bluuebunny/crossref_metadata_2025 huggingface dataset:
ETMR-27. ANTI-ANGIOGENIC METRONOMIC THERAPY OF RARE TUMOURS OF THE CENTRAL NERVOUS SYSTEM
Authors: Schned Hannah , Haberler Christine , Peyrl Andreas , Azizi Amedeo , Mayr Lisa , Aistleitner Barbara , von Hoff Katja , Kool Marcel , Kjaersgaard Mimi , Trkova Katerina , Andre Nicolas , Lippolis Maria Aliotti , Hedrich Cora , Köller Clara , Stepien Natalia , Slavc Irene , Gojo Johannes
Published: June 2024

BACKGROUND

Improvement of molecular diagnostics has led to significant changes in the categorization of paediatric brain tumours, unveiling novel tumour entities in the latest 2021 WHO classification of central nervous system (CNS) tumours (5th edition), particularly within the group of rare tumours of the CNS (encompassing rare embryonal and sarcomatous tumours (REST) and gliomas). However, treatment recommendations are currently based on small patient cohorts lacking standardized protocols, with even more limited options for progressive or relapsed disease.

METHODS

Patients from specialized European oncologic centres diagnosed or reclassified as REST receiving anti-angiogenic therapy after relapse (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial - MEMMAT) will be analysed.

RESULTS

So far, 14 patients from Austria, Czech Republic, Denmark and France were identified, with molecularly reclassified 4 CNS tumours with BCOR/BCORL1 alteration (CNS BCOR/BCORL1), 4 CNS astroblastomas, MN1-altered (ABM_MN1), 3 embryonal tumours with multi-layered rosettes (ETMR) and 1 DICER1-mutated intracranial sarcoma (CNS DICER1) as well as 2 primitive neuroectodermal tumours (PNETs, reclassification ongoing). Initial histological classifications ranged from ependymoma group 3, ETMR, malignant peripheral nerve sheath tumour (MPNST) to EGFR-positive glioblastoma. In 2 cases categorization was unclear with either anaplastic ependymoma, plexus carcinoma or ETMR. 10 patients received standard MEMMAT protocol (biweekly intravenous Bevacizumab with oral drugs: Celebrex, Thalidomide, Fenofibrate, Cyclophosphamide/Etoposide alternating and intrathecal Etoposide and Cytarabine). In 4 cases therapy was modified with an individualized metronomic treatment regimen.

CONCLUSION

Therapy at initial diagnosis, duration of relapse-treatment, clinical as well as radiological response, overall survival, progression-free survival and molecular hallmarks will be presented.
ETMR-31. A UNIQUE CASE OF CNS DIFFUSE, NON-SYSTEMIC ALK+ HISTIOCYTOSIS IN A PEDIATRIC PATIENT
Authors: DeMarsh Samantha J , Orr Brent , Willard Nicholas , Dahl Nathan
Published: June 2024

BACKGROUND

Histiocytic disorders are a group of rare diseases with accumulation of of macrophages, monocytes, or dendritic cells in various parts of the body. ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 that is very rarely described in pediatrics.

METHODS

A 20 month old male presented to an adult hospital after a prolonged period of headaches, vomiting, and loss of developmental milestones. Imaging demonstrated severe hydrocephalus and extensive thickened leptomeningeal enhacement with mass effect. He underwent VP shunt placement and revision, a T7-T10 laminectomy, and tumor debulking. Extensive molecular testing, including DNA and RNA analysis by NGS was performed and a CLTC::ALK fusion was identified, along with Tier III DNA variants, yielding a diagnosis consistent with ALK-Positive Histiocytosis, with diffusivity in the CNS system. Full evaluation demonstrated no involvement of the peripheral nervous system or other systemic involvement. He initially demonstrated signs of neuro-irritation, altered tone, and lower extremity clonus.

RESULTS

After review of very little literature published on similar patients, although none with a clinical picture matching his, he was started on a treatment course of high dose dexamethasone, vinblastine, and lorlatinib targeting the ALK+, likely driver, mutation of his disease. On evaluation scans two months into treatment, he showed no change in his disease burden. He was transitioned to clofarabine cycles with daily lorlatinib for continued targetted therapy. After six total cycles, he demonstrated a high partial to complete remission (allowing for evidence of scarred tissue) and tremendous neurologic and developmental milestone gains.

CONCLUSIONS

This case demonstrates a unique presentation in which there is little described in the literature in way of clinical features or treatment standards, and further none exactly similar to this patient. After undergoing extensive evaluation and therapy modication, he responded remarkably well and continues to have optimal quality of life.
EPEN-23. TARGETING TRISOMY MDM4 INDUCES CELL DEATH IN 1Q+ PFA EPENDYMOMA THROUGH REACTIVATION OF THE P53 PATHWAY
Authors: Calzadilla Annaliese J , Griesinger Andrea M , Donson Andrew M , Grimaldo Enrique , Madhavan Krishna , Alimova Irina , Pierce Angela M , Brunt Breauna , Vibhakar Rajeev , Foreman Nicholas K
Published: June 2024

BACKGROUND

Gain of chromosome 1q (1q+), gives a grave prognosis in pediatric posterior fossa group A ependymoma (PFA). The prevalence of 1q+ in newly diagnosed PFA stands at 25%, escalating to 50% upon recurrence. Conventional therapeutic modalities, such as complete resection and radiation, exhibit minimal efficacy in cases of 1q+ PFA, and the incorporation of additional chemotherapy in clinical trials has failed to yield substantial improvements. In this investigation, we delineate the trisomy-induced overexpression of the MDM4 gene on chromosome 1q as a driver of malignant progression in 1q+ PFA and a viable therapeutic target via idasanutlin, an MDM4 pathway inhibitor.

METHODS

We are using genetic and pharmaceutical inhibition of the MDM4/MDM2 pathway high-risk PFA 1q+ in vitro and in vivo models to test the efficacy of idasanutlin in a preclinical setting. Treatment effects are measured utilizing growth assays as well as genomic and transcriptomic analysis.

RESULTS

Our investigation reveals that two 1q+ in vitro models demonstrate a dose dependent sensitivity to idasanutlin compared to normal brain tissue. Upon exposure to idasnutlin, they also have an increase in p21 expression, a critical marker demonstrating reactivation of the p53 pathway, evidenced at both the gene expression and protein levels. Moreover, we found radiation synergistically enhances the efficacy of idasanutlin. Currently, we are evaluating our in vitro results with combination radiation and idasanutlin treatment in our 1q+ PFA preclinical in vivo models.

CONCLUSIONS

In summary, our study advocates for the exploration of small molecule inhibitors, with a primary focus on the promising idasanutlin compound, as a therapeutic avenue for addressing the challenge posed by ultra-high-risk 1q+ PFA. The compelling preclinical evidence presented herein lays the groundwork for advancing our understanding of the molecular intricacies underlying this malignancy, paving the way for novel and targeted treatment strategies.
EPEN-28. NOVEL TARGET IDENTIFICATION IN RECURRENT POSTERIOR FOSSA EPENDYMOMA GROUP A
Authors: Przelicki David , Rasnitsyn Alex , Richman Cory , MacLeod Graham , Diaz Jacob Torrejon , Angers Stephane , Ayrault Olivier , Michealraj Kulandaimanuvel A , Taylor Michael D
Published: June 2024

BACKGROUND

Posterior fossa ependymoma group A (PF-EPN-A) are an aggressive subgroup of ependymal tumors which occur predominantly in infants and possess a poor prognosis. Treatment is limited to surgical resection and adjuvant radiation with no approved chemotherapies or targeted therapies available. Despite treatment efforts, nearly half of all PF-EPN-A cases will experience tumor recurrence within a decade of initial diagnosis. Our current understanding of relapse is limited to clinical risk stratification based on subtotal resection of the primary tumor, male sex and specific chromosomal copy number aberrations. In an effort to overcome the shortcomings of current literature on PF-EPN-A recurrence, we present a concerted effort to investigate the biology of both recurrent human tissue specimens and patient-derived cell models to identify novel drivers of recurrence.

METHODS

Utilizing a multi-omics approach, we have conducted transcriptomic (bulk RNA-Seq), proteomic and phosphoproteomic (LC-MS/MS) analyses in order to identify molecular pathways that are enriched in recurrent disease as compared to primaries. We have also performed genome-wide CRISPR essentiality screens to further pinpoint essential genes and pathways with therapeutic potential.

RESULTS

Through the comparison of primary and recurrent PF-EPN-A samples, we have identified both previously implicated and novel genes and pathways in recurrent disease. Our multi-omic analyses identified the upregulation of genes involved in DNA repair, DNA damage response and cell cycle pathways in recurrent PF-EPN-A.

CONCLUSIONS

Our combined approach has enabled the identification of novel targets with therapeutic potential in the treatment of recurrent PF-EPN-A. The identified targets will be validated using a combination of drug screening and knockdown approaches in vitro. Top candidates will be further validated in vivo with established recurrent xenograft mouse models. PF-EPN-A is an aggressive disease with limited treatment options and the identification of novel targets with potential therapeutic utility will allow us to better treat this patient population.
METB-02. GENETIC COUNSELLING IN SOTOS AND NS1-RELATED OVERGROWTH SYNDROMES PREDISPOSING TO BRAIN TUMORS
Authors: Abdelmoula Nouha Bouayed , Abdelmoula Balkiss
Published: June 2024

BACKGROUND

Sotos and many other overgrowth syndromes are among the rare tumor predisposition syndromes that might be under-recognized in pediatric neuro-oncology practice. NSD1 gene (5q35), belonging to the histone lysine methyltransferases family, is involved in the majority of Sotos patients who exhibited haploinsufficiency and loss-of-function variants of the gene, but also in other overgrowth entities such as Beckwith-Wiedemann syndrome. Somatic mutations in this gene are likewise responsible of numerous cancers, particularly brain tumors. Here, we aim to assess the neurologic cancer risks and provide genetic counseling for appropriate clinical follow-up in Sotos syndrome.

METHODS

From our genetic counseling database at the medical University of Sfax (Tunisia), we selected among patients presented for genetic management of overgrowth syndromes, those with Sotos syndrome.

RESULTS

Only two Tunisian consanguineous pedigrees were enrolled in this study. Two boys were diagnosed with typical Sotos syndrome based on the three major clinical manifestations: specific facial dysmorphism, mental retardation and excessive growth including advanced bone age and macrocephaly. Chromosomes 5 in both pedigrees did not show structural abnormalities. During genetic counselling, parents were informed about the molecular testing options and the advantage of the exome sequencing. Furthermore, they were informed about the rate of cancer predisposition (3%) and the gains of neurologic and neuro-oncologic management, particularly regarding the intellectual disability and the increased risk of developing neural crest tumors, astrocytoma, glioma/glioblastoma and neuroblastoma cancer, during childhood.

CONCLUSIONS

Neurological pediatric malignancies are described in patients with Sotos syndrome, but the genotype-phenotype correlation is still unclear. It is suggested that NDS1 disruptions in Sotos patients trigger specific patterns of DNA methylation alterations leading to the development of cancer. Accurate molecular exploration is needed in the heterogeneous Sotos condition in order to improve the management according to the implicated gene and to benefit in the future from targeted therapies.
GCT-05. UPDATED REPORT ON TREATMENT MODALITIES IN METASTATIC GERMINOMA IN CHILDREN: A MULTI-INSTITUTIONAL ANALYSIS
Authors: Shatara Margaret , Thia Alexia , Abu-Arja Mohammad H , Su Jack M , MacDonald Shannon , Perkins Stephanie , Gorsi Hamza , Govender Dinisha , Dholaria Hetal , Schwartz Jonathan , Foo Jen Chun , Rajagopal Revathi , Bartels Ute , O’Halloran Katrina , Sleightholm Richard , Lafay-Cousin Lucie , Cansanay Rose Daynielle A , Schlosser Mary-Pat , Cappellano Andrea M , Dassi Natália , Fisher Michael J , Amayiri Nisreen , Yilmaz Yasin , Czogala Malgorzata , Graham Richard , Baglivo Sofia Jares , Ronsley Rebecca , Mastronuzzi Angela , Michaiel George , Khan Sara , Magnum Ross , Hoffman Lindsey M , Knowles Truman , Mueller Sabine , Zaghloul Mohamed S , Abdelhaleem Nada A , El-ayadi Moatasem , Abdelbaki Mohamed S
Published: June 2024

BACKGROUND

Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors; germinoma accounts for two-thirds of cases. While neoadjuvant chemotherapy followed by response-based reduced radiotherapy dose and field is the established approach for managing localized CNS germinomas, controversy persists regarding the treatment of primary metastatic disease. Additionally, limited research exists on the utilization of neoadjuvant chemotherapy in primary metastatic germinoma.

METHODS

A retrospective multi-institutional analysis was conducted to assess overall survival (OS) and event-free survival (EFS) among patients diagnosed with metastatic germinoma who were treated with various modalities.

RESULTS

We identified 88 patients, including 63 males and 25 females. The median age at presentation was 13.5 years. All patients, who had undergone both brain and spine MRIs, had their diagnoses confirmed through a biopsy, positive CSF cytology, and/or positive CSF tumor markers at presentation. Primary Tumor location was pineal (n=37), suprasellar (n=27), bifocal (n=14) and others (n=9). Eight patients underwent subtotal resection. Craniospinal irradiation (CSI; 21-24 Gy) was administered to 71 patients (81%), while eight patients (9%) received whole ventricular irradiation (WVI; 23.4-30 Gy). Whole brain radiation was given to four patients (5%; 24 Gy), and two patients (2%) had unknown fields. Boosts to primary and/or metastatic sites were administered in all but seven patients. Notably, thirty patients (34%) received CSI without neoadjuvant chemotherapy. At the end of therapy, 69 patients had complete response, 10 partial response and the response was unknown in six. Three patients did not receive irradiation, all died of disease progression. The median follow-up was 64 months (range 6-159 months), yielding an OS of 96.6%. Ongoing multi-institutional data collection and analysis will be presented at the meeting.

CONCLUSION

Our study is one of the largest studies to date in metastatic germinoma and may provide insight into the role of neoadjuvant chemotherapy with lower CSI doses.
GCT-09. VENTRICULAR RELAPSES OF INTRACRANIAL GERM CELL TUMORS FOLLOWING FOCAL RADIOTHERAPY
Authors: Dassi Natália , Abdelbaki Mohamed S , Cappellano Andrea M
Published: June 2024

BACKGROUND

Non-germinomatous germ cell tumors (NGGCTs) require treatment involving combinations of chemotherapy, surgery, and radiotherapy. The radiotherapy field is typically focal in Europe and craniospinal in North America. Unlike germinomas, there are conflicting results for the effectiveness of ventricular field irradiation, and there is not enough data documenting the histology and tumor markers for tumors that relapse along the ventricles in patients who receive focal irradiation.

METHODS

We performed a literature review for English-language literature from 1998 to 2024 to to analyze the incidence, histopathology and tumor marker levels for NGGCT patients who initially received chemotherapy followed by focal radiotherapy and ended up having of ventricular relapses.

RESULTS

We identified 47 cases with relapsed NGGCT. However, only 8 cases were along the ventricles. Six of these were ventricular only, including two presumed germinomas based on tumor markers, three biopsy-proven germinomas, and only one case with bHCG levels exceeding ≥1000 IU/l. Two had combined relapses involving both the ventricular and spinal regions; one had pathology-proven germinoma but with elevated alpha-fetoprotein, and the other exhibited bHCG levels between 50 and 200 IU/l.

CONCLUSION

Ventricular relapses in NGGCT patients who receive focal radiotherapy should be investigated further. Whole ventricular radiotherapy may be required to prevent the relapse of germinoma elements. However, further information is essential before making any changes in the radiotherapy doses and fields.
GCT-18. GERMINOMAS OF THE CENTRAL NERVOUS SYSTEM (CNS): 20 YEARS EXPERIENCE WITH WHOLE VENTRICULAR IRRADIATION (WVI) AT FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI, MILAN
Authors: Biassoni Veronica , Raimondo Paolo , Schiavello Elisabetta , Terenziani Monica , Nigro Olga , Gattuso Giovanna , Spreafico Filippo , Meazza Cristina , Podda Marta , Chiaravalli Stefano , Luksch Roberto , Puma Nadia , Ferrari Andrea , Casanova Michela , Bergamaschi Luca , Sironi Giovanna , Vennarini Sabina , Massimino Maura
Published: June 2024

BACKGROUND

Intracranial germ cell tumors account for 1-3% of pediatric CNS tumors, with germinomas constituting up to 65%, their prognosis being favourable compared to the non-germinomatous counterpart.

METHODS

After an unsuccessful experience with focal irradiation, from 2001 to 2021 we treated 68 patients (51 males/17 females, median age at diagnosis 16 years) with 4 PEB cycles (cisplatin 25 mg/sqm days 1-4, etoposide125 mg/sqm days 1-4, bleomycin 18 mg/sqm day 2, cycles every 21 days) followed by whole ventricular irradiation (WVI) 30,6 Gy/36Gy if CR/PR-SD. Patients with metastatic disease received craniospinal irradiation only (CSI 24 Gy+16Gy TB-tumor bed/WVI).

RESULTS

Fifty-nine patients had localized disease: 23 pineal, 22 suprasellar, 13 bifocal, 1 in the basal ganglia and 9 were metastatic. Suprasellar localization was associated with longer diagnostic delay. Five, 10 and 20 years OS and EFS were 100%, 97.5%, 97.5% and 95.3%, 92.8%.92.8% respectively. There was no statistical difference according to age at diagnosis, site and metastatic/bifocal disease. During follow-up 13/59 patients (22%) revealed moderate (2)/slight (11) impairment of the pulmonary function at spirometry assessment. Audiometric tests were available for 59 patients: 42 were normal (71%), 11 had a slight deficit, 4 moderate and 2 severe. Neurocognitive homogeneous evaluations were available only for 9 patients, so no clear correlation can be done, except observing the lowest scores in the patient with basal ganglia involvement. New endocrine deficits appeared in 9 patients after the treatment.

CONCLUSIONS

WVI tailored on response to chemotherapy proved effective in curing children CNS germinoma. Cisplatin and bleomycin-containing regimens induce high-response rates with known but in our experience limited sides effects. New collaborative protocols will investigate the reduction of the doses of irradiation and the use of less toxic drugs in order to achieve the same cure rates with less side effects.
GCT-26. INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMOR WITH MALIGNANT TRANSFORMATION TO EMBRYONAL RHABDOMYSARCOMA
Authors: Long Clayton , Mangum Ross , Keller Lisa , Bristol Ruth E , Ahmed Safia K , Kuwabara Michael , Tiwari Nishant , Hoffman Lindsey M
Published: June 2024

BACKGROUND

Non-germinomatous germ cell tumors (NGGCT) constitute 35%- 45% of intracranial germ cell tumors. Growing teratoma syndrome has been observed in patients with NGGCTs after starting chemotherapy. While growing teratomas are typically benign, this process can rarely involve malignant transformation and result in poor prognosis. We present the case of a patient with pineal NGGCT and growing teratoma syndrome with malignant transformation to embryonal rhabdomyosarcoma.

CASE REPORT

A 13-year-old male presented with headaches and vision changes. An MRI brain demonstrated a 26 x 25 x 19 mm (AP X TR X CC) mixed solid and cystic pineal mass with no evidence of metastatic disease. Due to elevated alpha fetoprotein levels in the serum and cerebrospinal fluid, he was diagnosed with intracranial NGGCT. Treatment was initiated with alternating cycles of Carboplatin/Etoposide and Ifosfamide/Etoposide. After 2 cycles of chemotherapy, a complete biochemical response was noted but MRI showed increased tumor size (presumed growing teratoma syndrome). The patient underwent complete tumor resection. Histology showed embryonal rhabdomyosarcoma as a somatic malignancy arising in a mature teratoma. Further molecular characterization revealed somatic NF1 and KRAS pathogenic mutations that are consistent with the primary diagnosis. Methylation profiling, however, did not exhibit a match with any known malignancies. Continued complete response was noted following two additional chemotherapy cycles. The patient is planned for six total chemotherapy cycles followed by high-dose craniospinal radiation with boost to the primary tumor.

CONCLUSIONS

Malignant transformation is a rare phenomenon in NGGCT. There is no standard of care for these patients. Further studies are needed to define ideal therapy for this patient population.
GCT-28. THE IMPACT OF RESIDUAL TUMOR ON THE OUTCOMES OF CENTRAL NERVOUS SYSTEM GERMINOMA
Authors: Baroni Lorena V , Alderete Daniel , Abdelbaki Mohamed S
Published: June 2024

BACKGROUND

The inclusion of chemotherapy in the treatment backbone of central nervous system germinoma has helped reduce the field and dose of radiotherapy. Typically, patients wirh residual disease after chemotherapy are treated with higher doses of radiotherapy, which may not be necessary. Hence, we aimed to assess the impact of residual disease at different points during therapy on the outcomes of germinoma patients.

METHODS

We performed an extensive review of all germinoma patients diagnosed at Hospital Garrahan in Argentina over the last 20 years. We evaluated the chemotherapy response after 2 cycles and 4 cycles of chemotherapy and after radiotherapy.

RESULTS

Thirty nine germinoma were included (localized 34; disseminated 5). All patients were treated as per the SIOP-CNS-GCT-96 strategy. At the end of 2 cycles of chemotherapy, 21 patients achieved a complete response (CR), 10 had a partial response (PR), and 8 patients didn’t have MRI evaluation. At the end of 4 chemotherapy cycles, 10 additional patients achieved a CR, 7 still had a PR, while one patient didn’t have MRI evaluation. Only 3 patients had residual tumour after radiotherapy; one had a second-look surgery that didn’t show any evidence of viable tumour. None of the patients with residual tumour at the end of chemotherapy or radiotherapy relapsed with a median follow up of 6.3 years.

CONCLUSION

Residual tumor at the end of both chemotherapy and radiotherapy does not have an impact on the outcomes. Clinical trials in germinomas may need to investigate administering the same dose of radiotherapy for patients regardless of the presence of residual disease at the end of chemotherapy. Furthermore, patients with no residual disease at the end of two cycles of chemotherapy may benefit from moving directly to radiotherapy without the need to receive two additional cycles of chemotherapy.
HGG-03. TRUNCATING MUTATIONS IN PPM1D COOPERATE WITH PI3K ALTERATIONS TO DRIVE PEDIATRIC DIFFUSE MIDLINE GLIOMAS
Authors: Kebede Adam F , Morin Eric , Kundu Ipsita , Blumenshine Olivia , Rendo Veronica , Phoenix Timothy N , Bandopadhayay Pratiti
Published: June 2024

Mutations in PPM1D – coding for the phosphatase WIP1 - are present in 8 -12% of all Diffuse Midline Glioma (DMG), H3 K27-altered – a universally fatal subtype of pediatric high-grade tumors. PPM1D mutations are mutually exclusive with TP53 mutations and mainly lead to a truncation of its C-terminal regulatory domain. Truncated PPM1D (PPM1Dtr) has increased protein stability and impairs the p53-dependent DNA Damage Response (DDR) by dephosphorylating its numerous targets (e.g p53, H2A.X, CHK1) which contributes to its oncogenicity. However, because wildtype p53 is present in PPM1Dtr tumors, its activation is suppressed but not completely ablated suggesting that PPM1D mutant tumors may evolve differently from p53 mutant ones. Our analysis of whole genome sequencing datasets indeed found that PPM1D mutations uniquely co-occur with alterations in the PI3K/mTOR pathway suggesting potential cooperativity in enhancing tumorigenesis. Using mouse neural stem cells (mNSCs) as an isogenic model system, we have engineered specific combinations of oncogenic alterations to study their impact on cell proliferation, PI3K/mTOR pathway activation and response to DNA damage and replication stress. We find that PPM1Dtr cooperates with PIK3CA alterations to increase proliferation and signaling through the PI3K/mTOR pathway. Notably, in an in utero electroporation model, mutant PIK3CA accelerates the development of high-grade tumors that infiltrate deep into the brainstem. Our study also indicates a vulnerability to inhibition of the PI3K/mTOR pathway in PPM1Dtr-PI3K co-altered tumors. Future work will aim at 1) exploring the mechanism of cooperation and impact on replicative stress response and 2) developing and testing a rational therapeutic strategy for PPM1D-mutant tumors.
HGG-47. SPATIAL SINGLE-CELL PROTEOMIC ANALYSIS MAPS THE DISTINCT PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA TUMOR ENTITIES AND DEFINES THEIR TUMOR AND IMMUNE MICROENVIRONMENTS
Authors: Petrilli Lucia Lisa , Spinozzi Giulio , Crocco Lucia Di , Salanitro Antonio , Rossi Sabrina , Bressan Dario , Cerimele Alfredo , Diomedi-Camassei Francesca , Miele Evelina , Cacchione Antonella , Baldo Giada Del , Colafati Giovanna Stefania , Carai Andrea , Locatelli Franco , Mastronuzzi Angela , Vinci Maria
Published: June 2024

Paediatric-type diffuse high-grade gliomas (pDHGG) are a group of molecularly and clinically defined tumor entities of the central nervous system. The investigation of the spatial organization of pDHGG tissues may provide new insights to decipher their heterogeneous nature and identify vulnerabilities in their aggressive behaviour. Here we exploit Imaging Mass Cytometry (IMC), a spatial biology approach enabling multiplex tissue phenotyping at single-cell resolution. We used 16 total formalin-fixed paraffin-embedded (FFPE) tissues from 4 patients including 1 Diffuse hemispheric glioma H3G34-mutant (DHG-H3G34), 1 Diffuse pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (DHGG-WT) and 2 Diffuse midline glioma H3K27-altered (DMG-H3K27, 1 H3.3K27M and 1 H3.1K27M). Classical pathology assessment and DNA methylation profile were also performed. For IMC staining, 2 metal-tag custom-designed antibody panels (tumour and immune) of 31 antibodies were used. The panels include antibodies for differentiated and stem-cell markers, extracellular matrices, immune markers and H3K27M and H3.3G34R variants. An IMC analysis pipeline was developed: images are extracted in tiff format from the proprietary MCD files produced by Hyperion instrument, filtered to remove hot pixels via top-hat and OpenCV in Python, segmented using steinbock and analysed using the IMC Data Analysis toolbox in R, using docker. A total of 209 mm2 of tissue were analysed. IMC analysis showed that DHG-H3G34 displays a higher heterogeneity in terms of cell phenotypes compared to the other tumor entities. Moreover, immune infiltrate of T, B cells, NK and monocytes was observed in the DHG-H3G34 and DHGG-WT tissues, while the DMG-H3K27 had low/no immune infiltrate with the H3.3K27M showing higher PDL-1 expression. Analysis of longitudinal and multi-region samples highlighted trajectories of tumor evolution and identification of extracellular matrix niches in tumor core versus the infiltrative front. Our study provides novel insights into pDHGG complex biology by investigating their tissue architecture, spatial organization and cell-cell interactions.
IMG-03. PRE-TREATMENT EVIDENCE OF ABNORMAL SUPRATENTORIAL WHITE MATTER IN CHILDREN WITH POSTERIOR FOSSA TUMOURS USING DIFFUSION MRI
Authors: Drabek-Maunder Emily , Mankad Kshitij , Aquilina Kristian , Dean Jamie A , Nisbet Andrew , Clark Chris A
Published: June 2024

BACKGROUND

Over half of childhood brain tumours originate in the posterior fossa, which includes low-grade (e.g. pilocytic astrocytoma) and high-grade (e.g. medulloblastoma) tumours. Even though overall survival rates of paediatric brain tumours have substantially increased, survivors face neuropsychological impairments impacting behaviour, cognition, language and motor skills. Post-treatment outcomes are associated with structural changes within the brain, but it is unclear if observed microstructural damage is caused exclusively by radiotherapy or if there is earlier damage from the tumour and related effects. Diffusion MRI is a non-invasive technique that can be used to better understand white matter microstructure by quantifying water diffusion in the brain. Diffusion tensor imaging (DTI) can be used to assess white matter damage.

METHODS

In this work, we used DTI to understand white matter microstructure in 8 posterior fossa tumour patients prior to surgery. We compared individual patients to age- and sex-matched healthy controls in a one-against-many approach.

RESULTS

We demonstrate the presence of supratentorial white matter abnormalities prior to treatment in 3 patients. Before treatment, all patients are found to have significantly enlarged lateral ventricles relative to total brain volume (p<0.05). Patients with ventricle volumes >4% relative to brain volume correspond to significant changes in DTI parameters found in pre-treatment images, suggesting that hydrocephalus impacts white matter microstructure before surgery. Observed white matter changes are complex and patient-dependent, patients demonstrate compression (increased fractional anisotropy; FA) or diffuse oedema and damage (decreased FA). These white matter abnormalities persist over time, which could lead to cumulative damage, for example when adjuvant treatment involves radiotherapy.

CONCLUSIONS

To improve patient outcomes, pre-treatment imaging could be considered during individual treatment planning and risk evaluation to avoid further injury to white matter. Pre-treatment white matter abnormalities may have a bearing on neurocognitive patient outcomes, which will be the focus of future work.
IMG-20. IDENTIFICATION OF PRE-OPERATIVE IMAGING FEATURES ASSOCIATED WITH COGNITIVE IMPAIRMENT IN CHILDREN WITH BRAIN TUMOURS USING A LANGUAGE MODELLING SYSTEM COMBINED WITH MACHINE LEARNING ANALYSIS
Authors: Dockrell Simon , Tsakiroglou Anna Maria , Vaughan Kate , Albutt Lesley , Kilday John-Paul , Kamaly-Asl Ian , McCabe Martin , Fergie Martin , Stivaros Stavros
Published: June 2024

BACKGROUND

Cognitive impairments caused by paediatric brain tumours negatively impact future quality-of-life. Impairments of processing speed and working memory are important contributors to challenges these children encounter in education. Inconsistent image acquisition and poor imaging quality can restrict advanced radiomic analysis in historical datasets. We developed and refined a language modelling human image-analysis support system, passing data to specific machine learning techniques that can utilise datasets with many data points in a limited population.

METHODS

Medical records of children treated for brain tumours with surgery and radiotherapy in Manchester between 2000-2020 were reviewed with imaging accessible from 2006-2020. Pre-operative MRI scans were reviewed for 52 patients along with their most recent processing speed and/or working memory test scores. 274 radiological variables analysing tumour features and damage to brain structures were reported per patient using a standardised reporting tool. Univariate analysis was performed using Linear Regression with time-to-test analysed as a covariate. Multivariate analysis used Elastic Net Regression.

RESULTS

Univariate analysis revealed risk factors for slower processing speed included midline shift, tumour in the corpus callosum, right temporal periventricular white matter oedema, diffusion changes in the left frontal lobe or amygdala and FLAIR changes in the left caudate nucleus (p<0.005). Risk factors for impaired working memory included midline shift, cortical tumour location, left periventricular white matter oedema and diffusion or FLAIR changes in the left frontal lobe (p<0.005). Despite the limited population size and review of only pre-operative features, multivariate analysis produced multiple predictive models able to outperform chance when predicting processing speed and working memory outcomes.

CONCLUSIONS

This study provides evidence that a radiological language modelling approach can be utilised for outcome prediction. It identified imaging features predictive of cognitive impairments prior to surgery and radiotherapy. Further work is needed to assess inter-observer variability and validate these findings.
IMG-26. USING [18F]FET-PET/CT SCAN TO DIFFERENTIATE RADIONECROSIS FROM RECURRENCE/NEW TUMOURS: THE CASE OF A CNS SARCOMA
Authors: Pilotto Chiara , Coassin Elisa , Borsatti Eugenio , Tuniz Francesco , Pegolo Enrico , D’Agostini Serena , De Colle Cristina , Rombi Barbara , Vindigni Marco , Vitullo Angelo , Toniutti Maristella , Tanzi Giorgia , Mascarin Maurizio , Cogo Paola Elisa , Liguoro Ilaria
Published: June 2024

CASE REPORT

A 5-year-old girl diagnosed with a posterior fossa standard-risk medulloblastoma underwent surgery followed by proton therapy (PT) 23.4 Gy(RBE) (1.8 Gy(RBE)/fr) to the craniospinal axis plus a boost of 30.6 Gy(RBE) (1.8 Gy(RBE)/fr) to the tumor bed and maintenance chemotherapy according to HIT-SIOP PNET 4 protocol. The patient remained disease-free for 4 years after the end of treatmen. MRI showed a new left temporo-occipital lesion 8x10x10 mm which was irradiated from cranial field during the craniospinal phase but outside of the boost area, consistent with inoperable recurrence. She was then re-irradiated with a second course of PT 50.4 Gy(RBE) (1.8 Gy(RBE)/fr) and subsequently started on temozolomide. Periodic MRI scans showed progressive reduction of the lesion for 10 months, when new lesion progression occurred within the re-irradiated fieled. Considering the stable clinical conditions of the patient, the minimal size of the lesion, and the uncertain nature between actinic damage or cancer, a watchful waiting approach was adopted. Few months later, the area increased. [18F]FET-PET/CT evaluation documented an uptake of the drug compatible with metabolically active lesion. A biopsy was performed, and histology showed a CNS sarcoma. Genetical testing excluded cancer predisposition syndromes. Chemotherapy with bevacizumab and irinotecan was started, but the MRI showed significant progression of the disease and the patient died 6 months after the diagnosis.

CONCLUSION

MRI is the main diagnostic method in the follow up of CNS neoplasms, but it has limitations in discriminating recurrences/secondary tumours and tissue changes due to previous treatments, particularly radiotherapy. Recently, the use of [18F]FET-PET/CT is being investigated, but literature is still poor in children and most cases refer to high-grade gliomas. It is desirable to study it further, as it may play a relevant role in differentiating equivocal cases, as in our patient.
IMG-31. DEUTERIUM METABOLIC IMAGING OF RESPONSE TO PRECISION THERAPY IN BRAF-V600E MUTANT GLIOMAS
Authors: Batsios Georgios , Udutha Suresh , Gillespie Anne Marie , Petritsch Claudia , Mueller Sabine , Viswanath Pavithra
Published: June 2024

BACKGROUND

Oncogenic BRAF-V600E mutations are frequently observed in low- and high-grade gliomas in children. BRAF transduces signals from receptor tyrosine kinases to downstream effectors such as MEK1/2 and ERK, which regulate metabolism and proliferation. The combination of the BRAF-V600E inhibitor dabrafenib and the MEK1/2 inhibitor trametinib (Dab/Tra) improves patient survival. However, there is considerable variation in response durability, underscoring the need for early biomarkers of treatment response. Magnetic resonance imaging (MRI), which is the gold standard for patient management, does not reliably assess response to therapy. Since the BRAF/MEK pathway regulates metabolism, the goal of this study was to determine whether Dab/Tra induces alterations in glucose metabolism that can be leveraged for non-invasive imaging of response to therapy.

METHODS

We performed gene expression profiling, in vivo metabolomics, stable isotope tracing, and deuterium metabolic imaging in patient-derived and syngeneic BRAF-V600E mutant models (AM38, 2341).

RESULTS

Our studies indicate that Dab/Tra downregulates glucose metabolism to lactate in AM38 and 2341 cells. In vivo infusion with [U-13C]-glucose in mice bearing intracranial AM38 tumors confirmed that Dab/Tra downregulates 13C-lactate production in the tumor. Mechanistically, Dab/Tra destabilizes hypoxia inducible factor-1a and downregulates glycolytic genes, including SLC2A1, HK2, PFKFB3, and LDHA. Importantly, deuterium metabolic imaging using [6,6’-2H]-glucose, which is a clinical stage method of imaging glycolysis, shows a reduction in lactate production within 48h of treatment with Dab/Tra in AM38 tumor-bearing mice.

CONCLUSIONS

Our studies mechanistically link BRAF/MEK inhibition with reduced glycolysis and identify [6,6’-2H]-glucose as a novel, non-invasive agent for imaging early response to therapy. Since [6,6’-2H]-glucose is a safe, orally administered agent, our studies can be rapidly translated to the clinic, where they will provide physicians with a much-needed tool to determine whether patients are responding to therapy at an early timepoint that predicts extended survival.
IMMU-07. COMBINED PD1 AND LAG3 INHIBITION IN PRECLINICAL MODELS AND PATIENTS WITH DNA REPLICATION REPAIR DEFICIENT GLIOBLASTOMA (RRD-GBM): AN IRRDC STUDY
Authors: Das Anirban , Crump Owen , Kos Olha , Stengs Lucie , Li Amanda , Levine Adrian , Nakano Yoshiko , Stein Alexander , Abebe-Campino Gadi , Bronsema Annika Eva Charlotte , Bianchi Vanessa , Edwards Melissa , Zacharoulis Stergios , Ertl-Wagner Birgit , Morgenstern Daniel , Pugh Trevor J , Ohashi Pamela S , Bouffet Eric , Hawkins Cynthia , Dirks Peter , Tabori Uri
Published: June 2024

BACKGROUND

RRD-GBM harbour high tumor mutation burden (TMB) and respond to anti-PD1 immune checkpoint inhibition (ICI). However, the majority ultimately progress, highlighting the need for combinatorial therapies for sustained immune-surveillance.

METHODS

We performed transcriptomic analyses of human RRD-GBM specimens for immune checkpoint expression, and accordingly, tested combined ICI in immunocompetent murine models. Based on these preclinical data, we treated refractory patients using a combination of anti-PD1 and anti-LAG3 through single-patient trials/ compassionate access. Complimentary immuno-genomic biomarker analyses including circulating tumor DNA (ctDNA) were performed to study mechanisms and track responses.

RESULTS

Human RRD-GBM (n=80) demonstrated high LAG3 expression, providing a strong rationale for targeting. We tested combined anti-PD1 and anti-LAG3 inhibition in three immunocompetent RRD-GBM murine models. In the anti-PD1-responsive (Nestin-Cre-MSH2LoxP/LoxP-POLES459F/+) model, combined inhibition resulted in universal tumor response and survival. In the anti-PD1 resistant models (Mlh1-/-/Nestin-Cre+/Trp53LoxP/LoxP and therapy-induced hypermutant ENU/Trp53-/- gliomas), the combination improved survival despite a lack of response to anti-PD1 monotherapy. Biologically, high LAG3 expression and exhaustion was observed in CD8 T-cells after treatment with anti-PD1, which was subsequently ablated by the addition of anti-LAG3. Serially transplanted mice showed response and improved survival to the combination, suggesting that resistance to anti-PD1 could be abrogated by the combination. Four patients with RRD-GBM who had failed anti-PD1 treatment were treated using the combination, resulting in objective radiological responses and prolonged ongoing survival in patients with RRD-GBM and high LAG3 expression. Tolerability was better than a previous study of combined CTLA4 and PD1 inhibition for similar patients. Correlation with paired immuno-genomic tumor analyses, flow-cytometry, T-cell receptor clonotype and CSF ctDNA are ongoing prospectively.

CONCLUSION

LAG3 is an effective target in refractory RRD-GBM. Combined inhibition with anti-PD1 inhibition demonstrated radiological response, prolonged survival and manageable toxicities in patients, and will be tested in future clinical trials.
IMMU-16. LOCOREGIONAL DELIVERY OF MRNA CAR T CELL THERAPY INTO THE CEREBROSPINAL FLUID IN PRECLINICAL MODELS OF DIFFUSE MIDLINE GLIOMA
Authors: Harvey Kyra , Al-atrache Zein , McManus Olivia , Dickson Conor , Patterson Luke , Beaubien Ezra , Wilson Cullen , Hajeebu Sreehita , Keil Samantha , Braun Molly , Meechan Michael , Vitanza Nicholas A , Iliff Jeff , Madsen Peter , Foster Jessica
Published: June 2024

BACKGROUND

GD2-directed Chimeric Antigen Receptor (CAR) T cell therapy is a promising immunotherapeutic modality for diffuse midline glioma (DMG). We developed mRNA CAR T cells as a safe alternative to virally transduced CAR T cells and have shown that intra-tumoral (IT) infusions of mRNA GD2-directed CAR T cells result in significant tumor regression with improved toxicity in murine DMG models. For clinical translation, we sought to determine the optimal route and trafficking patterns of CAR T cells administered into the cerebrospinal fluid (CSF).

METHODS

NSG mice engrafted with DMG xenograft SU-DIPG13P* in the pons were treated with 5x106 mRNA CAR T cells either into the lateral ventricle (LV) or into the cisterna magna (CM), with brains harvested after 24 hours for analysis using confocal microscopy.

RESULTS

Both LV and CM treated mice showed higher GD2-directed CAR T cell migration to tumors compared to CD19-directed controls, with higher accumulation of GD2-directed CAR T cells in the parenchyma for LV treated mice compared to CM (p<0.001). To evaluate efficacy of delivery in the CSF, NSG mice engrafted with DMG xenograft 7316-6349 in the pons were treated with 5x106 mRNA CAR T cells IT, LV, or CM twice a week for 3 weeks totaling 6 doses. Mice were imaged weekly to monitor bioluminescent tumor signal, showing that mice treated with GD2-directed CAR T cells IT had significantly decreased tumor burdens compared to LV and CM GD2 CAR treated groups (p < 0.05 and p < 0.01 respectively), as well as compared to CD19 controls (p < 0.01).

CONCLUSIONS

Despite local infiltration, mRNA CAR T cells delivered into the CSF did not fully reduce tumor burden, and thus, future work is aimed at evaluating potential routes of priming tumors to attract subsequent cellular therapy doses delivered intra-ventricularly.
LGG-01. PROGNOSTIC UTILITY AND CHARACTERISTICS OF MIB-1 LABELING INDEX AS A PROLIFERATIVE ACTIVITY MARKER IN CHILDHOOD LOW-GRADE GLIOMA: A RETROSPECTIVE OBSERVATIONAL STUDY
Authors: Gorodezki David , Zipfel Julian , Thomas Nägele , Ebinger Martin , Schuhmann Martin U , Schittenhelm Jens
Published: June 2024

BACKGROUND

The prognostic utility of MIB-1 labeling index (LI) in pediatric low-grade glioma (PLGG) has not yet conclusively been described. We assess the correlation of MIB-1 LI and tumor growth velocity, aiming to contribute to the understanding of clinical implications and the predictive value of MIB-1 LI as an indicator of proliferative activity and progression-free survival (PFS) in pediatric low-grade glioma.

METHODS

MIB-1 LI of a cohort of 172 pediatric low-grade gliomas were comprehensively characterized. Correlation to tumor growth velocity, assessed by sequential MRI-based three-dimensional volumetric analyses, and PFS was analyzed.

RESULTS

Mean MIB-1 LI accounted for 2.7 % (range: <1 – 10) and showed a significant decrease to 1.5 % at secondary surgery (p =.0013). A significant difference of MIB-1 LI in different histopathological types and a correlation to tumor volume at diagnosis could be shown. Linear regression analysis showed a correlation between MIB-1 LI and preoperative TGV (R² =.55, p <.0001), while correlation to tumor growth velocity remarkably decreased after incomplete resection (R² =.08, p =.013). Log-rank test showed no impact of MIB-1 LI on 5-year PFS after incomplete (MIB-1 LI > 1 vs ≤ 1%: 48 vs 46 %, p =.73) and gross-total resection (MIB-1 LI > 1 vs ≤ 1%: 89 vs 95 %, p =.75).

CONCLUSIONS

This data confirms a correlation of MIB-1 LI and radiologically detectable tumor growth velocity in PLGG for the first time. Compared to preoperative tumor growth rates, a crucially decreasing correlation of MIB-1 LI and tumor growth velocity after surgery may result in limited prognostic capability of MIB-1 LI in pediatric low-grade glioma.
LGG-10. RECOMBINANT HUMAN ENDOSTATIN IN COMBINATION WITH CHEMOTHERAPY FOR PEDIATRIC LOW-GRADE GLIOMAS
Authors: Zhang Jun-ping , Ge Jing-jing , Liu Ya-jing
Published: June 2024

BACKGROUND

Pediatric low-grade gliomas (pLGGs) entail highly effective treatment regimens. In this study, we aimed to examine the efficacy and safety of recombinant human endostatin (rh-ES) combined with chemotherapy for pLGGs.

METHODS

We collected the clinical data of pLGG patients treated with carboplatin and vincristine (CV) plus rh-ES in the Department of Neuro-oncology, Sanbo Brain Hospital Capital Medical University, Beijing, China, from July 2015 to October 2019 and retrospectively analyzed the effectiveness and safety of this regimen.

RESULTS

A total of 41 eligible patients were enrolled. Median age at diagnosis was 4 years. Median follow-up lasted for 22.7 months (range 8-73.4 months). Six patients achieved complete response, 7 attained partial response, 4 had minor response, the disease was stable in 3 cases, and in 1 the condition progressed. The objective response rate was 90.2% and complete response rate was 14.6%. The median time to response was 4.1 months. The duration of response was 28.1 months. The progression rate within 6 months of treatment completion was 6.9%. 5-year rates were 74% for progression-free survival and 92% for overall survival. The main toxicities included myelosuppression and carboplatin allergy. No serious rh-ES-related toxicities were observed.

CONCLUSIONS

Rh-ES in combination with CV in pLGG patients was effective and safe and could achieve rapid and lasting responses.