are largely transient, so that an early treatment window of opportunity may exist during which anti-VEGF treatment in combination with an effective immunotherapy could have a substantial supportive effect, extending beyond its anti-edema activity.
P13.13.B RADIONECROSIS VERSUS SECOND MALIGNANCY: BRAINSTEM LESION 19 YEARS AFTER PAEDIATRIC MEDULLOBLASTOMA TREATMENT
Authors: Turcas A , Mihut E , Homorozeanu B , Avram G , Roman A , Fekete Z 
Published: October 2024

Abstract

BACKGROUND
Brain radionecrosis is a rare, but severe complication of radiotherapy. In children, the incidence ranges around 2-4% of patients and peaks around 5-7 years after conventional radiotherapy, wherease in adults treated with stereotactic radiotherapy it can occur more often and sooner, usually between 6 monts up to 2 years. Other important late side effects of radiotherapy in paediatric patients are second malignancies, which usually occur in the irradiated region, around 15-20 years after treatment.

CASE REPORT
We present the case of a 36-year old patient treated at the age of 16 (in 2005) with surgery, followed by standard chemotherapy and cranio-spinal irradiation (36Gy) with a boost up to 54 Gy to the entire posterior fossa for a non-metastatic medulloblastoma. Complete remission was obtained and maintained until October 2023, when the patient developed new symptoms in terms of headache, balance issues and accentuated motor deficits in the lower limbs. The MRI showed a new infiltrative, enhancing lesion in the pontine region, with diffusion restriction and heterogenous hyper-intense T2. We raised the suspicion of a second, radiation-induced malignancy or a late radionecrosis. MRI spectroscopy showed high Lactate, low NAA, Choline and Creatinine, being suggestive of radionecrosis, thus the patient was offered corticosteroids (16mg Dexamethasone for 1 week with progressive reduction of doses and cessation after 4 weeks). Monthly follow-up MRI’s showed a progressive volume and enhancement reduction of the lesion, with significant improvement of the symptoms. The last MRI (April 2024) shows a major reduction of the lesion, from 3/2cm at diagnosis to 0.6/1cm at 6 months, with good clinical status.

CONCLUSION
The presented case is impressive in terms of the timing of radionecrosis, given that with standard-fractionated radiotherapy this toxicity occurs very rare and usually much sooner. Also, the radiologic and clinical response to steroids was impressive. This report aims to raise awareness on the importance of long-term follow-up in paediatric brain tumour patients and underlies the importance of advanced imaging techniques for differentiating between tumour relapse, radio-necrosis and second malignancies.
P16.04.B LONG TERM SURVIVAL AND TOXICITY OUTCOMES IN PEDIATRIC MEDULLOBLASTOMA: SINGLE CENTER EXPERIENCE
Authors: Kamer S , Karaman E , Acar M S , Anacak Y 
Published: October 2024

Abstract

BACKGROUND
Craniospinal radiotherapy(CSRT) is a crucial part of medulloblastoma treatment. Due to the diverse age range of patients and large treatment fields, long term toxicity results, as well as survival outcomes, must be evaluated. This study aims to assess treatment outcomes of CSRT in medulloblastoma patients at a single tertiary center, considering both long-term toxicity and survival.

MATERIAL AND METHODS
Pediatric medulloblastoma patients who underwent postoperative CSRT between 2000-2021 were included in the analysis. CSRT was planned with 3D CRT technique for all patiens. Craniospinal axis doses were 23,4 Gy for standard risk and 36 Gy for high risk group. Patients received posterior fossa or tumor bed boost according to their risk status. Clinical characteristics and survival outcomes were obtained from follow-up visits. For late toxicity analysis, patients with less than 2 years of follow-up were excluded. Assessments included educational issues, neurological deficits, hearing impairment, endocrinopathy, and growth impairment.

RESULTS
120 cases (median age: 7 (2-17)) were analyzed with %61,7 being male. Gross total resection was achieved in 80,8% of cases. Most common histopathologic subtype was classical histology (76.7%). Forty-eight case (40%) was diagnosed in metastatic stage (M+) according to Chang’s classification. 52.5% of the cases were classified as high-risk group. Median follow-up was 64 months (4-252). 5- and 10-year overall survival was estimated to be 71.6% and 63.3% respectively. For the recurrence free survival; 5- and 10-year estimates were 68.5% and 61.6%. High risk group correlated adversely with overall survival (p&lt;0.01). In follow-up, recurrence was detected in 41 cases (34.2%) with a median of 16 months (1-52). Recurrence sites included 22 cases in the primary site, 8 cases in the spinal region, and 11 cases in both region. Although a higher recurrence rate was observed in the high-risk group (41.2% vs. 26.3%), difference was not statistically significant. Seventy-five cases underwent late toxicity analysis, with 72% exhibiting at least one late toxicity. Educational issues were found in 36% of cases, permanent neurological deficit in 34.7%, hearing impairment in 32%, endocrine insufficiency in 40%, and growth impairment in 49.3%.Higher spinal dose (p:0,019), age ≤8 (p:0,011) and female sex (p:0,034) correlated with growth impairment. Endocrinopathy was significantly more prevalent in children over 12 years of age (p=0.032). During follow-up, three cases developed secondary malignancies: one meningioma and two papillary thyroid carcinomas.

CONCLUSION
CSRT is an effective treatment modality for pediatric medulloblastoma and must be meticulously administered in order to achieve acceptable survival outcomes and minimize late toxicity. Long-term follow-up is crucial for monitoring late adverse effects and recurrences in patients.
P16.08.B TARGETING MYELOID CELLS IN COMBINATION IMMUNOTHERAPIES FOR PAEDIATRIC MEDULLOBLASTOMA
Authors: Abbas Z , Hii H , Buck J , Byrne J , Johnson I , Howlett M , Johns T , Gottardo N G , Endersby R 
Published: October 2024

Abstract

BACKGROUND
Stagnation in clinical outcomes, as well as severe side-effects of current treatments for high-risk medulloblastoma, have prompted the search for novel therapies. To date, immunotherapies have not demonstrated success in medulloblastoma. Due to the highly aggressive nature of relapsed medulloblastoma, we posit that immunotherapies have the greatest chance of success if applied first-line, alongside conventional therapies. We have previously shown that while conventional therapies deplete adaptive immune cells from the medulloblastoma microenvironment, macrophages persist following treatment. Moreover, medulloblastomas are myeloid dominant tumours and blocking the anti-phagocytic CD47-SIRPa interaction has demonstrated preclinical efficacy as a monotherapy.

MATERIAL AND METHODS
We tested the combination of anti-CD47 immunotherapy with craniospinal irradiation in patient-derived xenograft models of medulloblastoma and have characterised treatment responses using flow cytometry, RNA sequencing, and immunohistochemistry.

RESULTS
We found that the combination of anti-CD47 and radiotherapy is remarkably effective in radiosensitive tumours, resulting in long-term tumour-free survival. We found that the combination therapy results in enhanced macrophage infiltration and phagocytic activation in radiosensitive tumours compared to either monotherapy. However, we found this combination to be ineffective in tumours which do not regress in response to irradiation.

CONCLUSION
Although this combination treatment may not be a one-size-fits-all approach, biomarkers of radiosensitivity may allow for the identification of patients most likely to benefit from this combination.
P17.22.B SILMET TRIAL: A RANDOMIZED, PLACEBO-CONTROLLED STUDY TO EVALUATE THE STAT3 INHIBITOR SILIBININ IN PREVENTING INTRACRANIAL RECURRENCE AFTER COMPLETE RESECTION OF A SINGLE BRAIN METASTASIS FROM NON-SMALL-CELL LUNG CANCER (NSCLC) OR BREAST CANCER
Authors: Pellerino A , Pace A , Angileri F , Caffo M , Gatti M , Benicelli E , Bertero L , Ricci A , Mangherini L , Garbossa D , Priego N , Bosch-Barrera J , Valiente M , Rudà R , Soffietti R 
Published: October 2024

Abstract

BACKGROUND
A subpopulation of reactive astrocytes (RAs) with activated signal transducer and activator of transcription 3 (STAT3) signalling in peritumoral tissue of brain metastases (BM) has been shown to favor a pro-metastatic microenvironment. High-pSTAT3 expression in RAs of BM has been correlated with a shorter intracranial progression-free survival (i-PFS) as compared with low-pSTAT3 BM. Pharmacological inhibition of the STAT3 pathway with silibinin has been suggested to be active in preliminary cohort of patients with BM.

PATIENTS AND METHODS
A new “prevention” trial has been initiated in June 2023 to investigate the efficacy of silibinin in comparison to placebo (PCB) to prevent a secondary intracranial relapse in a multicentric cohort of patients with gross-total resected BM from NSCLC and breast cancer. Inclusion criteria are as follows: histologically confirmed BM from NSCLC or BC; single BM who underwent a complete resection; systemic disease not requiring a change of antineoplastic therapy; pSTAT3 presence in RAs of peritumoral tissue confirmed by central assessment; ≥ 18 - 70 years of age; KPS ≥ 70. The primary endpoint is to demonstrate a superiority of silibinin in prolonging time to local recurrence as compared to PCB. The secondary endpoints are time to distant recurrence of BM in the brain, i-PFS, overall PFS (intracranial and/or systemic), overall survival, tolerability, quality of life. Collection of blood and CSF samples for the analysis of STAT3 downstream pathways is an exploratory objective. The sample size (70 patients) was calculated by assuming a median time to local recurrence of BM of 7.5 months for PCB (control arm) according to Mahajan [1] and ≥15 months for silibinin arm. Clinical trial information: NCT05689619 [1] Mahajan A et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017
P17.23.B SINGLE INSTITUTION RETROSPECTIVE ANALYSIS OF COMPLICATIONS ASSOCIATED WITH SURGICAL DEBULKING OF BRAIN METASTASIS: SINGLE VS MULTIPLE LESIONS
Authors: Kannan S , Liew Y , Ray A , Hall G , Phang I , Hazra A 
Published: October 2024

Abstract

BACKGROUND
Surgical resection of brain metastasis is associated with complications, which worsens patient’s quality of life, resulting in oncological treatment delays and death. Surgical complication data aids decision making, leads to objective risk benefit analysis and informed consent. The aim of this study is to quantify the impact of the number of intracranial metastases on the rate and types of post-operative complications.

MATERIAL AND METHODS
Retrospective analysis on adult patients with brain metastasis, who underwent surgical debulking between 2017 and 2023 at Royal Preston Hospital. Data collected included demographics, primary tumour, number of lesions, 30-days post-operative complications, 30-days post-operative mortality and palliation, Karnofsky-Performance Score (KPS), and first vs. repeat resection. Univariate analysis carried out using R studio software.

RESULTS
Our patient cohort (n=226), 80 (35.6%) experienced post-operative complications. Top-five most common complications were Hospital-acquired pneumonia (HAP) (n=30, 13.3%), surgical site infection (SSI) (n=23, 10.2%), wound dehiscence (n=11, 4.9%), thromboembolic events (n=14,6.2%) and CSF leak (n=8, 3.5%). Average length of admission was 19.9 days (1-120) for patients with complications compared to 6.9 days (2-31) for patients without complications. Thirty (37.5%) patients with complications were readmitted. One-hundred twenty-seven patients (56.1%) had solitary lesion and 99 patients (43.9%) had multiple lesions. The most common primaries for patients with solitary lesion were lung (n=51, 40.2%), breast (n=25, 19.7%), and gastrointestinal (n=21, 16.5%). Whereas the most common primaries for multiple metastases were lung (n=41, 41.4%), breast (n=18, 18.2%), and skin (n=18, 18.2%). Amongst patients with complications, 45 (45.5%) had multiple metastases whilst 35 (27.6%) had solitary. The most common complications for patients with solitary lesion were HAP (n=10, 7.9%), SSI (n=9, 7.1%) and thromboembolism (n=8, 6.3%). Common complications for multiple lesions were HAP (n=20, 20.2%), SSI (n=14, 14.1%) and wound complications (n=10,10.1%). Patients with multiple metastases had higher 30-days post-operative palliation [(n=12) 12.1% vs (n=0) 0% solitary) and higher 30-days mortality [(n=4) 4% vs (n=4) 3.1% solitary). Multiple metastases were statistically significant for complications (p=0.005), HAP (p=0.006) and 30-days palliation (n=0.0001) but not statistically significant for SSI, 30-days mortality or thromboembolism. Conclusion: Surgical debulking is associated with significant post-operative complications, especially patients with multiple metastases with 16% either dying or not receiving any further treatment. Furthermore, 14.1% develop serious complications requiring further surgical interventions whilst 34.3% requires medical treatment.
P18.09.A CLINICAL AND MOLECULAR CHARACTERIZATION OF ADULT DIFFUSE MIDLINE GLIOMAS, H3 K27M-MUTANT
Authors: Grassl N , Suwala A , Kessler T , Etminan N , Unterberg A , Breckwoldt M , Bendszus M , Groden C , Debus J , Ehmann M , Wick W , Sahm F , Platten M , Sahm K 
Published: October 2024

Abstract

BACKGROUND
Diffuse midline glioma (DMG), H3 K27M-altered is a central nervous system tumor that occurs predominantly in children and young adults. They are characterized by distinct epigenetic features, whose therapeutic consequences remain ill defined.

MATERIAL AND METHODS
In this retrospective multicenter cohort study 52 adult patients with H3 K27M-mutant DMG and matched H3-wildtype glioma were characterized with respect to location, radiological features, methylation profile and clinical course.

RESULTS
DMGs were predominantly located in the thalamus, brainstem or spinal cord, but also occurred in the cerebellum and cerebral hemispheres. 35% of H3 K27M-mutant gliomas did not show contrast enhancement on MRI and only 43% had central necrosis. A third of adult H3 K27M-mutant gliomas, especially in spinal location, had distant progression resulting in shorter progression free survival (PFS). Addition of alkylating chemotherapy with temozolomide to radiotherapy did not result in prolonged PFS or overall survival (OS). A distinct methylation signature on the q arm of chromosome 15 differentiated patients with favorable OS form patients with short OS.

CONCLUSION
Adult DMGs occur throughout the CNS and are characterized by distinct epigenetic, radiological and clinical features.
P18.15.B DRUG SENSITIVITY OF RECURRENT GBM PATIENT-DERIVED ORGANOIDS CORRELATES WITH PATIENTS’ RESPONSE TO SECOND LINE CHEMOTHERAPY
Authors: Morelli M , Santonocito O , Lessi F , Franceschi S , Pieri F , Gambacciani C , Grimod G , Aquila F , Cupini S , Stasi I , Zucchi V , Giusti A , Vannozzi F , Franceschi E , Berzero G , Mazzanti C , Di Stefano A 
Published: October 2024

Abstract

OBJECTIVE
This study aimed to explore the correlation between the effectiveness of second-line chemotherapy in patients with recurrent glioblastoma (rGBM) who underwent a second surgery and drug treatment tests on patient-derived organoids.

METHODS
Sixteen adult patients diagnosed with IDH wild-type glioblastoma underwent a second surgery for recurrent GBM, with nine cases studied retrospectively and seven prospectively. Patient-derived 3D glioblastoma organoids (GBM-EXPs) were established from resected tumors and treated with chemotherapy agents. The response to treatment was evaluated using the NADH-FLIM method.

RESULTS
Among patients experiencing progression during first-line TMZ therapy (or within three months of discontinuation), a majority showed resistance to TMZ in the NADH-FLIM assay (p=0.02), with a longer PFS1 in TMZ-sensitive rGBM-EXPs compared to TMZ-resistant ones (15.9 versus 10.9 months; p=0.07). We did not observe different pMGMT hypermethylation between sensitive and resistant to TMZ rGBM-EXPs. Among patients treated with regorafenib in their second-line chemotherapy, those with regorafenib-sensitive rGBM-EXPs showed a significantly longer PFS2 compared to those with regorafenib-resistant organoids (PFS2 of 7.5 months versus 3.6 months respectively, p=0.04). In the prospective study, seven patients underwent ex-vivo testing before starting second-line therapy. Results from rGBM-EXP were considered by the multidisciplinary tumor board regarding second-line chemotherapy options among other clinical criteria. A trend for a longer median PFS2 was found in the prospective cohort compared to that of the retrospective cohort (7.4 vs 4.6 months, p=0.08) as well as a longer OS2 (defined as the interval from first recurrence and death/last evaluation 6.3 months versus not reached, p=0.03). pMGMT hypermethylation rate was not significantly different between the retrospective and prospective cohort. Paired analysis of specific longitudinal cases of untreated GBM-EXPs compared to rGBM-EXPs showed acquired resistance to TMZ in rGBM. The combination of TMZ and lomustine in ex-vivo testing showed better efficacy than monotherapies with TMZ and lomustine alone: mean % drug-sensitive tissue (DS%) respectively 51.4% vs 5.2% vs 35.8%, p=0.02.

CONCLUSIONS
This study shows that the sensitivity of rGBM-EXP to TMZ mirrors the timing of recurrence observed in vivo. Our findings suggest a potential role for NADH-FLIM-based drug response assessment in rGBM-EXP for predicting the efficacy of second-line therapies and improving the overall clinical outcome. Further prospective studies are warranted to validate these findings and potentially guide treatment decisions in clinical practice.
P18.45.A THE INCONSISTENT TERMINOLOGY FOR EXTENT OF RESECTION IN GLIOBLASTOMA: A SYSTEMATIC REVIEW ON SIX DECADES OF NEURO-ONCOLOGICAL STUDIES
Authors: Teske N C , Jung L B , Teske N , Thon N , Tonn J , Karschnia P 
Published: October 2024

Abstract

BACKGROUND
More extensive resection translates into improved outcome in patients with newly diagnosed glioblastoma. Insufficient acknowledgment of extent of resection may therefore introduce substantial bias in clinical trials. We herein aimed to systemically characterize the terminology used to describe resection in the context of neuro-oncological studies.

MATERIAL AND METHODS
A thorough review of the PubMed database was conducted to identify neuro-oncological trials between January 1966, and January 2024. Only studies which included information on extent of resection for newly diagnosed glioblastoma in adult patients were selected for our analysis. A standardized set of semantic and clinical variables was extracted for each study.

RESULTS
A total of 1862 neuro-oncological studies were screened, and 117 studies including 44 prospective interventional trials and 73 retrospective studies met our inclusion criteria. While a favorable association between outcome and more extensive resection was virtually uniformly reported, a broad range of 15 different semantic terms were used to describe the extent of resection (e.g., “complete/incomplete”, “gross-total/subtotal”, or “total/partial” resection). In line with this inconsistent terminology, only 60 studies (60/117, 51%) provided explicit definitions on how much tumor needed to be removed in order for a patient to match into a category corresponding to more extensive resection. Of these 60 studies, 17 (17/60, 28%) relied on subjective measurements including intraoperative estimations for extent of resection, while 43 studies (43/60, 72%) required objective measurements of volumetrics on pre- and post-operative imaging. There was no difference in the number of objective definitions between prospective and retrospective studies. However, the number of studies with objective definitions were significantly higher in surgical studies compared to medical neuro-oncological studies and increased over the last years (before 2010: 21%; after 2010: 41%).

CONCLUSION
The terminology used to describe the extent of resection is highly inconsistent across different clinical studies in neuro-oncology. To reduce potential imbalances between study arms and enable comparisons across different institutions, adaption of a standardized surgical nomenclature appears crucial. The recent RANO resect classification for extent of resection might form the basis for such a standardized terminology.