bluuebunny/crossref_metadata_2025_split huggingface dataset:
GCT-03. MONOGERM, A NOVEL PROOF-OF-PRINCIPLE BAYESIAN PHASE II TRIAL DESIGN OF CARBOPLATIN OR VINBLASTINE MONOTHERAPY INDUCTION PRIOR TO RADIOTHERAPY FOR INTRACRANIAL GERMINOMA
Authors: Kirton Laura , Apps John R , Lawson Anna , Arvanitis Theodoros , Mitra Dipayan , Gagen Richard , Patel Hiten , Peet Andrew , Fern Lorna , Williams Emma , Coleman Nicholas , Ajithkumar Thankamma , Bison Brigitte , Veal Gareth , Stark Daniel P , Morana Giovanni , Nicholson James C , Billingham Lucinda , Murray Matthew J 
Published: June 2024

Abstract

BACKGROUND
Current European standard-of-care for localised intracranial germinoma is multi-agent chemotherapy (carboPEI: carboplatin/etoposide/ifosfamide) followed by definitive radiotherapy, with excellent survival. MonoGerm is a de-escalation, non-inferiority trial aiming to reduce toxicity. Twelve-week carboplatin (PMID:8039122) AUC10 or vinblastine (PMIDs:32642701/34520101) induction will be evaluated to test if as effective as carboPEI from SIOP-CNS-GCT-II. A novel trial design was required to answer this question pragmatically/safely.

METHODS
Clinical trials in rare diseases recruit slowly, allowing continuous monitoring of efficacy outcomes. Efficacy-transition-pathways (ETP) are innovative visual tools to aid determination of trial design parameters, and an extension of the dose-transition-pathways concept introduced for dose-finding trials (PMID:28733440).

RESULTS
MonoGerm includes two monotherapies, with each single arm recruiting six cohorts of three patients, with interim assessment after each recruited cohort and final analysis at 18 patients (total n=36). Insufficient tumour volume response (&lt;30%) at 6-week safety MRI results in 12-weeks carboPEI. Primary outcome is radiological complete response (CR) by 12-weeks of induction monotherapy. A beta-binomial conjugate analysis will generate posterior probability distributions, combining observed trial data as realisations from a binomial distribution with a minimally informative Beta (1,1) prior. Decision criteria to allow early stopping at interim analyses and go/no-go decisions at final analysis are based on probabilities from these posterior distributions. ETP visually maps out parameters used to assert decisions after each interim assessment as a pyramid decision tree. For each recruited cohort and every CR outcome, estimates of the true CR rate and probabilities with associated decisions are mapped out. ETP allows clear communication between statisticians, clinicians, and patient-public-involvement (PPI) teams, facilitating informed decisions in an efficient/realistic trial design.

CONCLUSION
MonoGerm, a novel Bayesian de-escalation trial, funded by Little Princess Trust (https://www.littleprincesses.org.uk/), uses ETP and continuous monitoring with built-in stopping rules to ensure patient safety in this treatment de-escalation trial.
GCT-19. SIOP CNS GCT II: PRESENTATION AND OUTCOME OF BIFOCAL NON-GERMINOMATOUS GERM CELL TUMOURS (NGGCTS)
Authors: Calaminus Gabriele , Kortmann Rolf Dieter , Alapetite Claire , Bison Brigitte , Frappaz Didier , Ajithkumar Thankamma , Gerber Nicolas , Peyrl Andreas , Morana Giovanni , Murray Matthew , Schoenberger Stefan , Brisse Herve , Zimmermann Martin , Nicholson James , Conter Cecile Faure 
Published: June 2024

Abstract

BACKGROUND
Between 2/2012 and 7/2018, 112 patients with non-germinoma were registered as intend-to-treat patients within the SIOP CNS GCT II trial: 88 patients were male and 24 female. Median age was 13 years (range: 0,1-25,1 years). 95 patients had localised and 17 metastastic disease. 21 patients with bifocal tumors were reported, defined as a synchronous suprasellar and pineal tumour at diagnosis. 6/21 had metastases.

PATIENTS/METHODS
All Patients presented with several main clinical symptoms: diabetes insipidus (DI) (18), vision impairment (16), raised intracranial pressure (10), headache (10), cognitive impairments (7), somnolence (5). Diagnosis was confirmed by tumor markers in all, two with additional resection and 4 with biopsy. All patients received upfront PEI (cisplatin/etoposide/ifosfamide) chemotherapy, with dose-intensification (HD-PEI) for those with diagnostic serum or CSF AFP &gt;1000 ng/ml (high-risk), before RT. Patients without dissemination received local radiotherapy (RT) of 54 Gy to both sites. Patients with dissemination received CSI 30 Gy plus boost to primary sites of 24 Gy and RT to visible metastases.

RESULTS
Among 12 standard-risk patients with localised disease 3/12 achieved CR, 1/12 PR and 8/12 relapsed. Of the 8 relapses, 3 achieved a 2nd CR. Three patients with localised disease were high risk. Among them only one patient achieved CR after treatment, but all 3 -pts relapsed and 2 died. Among 6 patients with dissemination and standard risk 5/6 achieved CR, 1/6 PR, no relapses occurred. Bifocal localised non-Germinoma are not sufficiently controlled by chemotherapy and focal tumor boost. Other treatment concepts including upfront chemo-intensification in standard risk patients and whole-ventricular RT need to be explored. For the SIOP CNS GCT group, supported in part by German Childhood Cancer Aid
GCT-20. PRESENTATION AND OUTCOME OF BIFOCAL GERMINOMA TREATED ACCORDING TO SIOP CNS GCT II
Authors: Calaminus Gabriele , Alapetite Claire , Kortmann Rolf Dieter , Bison Brigitte , Conter Cecile Faure , Ajithkumar Thankamma , Gerber Nicolas , Peryl Andreas , Morana Giovanni , Murray Matthew , Schönberger Stefan , Brisse Herve , Zimmermann Martin , Frappaz Didier , Nicholson James 
Published: June 2024

Abstract

BACKGROUND
Between 2/2012 and 7/2018, 261 patients with germinoma were registered as intent-to-treat patients within the SIOP CNS GCT II trial. 209 patients were male/ 52 female. The median age was 14.1 years (range 5,0-41,0 years). 194 patients had localised and 67 had metastatic disease. 64 patients had bifocal germinoma, defined as synchronous suprasellar and pineal tumours at diagnosis.

PATIENTS/METHODS
The main symptoms were diabetes insipidus (DI) (n=47), visual impairment (33), raised intracranial pressure (21), headache (20), neurological symptoms (14), non-DI endocrine disturbances (14), and somnolence (12). Diagnosis was confirmed by biopsy in 38/64 patients and by resection in 4/64. 22/64 were diagnosed by imaging only. Patients with localised disease received 24 Gy whole-ventricular irradiation (WVI) alone if they achieved complete response (CR) after induction chemotherapy, or WVI with boost to both tumour sites (16 Gy) if partial response (PR) or stable disease (SD) was documented. Patients with metastases (dissemination on MRI or positive CSF cytology) received cranio-spinal irradiation (CSI) 24 Gy with boost to primary sites/ to visible metastases (16 Gy).

RESULTS
After induction chemotherapy, 17/40 with localised disease achieved CR, 21/40 PR, and 2/40 SD. After completion of treatment, 16/17 patients who achieved CR after chemotherapy remained in CR and one patient died after a relapse. 13/21 patients with PR post-chemotherapy achieved CR post-treatment, 3/21 remained in PR and 5/21 relapsed, one of which achieved a second CR. Both patients with SD remained in CR after radiotherapy and additional surgical intervention. Among patients with dissemination 21/24 achieved CR and 3/24 PR after completion of treatment (CSI). No relapses occurred.

CONCLUSION
Localised bifocal germinoma can be treated with WVI ± tumour boost depending on the response to chemotherapy. Bifocal germinoma with or without dissemination have an excellent prognosis. For the SIOP CNS GCT group, supported in part by German Childhood Cancer Aid
GCT-25. THE IMPACT OF RESIDUAL DISEASE ON THE OUTCOMES OF CENTRAL NERVOUS SYSTEM GERMINOMAS – A MULTICENTER INSTITUTION EXPERIENCE
Authors: Shin Jimin , Cochrane Anne , Ogle Andrea , Meyer Ashley , Brossier Nicole M , Shatara Margaret , Cluster Andrew , Knowles Truman , Mueller Sabine , Czogała Małgorzata , Cantor Evan , Abdelbaki Mohamed S 
Published: June 2024

Abstract

BACKGROUND
Germinomas make up about two-thirds of central nervous system (CNS) germ cell tumors and are highly radio-sensitive with excellent survival rate of more than 90%. Current standard of care involves the combination of chemotherapy with reduced-dose radiotherapy. Typically, patients with residual disease receive a higher dose of radiotherapy. However, recent clinical trials showed that there were no differences in the outcomes between those who had complete response (CR) versus partial response (PR) to initial chemotherapy. Hence, we aimed to assess the outcomes of germinoma patients based on the responses to both chemotherapy and radiotherapy.

METHODS
A multicenter retrospective chart review of patients with germinoma from four large academic institutions was conducted.

RESULTS
Data from 41 germinoma patients treated between 2011 and 2022 were analyzed. Thirty-two patients had stable disease (SD)(2), PR(28), or CR(2) to chemotherapy. At the end of radiotherapy, 12 had CR, 5 had PR, and 13 had SD. All patients were alive at the time of review, with a median duration of survival from diagnosis of 78.85 months (range 3.90-278.67). One patient experienced radiographic progression following chemotherapy with SD noted following radiotherapy.

CONCLUSION
Relapses are extremely rare in patients who have residual disease at the end of therapy for germinoma. Future prospective clinical trials are needed to test the possibility of treating germinoma patients who have residual disease with a dose of radiotherapy comparable to that used in patients who achieve complete response.
HGG-02. LONG-TERM EFFICACY AND SAFETY OF LAROTRECTINIB IN PEDIATRIC PATIENTS WITH TRK FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS: AN UPDATED ANALYSIS
Authors: Perreault Sébastien , Doz François , Deyell Rebecca J , Kebudi Rejin , Nilsson Anna , Nysom Karsten , Geoerger Birgit , Zhang Yi-Zhuo , Bernard-Gauthier Vadim , Neu Natascha , De La Cuesta Esther , Laetsch Theodore W , van Tilburg Cornelis M 
Published: June 2024

Abstract

BACKGROUND
Larotrectinib is the first-in-class, highly selective TRK inhibitor approved for tumor-agnostic use in patients with TRK fusion cancer. We report data on larotrectinib-treated pediatric patients with TRK fusion primary CNS tumors.

METHODS
Patients aged &lt;18 years with TRK fusion primary CNS tumors enrolled in two clinical trials (NCT02637687, NCT02576431) were included. Responses were independent review committee (IRC)-assessed per RANO. Patients were permitted to stop larotrectinib in the absence of on-treatment progression (wait-and-see) and remain on trial.

RESULTS
As of July 2023, 38 patients were eligible for efficacy analyses by IRC, including 11 patients with only non-measurable disease at baseline. Median age at enrollment was 7 years (range 0–17). Tumor histologic groups included: high-grade glioma (HGG; n=18), low-grade glioma (LGG; n=12), and other (n=8). Eleven (29%) patients had received ≥2 prior systemic therapies. Overall response rate was 37% (95% CI 22–54): three complete response, 11 partial response, 17 stable disease, five progressive disease, and two not evaluable. The 24-week disease control rate was 74% (95% CI 57–87). Medians for duration of response, progression-free survival, and overall survival (OS) were 17.2 months (95% CI 5.7–not estimable [NE]), 19.8 months (95% CI 11.1–50.8), and not reached (95% CI 32.7–NE), respectively. The 48-month OS rate was 60%. At data cutoff, one patient with HGG and four with LGG entered wait-and-see; median duration of the first wait-and-see period was 20.2 months (range 4–29). One patient with LGG resumed treatment following wait-and-see. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. No patients discontinued treatment due to TRAEs.

CONCLUSION
Larotrectinib demonstrated rapid, durable responses and a manageable safety profile in pediatric patients with TRK fusion primary CNS tumors. This supports the wider adoption of next-generation sequencing panels that include NTRK gene fusions when testing pediatric patients with CNS tumors.
HGG-12. A PHASE IB/II STUDY ON ASIDNA™ IN ASSOCIATION WITH RE-IRRADIATION IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS WITH RELAPSING HIGH-GRADE GLIOMA
Authors: DOZ François , LEBLOND Pierre , CARDOEN Liesbeth , GRILL Jacques , JDEY Wael , DUTREIX Marie , AZZOUZ Fouzia , DIALLO Mamadou , CLAUDE Line , VARLET Pascale , ALAPETITE Claire 
Published: June 2024

Abstract

BACKGROUND
AsiDNA is a synthetic cholesterol-oligodeoxyribonucleotide conjugate, inducing false DNA damage signaling, which prevents DNA repair in tumor cells. AsiDNA therefore increases the vulnerability of tumor cells to irradiation without increasing toxicity in healthy tissues. Preclinical data showed encouraging results of AsiDNA combined to irradiation in glioma and medulloblastoma models. We aimed to determine the safety and efficacy of AsiDNA, a DNA-repair inhibitor, in children, adolescents and young adults with recurrent High-grade Glioma (HGG) eligible for re-irradiation.

METHODS
AsiDNA was administered intravenously using a 3 consecutive days loading dose, followed by a weekly dose (350 mg/m2/dose or 600 mg for patients ≥ 50kg) for 11 weeks. Focal radiotherapy, using 1.8 Gy daily fraction, 5 days a week, was administered in combination during the first weeks: 18 Gy for brainstem diffuse midline glioma (DMG) and 36 Gy for supra-tentorial HGG (DMG or non-DMG). The first part of the study aimed to assess the safety and to confirm the recommended phase-II dose based on dose limiting toxicities (DLT) during the first 8 weeks. A second part was planned to assess activity/efficacy of the combination based on the progression-free survival (PFS) rate at 3 months. AsiDNA pharmacodynamics (PD) was studied in peripheral blood mononuclear cells (PMBC).

RESULTS
Eight (8) patients were enrolled: median age 14 y (6.2-24.5), 5 DMG. No DLT was observed. Median FU was 9.1 months, disease progression was observed in 8 patients; 6 died because of disease progression. Median PFS was 3.9 months. The PD results showed no significant target engagement in PBMCs.

CONCLUSIONS
Considering the low PFS as well as lack of efficacy on PD markers, the DSMB recommended stopping the study.
HGG-13. INFANT-TYPE HEMISPHERIC GLIOMA (IHG): AN INDIVIDUAL PATIENT DATA META-ANALYSIS
Authors: Chavaz Lara , Bagchi Aditi , Toutain Fabienne , Pfister Stefan M , Sturm Dominik , Pietsch Torsten , Gielen Gerrit H , Waha Andreas , Clarke Matthew , Karremann Michael , Benesch Martin , Perwein Thomas , Nussbaumer Gunther , Kramm Christof , Massimino Maura , Biassoni Veronica , Vinci Maria , Mastronuzzi Angela , van Vuurden Dannis , van Zanten Sophie E M Veldhuijzen , Mackay Alan , Jones Chris , Jones David T W , Stucklin Ana S Guerreiro , Tabori Uri , Hawkins Cynthia , Ryall Scott , La Madrid Andrés Morales , Lassaletta Alvaro , Bailey Simon , Hargrave Darren , Chiang Jason , El-Ayadi Moatasem , Mançano Bruna Minniti , Reis Rui Manuel , Hagel Christian , Robinson Giles W , Gajjar Amar , Gorsi Hamza , Silvestrini Nicolas , von Bueren Andre O 
Published: June 2024

Abstract

BACKGROUND
Infant-type hemispheric gliomas (IHG) are epigenetically distinct pediatric high-grade gliomas characterized by fusions in receptor tyrosine kinase (RTK) genes.

METHODS
We performed a methodical literature search, including 30 publications (22 case reports), to identify patients who met the diagnostic criteria of IHG based on the 2021 WHO Classification of CNS Tumors. Individual patient data were obtained from published literature and/or via the authors of the publications. Survival analysis was conducted using the Kaplan-Meier method, and multivariate analysis was performed to investigate the effect of clinical and molecular variables on outcomes.

RESULTS
Hundred-fifty-five previously reported and one unpublished IHG were identified: 131 (84%) had fusions in RTK genes, of which ALK was most prevalent (62/131), followed by NTRK1/2/3 (30/131), ROS1 (30/131), and MET (9/131). Twenty-five patients, with either no identified RTK fusion (6/156) or not assessable fusion (19/156), had methylation scores ≥ 0.9 for IHG (using the Molecular Neuropathology brain tumor classifier versions ≥ 11b4). Surgery followed by adjuvant chemotherapy in 69% (67/97) was the most common primary treatment used in our cohort. The 3-year EFS and OS were 55% (95%CI: 45-67) and 81 % (95%CI: 73-89). 41 patients with relapsed or progressive tumors received various second-line treatments including surgery, chemotherapy, radiotherapy, and targeted therapy. Based on multivariate analysis, complete resection resulted in better EFS (p = 0.05) and OS (p = 0.009), and the presence and type of RTK gene fusion were not associated with clinical outcomes.

CONCLUSION
Our results show that despite favorable OS, patients with IHG often show early progression, indicating that the primary optimal treatment for IHG is yet to be established. Our analysis further indicates that achieving a safe, complete resection may play an important role in treating these patients. A comprehensive analysis of the salvage regimen is required to understand their role in OS.
HGG-14. COMPARING THE RADIOSENSITIZATION POTENTIAL OF VARIOUS COMPOUND CLASSES IN PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA
Authors: Cais Alessia , Lipiec Szymon , Chan Kenneth Chun-Ho , Hofmann Nina , Gade Clara , von Soosten Laura , Imle Roland , Roscher Mareike , Euler-Lange Rosemarie , Zheng Tuyu , Manz Frederik , Kutscher Lena M , Pajtler Kristian W , Peterziel Heike , Oehme Ina , Witt Olaf , Kurth Ina , Jones David T W , Pfister Stefan M , Zuckermann Marc 
Published: June 2024

Abstract

BACKGROUND
The 5-year survival rate of patients suffering from pediatric-type diffuse high-grade glioma (pHGG) remains at only ~20%. Often resection and/or X-ray radiation therapy (RT) are the only treatment options for these patients, though only providing palliative benefits. To date, the concomitant combination of RT and targeted agents is largely unexplored, especially as first line treatment.

METHODS AND RESULTS
To identify drugs and compound classes that radiosensitize pHGGs, we performed a series of high-throughput drug screens in combination with RT. Using a custom library of ~90 FDA-approved compounds, we analyzed combinatorial efficacies in 10 pHGG cell cultures. We identified a variety of drugs demonstrating increased efficacy with RT that have not been described as radiosensitizers yet. Of these, we prioritized compounds that presumably cross the blood-brain-barrier (BBB) and are clinically relevant, yielding a selection of 6 drugs comprising HDAC-, Proteasome-, MEK- and BCL-inhibitors. Next, we analyzed whether these compounds act tumor-specifically by screening two non-cancer cell cultures: Neural stem cells and HEK293T cells. While 3 of those compounds also demonstrated efficacy in one of the control cell lines, the 3 remaining drugs potentiated RT specifically in pHGG. We then successfully validated the radiosensitization of selected compounds using cell viability and apoptosis assays, and are currently performing clonogenic assays to prioritize the most effective drug-RT combinations for in vivo trials.

OUTLOOK AND CONCLUSION
We will evaluate the most promising treatment combinations preclinically using established PDX-mouse models. We are also planning to perform pharmacokinetic analyses of selected compounds to validate BBB permeability. Ultimately, mechanisms of radiosensitization will be functionally investigated. Our comparative results will generate a comprehensive overview of the radiosensitization potential of different compound classes in a variety of pHGG models, allow mechanistic insights into the interplay of both modalities, and provide a basis for future clinical trials.
HGG-15. SYNERGISTIC EFFECTS OF COMBINED MEK/CDK4/6 INHIBITOR TREATMENT ON BRAFV600E POSITIVE HIGH-GRADE GLIOMA
Authors: Mayr Lisa , Mager Leah , Gabler Lisa , Madlener Sibylle , Kirchhofer Dominik , Lämmerer Anna , Bruckner Katharina , Lang Alexandra , Walter Romina , Schueler Julia , Peyrl Andreas , Azizi Amedeo A , Dorfer Christian , Haberler Christine , Müllauer Leonhard , Berger Walter , Lötsch-Gojo Daniela , Gojo Johannes 
Published: June 2024

Abstract

BACKGROUND
Pediatric high-grade glioma (pHGG) is associated with poor overall survival and standard care has remained unchanged for the past decade. BRAFV600E mutations occur in 5-10% and dabrafenib in combination with mekinist is approved in this subtype. Nevertheless, acquired resistance to targeted therapeutics is a common setback in highly aggressive tumors. Homozygous CDKN2A/B loss co-occurs in approximately 60% of this pHGG subtype. Taking advantage of those combined molecular alterations and exploiting acquired resistance mechanisms is of utmost importance to increase overall survival in these patients.

METHODS
Four HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss were tested for the effects of CDK4/6 inhibitor monotherapy (palbociclib, ribociclib, abemaciclib) and/or combination treatment with trametinib on cell survival, cell cycle, apoptosis and senescence.

RESULTS
Abemaciclib showed the highest efficacy of CDK4/6 inhibitors comparable to trametinib monotherapy in our cell models. Abemaciclib led to a cell cycle arrest and combined treatment with trametinib induced distinctly increased levels of apoptosis in our tumor models when compared to monotherapy and a great proportion of surviving cells were senescent. One cell model was orthotopically implanted in mice and abemaciclib and combined treatment with trametinib showed a slightly increased response when compared to trametinib alone.

CONCLUSIONS
Summarizing, treatment with abemaciclib showed promising therapeutic effects in HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss comparable to trametinib alone. Levels of apoptosis were distinctly higher with combinatorial abemaciclib and trametinib treatment when compared to monotherapy alone and senescence was induced in a great number of surviving cells. In vivo abemaciclib was more efficient when compared to trametinib alone. Currently we are working on in vivo experiments and the effect on sustained induction of senescence and mechanisms of tumor cell growth after discontinuation of therapy and in a combinatorial metronomic approach and in combination with radiotherapy.