bluuebunny/crossref_metadata_2025_split huggingface dataset:
RARE-04. Hypothalamic syndrome – severe sequelae due to different sellar and parasellar masses
Authors: Müller Hermann L 
Published: June 2022

Abstract
Hypothalamic syndrome is a rare disorder caused by disease- and/or treatment-related injury to the hypothalamus, most commonly associated with rare, noncancerous parasellar masses such as craniopharyngioma, germ cell tumours, gliomas, cysts of Rathke’s pouch and Langerhans cell histiocytosis as well as genetic neurodevelopmental syndromes such as Prader-Willi syndrome and septo-optic dysplasia. Hypothalamic syndrome is characterized by intractable weight gain associated with severe morbid obesity and memory impairment, attention deficit, reduced impulse control as well as increased risk of cardiovascular and metabolic disorders. Currently, there is no cure for this condition. Treatments used for general obesity such as surgery, medication and counselling are often tried in hypothalamic syndrome, but are mostly ineffective, and there are no medications specifically approved for hypothalamic syndrome. The most important aspects of presentation and outcome of hypothalamic syndrome due to different neuro oncological diseases, its risk factors and an overview of currently available therapeutic interventions aiming to decrease and ameliorate the consequences of hypothalamic dysfunction will be presented. Furthermore, novel aspects and perspectives for future research will be discussed.
RARE-09. Treatment of childhood-onset craniopharyngioma patients using proton beam therapy versus photon-based radiation therapy in the prospective KRANIOPHARYNGEOM 2007 trial
Authors: Friedrich Carsten , Boekhoff Svenja , Sowithayasakul Panjarat , Eveslage Maria , Bison Brigitte , Timmermann Beate , Müller Hermann L 
Published: June 2022

Abstract
BACKGROUND: Proton beam therapy (PBT) compared to photon-based radiotherapy (XRT) offers the benefit to administer lower radiation doses to critical organs thereby possibly minimizing the risk of sequelae in patients with residual craniopharyngiomas (CP) after hypothalamus-sparing surgery. The validation in large CP patient cohorts is still pending. PATIENTS AND METHODS: Of 290 childhood-onset CP patients included 2007-2019 in the prospective multicenter trial KRANIOPHARYNGEOM 2007, 99 (34%) received external RT (65% PBT, 35% XRT). Outcome was compared between the different groups in terms of overall (OS) and event-free survival (EFS), quality of life (QoL using PEDQOL), functional capacity (FMH), and auxological data (BMI and height SDS) one, three and five years after irradiation/CP diagnosis. RESULTS: PBT became the predominant irradiation technique during the study period (used in 23% and 77% of all irradiated patients registered within the first and second half of the enrollment period, respectively). PBT as well as XRT were associated with high (p&lt;0.001) EFS (PBT: 0.917 ± 0.040; XRT: 0.940 ± 0.041) compared to non-RT (EFS: 0.669 ± 0.044). OS was similar in all groups. No differences between PBT, XRT and non-RT CP patients concerning functional capacity and anthropometric parameters (height SDS, BMI SDS) have been obtained. Only in the PEDQOL domain “physical function”, proxy-assessed QoL was lower one year after PBT when compared to XRT treated and non-irradiated CP patients. CONCLUSION: PBT is similar efficient in preventing relapses and recurrences in childhood-onset CP patients. During follow-up, no clinically relevant differences between PBT and XRT in terms of QoL, functional capacity and degree of obesity as a marker of hypothalamic syndrome were detectable. While PBT is increasingly applied, studies on larger CP cohorts with longer follow-up after RT are warranted to analyze, whether it can prevent sequelae such as hypothalamic syndrome and severe obesity compared to XRT.
RARE-16. Differential expression of miRNAs in adamantinomatous craniopharynngioma reveals dysregulation of pathogenic pathways
Authors: Apps John 
Published: June 2022

Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of target mRNAs and can control whole gene networks. ACPs are benign pituitary tumours that can result in significant morbidity and premature mortality. ACPs harbour mutations in CTNNB1 and are driven by the activation of the WNT/beta-catenin pathway. We sought to explore the expression of miRNAS in adamantinomatous craniopharyngioma (ACP) in a cohort of samples previously subjected to RNA-Seq analysis (Apps et al, Acta Neuropathologica, 2018, May;135(5):757-777). Total RNA ACP samples (n=18), non-functioning pituitary adenomas (n=3) and normal foetal pituitaries (n=3) underwent miRNA sequencing using the Qiagen miRNA library prep kit on a NextSeq 500 to a depth of 16 million reads. Differential expression was performed using DESeq2 and functional analysis with mirPath v.3. Expression of miRNAs was correlated with previously published mRNA expression We found that 210 miRNA were upregulated and 275 down regulated in ACP compared with controls (adjusted p-value &lt;0.1). MIR-205-5p was the most upregulated miRNA (619 fold) and its expression correlated with genes expressed within the tumour epithelium (e.g. TP63). miR-375 an inhibitor of the WNT pathway was the most down regulated miRNA (361 fold). KEGG Pathway analysis identified Glycosphingolipid synthesis as the most enriched pathway targeted by upregulated miRNAs. Pathways that were enriched by down regulated miRNAs included: ECM-receptor interaction, fatty acid biosynthesis, Hippo, TGF-beta, WNT, and ErbB pathways. Down regulation of miR-132 has previously been suggested as a marker of aggressiveness in ACP, and was 16 fold down regulated (adjusted p-value&lt;0.001) in this cohort and expression was inversely correlated with genes relating to epithelial development. This data confirms previous studies indicating that miRNA expression is altered in ACP. In silico analysis suggest that the dysregulation of miRNA affects the expression of genes involved in pathogenic pathways in ACP.
RARE-19. Molecular characterization and treatment response of metastatic DIA/DIG
Authors: Petropoulos James , Finkbeiner Melanie , Assis Zarina , Gallagher Clare , Hader Walter , Chan Jennifer , Strother Douglas , Lafay-Cousin Lucie 
Published: June 2022

Abstract
INTRODUCTION: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are glioneuronal tumors of early childhood. Surgical resection is usually sufficient to cure these benign tumors. The presence of metastatic seeding is rare and has been reported as an adverse prognostic factor. We present 2 cases of young children with recurrent metastatic DIA/DIG to describe their presentation, therapeutic management and outcome and to highlight the importance of molecular characterization of these rare tumors to guide adjuvant therapy. CASES DESCRIPTION: The first patient developed metastatic recurrence after initial gross total resection (GTR) of a localized DIG. The disseminated relapse was treated with monthly carboplatin and vincristine (CB/VCR). Complete response was achieved after 15 cycles and the patient has remained in continuous complete remission for 5 years. Post hoc molecular analysis of the tumor revealed a BRAF-RDX fusion. The second patient presented with a disseminated intraventricular relapse following an incomplete resection of a DIA associated with a SPECC1L-NTRK2 fusion. The patient received 2 cycles of CB/VCR with minimal response and was then switched to Larotrectinib leading to a very good partial response (VGPR) 3 months into therapy and has remained on treatment since then with significant clinical improvement. DISCUSSION/ CONCLUSION: In our 2 cases, metastatic recurrence was responsive to adjuvant therapy leading to complete response with conventional chemotherapy in the first one and to VGPR with NTRK inhibitor in the second patient. Early molecular characterization of these benign tumors is critical in case of incomplete resection or metastatic seeding to widen therapeutic options and maximize chance of cure. Response with NTRK inhibitor appears rapid and significant but the total duration of treatment and sustainability of response after discontinuation remain unknown.
RARE-23. Preservation of endocrine function after Ommaya reservoir insertion in children with cystic craniopharyngioma
Authors: Lohkamp Laura-Nanna , Kulkarni Abhaya V , Drake James , Rutka James T , Hamilton Jill , Bartels Ute K 
Published: June 2022

Abstract
INTRODUCTION: Children with craniopharyngiomas (CP) can be subjected to significant morbidities caused by radical surgery and/or radiation with deleterious long-term consequences. Ommaya reservoir insertion (ORI) into cystic CP represents a minimally invasive procedure allowing immediate decompression and aims to avoid additional injuries. The purpose of this study was to determine the relevance of upfront ORI (+/- intracystic treatment) for preservation of endocrine function. METHODS: We performed a retrospective chart review of children with CP treated at the Hospital for Sick Children between 01/01/2000 and 15/01/2020 for review of endocrinological outcome after ORI. Endocrine function was reviewed at the time of initial surgery and throughout the course of follow-up. Event-free survival (EFS) was defined as the time to further surgical resection or irradiation. RESULTS: Seventy-nine patients were identified with a median age of 8.3 (range 2.1-18.0) years, 31 were males. Sixty-six patients underwent surgical treatment, including 41 ORI. ORI was performed as upfront treatment in 32 patients; 33 patients underwent gross total or partial resection and 1 patient radiotherapy as first treatment. Fifty-five of 79 patients had sufficient endocrine follow-up data. Endocrine function remained stable after ORI with a mean EFS of 27.64 (± 5.22) months. Surgical resection was associated with worsened endocrine function postoperatively with an EFS of 5.48 (± 1.74) months (p&lt; 0.001). CONCLUSIONS: Upfront ORI (+/- intracystic treatment) resulted in endocrine preservation of all patients and a significantly longer EFS when compared to upfront surgical resection in this single institutional retrospective review. Further analyses will elucidate the implications of ORI with respect to ophthalmological, vascular and neurocognitive outcome.
DIPG-25. Patterns of cerebrospinal fluid diversion and survival in children with diffuse intrinsic pontine glioma: a report from the International Diffuse Intrinsic Pontine Glioma Registry
Authors: Cooney Tabitha , DeWire-Schottmiller Mariko , Lane Adam , Saab Raya , Bandopadhayay Pratiti , Dorris Kathleen , Packer Roger , Kilburn Lindsay , Minturn Jane , Dodgshun Andrew , Parkin Sara , Goldman Stewart , Sandler Eric , Greiner Robert , Gottardo Nicholas , Dholaria Hetal , Coven Scott , Hassall Tim , Hansford Jordan , Samson Yvan , Leary Sarah , Bartels Ute , Fonseca Adriana , Bouffet Eric , Tinkle Christopher , Monje Michelle , Fisher Paul , Ziegler David , Chintagumpala Murali , Wagner Lars , Koschmann Carl , Leach James , Jones Blaise , Benito Elisa Carrasquedo , Bond Hailey , Chaney Brooklyn , Black Katie , Asher Anthony , Fouladi Maryam , Hoffman Lindsey , Warren Katherine 
Published: June 2022

Abstract
BACKGROUND: There are no standard practice guidelines for cerebrospinal (CSF) diversion for diffuse intrinsic pontine glioma (DIPG), nor clear understanding of potential for palliation and life-prolongation. We evaluated CSF diversion characteristics in children with DIPG to determine incidence, indications, symptom effects, and survival. METHODS: Data were extracted from subjects registered in the International DIPG registry (IDIPGR). Univariable analyses was performed using the Fisher’s exact test or Wilcoxon rank sum test. Survival was estimated using the Kaplan-Meier method. RESULTS: Evaluable patients (n=542) met criteria for DIPG diagnosis by central radiologic review; of those, 126 (23%) had permanent CSF diversion. Median time from diagnosis to diversion was 0.5 months (IQR 0.1-4.5 months). Those with permanent diversion were significantly younger (median 5.4 years vs 7.0 years, p&lt;0.001) and had higher incidence of hydrocephalus at diagnosis (65.3% vs 11.9%, p&lt;0.001). Permanent CSF diversion did not significantly impact overall survival (OS) (p=0.4), even amongst the 124 patients with hydrocephalus at presentation (p=0.20). Those with permanent diversion prior to radiation therapy demonstrated longer median OS than those in whom diversion was placed after radiation (14.3 vs 9.6 months, p=0.001). Patients reported significantly less headache and vomiting at last follow up after permanent CSF diversion compared to pre-diversion (p&lt;0.0001 and p=0.001, respectively), however steroid use was also significantly higher at last follow-up after CSF diversion (p&lt;0.001). CONCLUSIONS: Amongst an international cohort, DIPG patients who had permanent CSF diversion were significantly younger and had higher rates of hydrocephalus at initial presentation than those without permanent diversion. Symptoms of increased intracranial pressure improved in those with CSF diversion, although a direct effect may be confounded by increased steroid use. Permanent CSF diversion did not prolong overall survival in this large cohort of patients, even amongst those who presented with hydrocephalus.
DIPG-32. Paediatric histone-mutant diffuse midline glioma: real world outcomes from a low-middle income country (LMIC) setting
Authors: Gupta Tejpal , Chatterjee Abhishek , Dasgupta Archya , Mangaj Akshay , Epari Sridhar , Sahay Ayushi , Choudhari Amit , Moiyadi Aliasgar , Shetty Prakash , Chinnaswamy Girish 
Published: June 2022

Abstract
BACKGROUND: Histone-mutant diffuse midline glioma (H3K27M) is a distinct high-grade central nervous system (CNS) tumor arising in the midline structures of the brain and/or spinal cord in children and young adults with dismal clinical outcomes. Real world data on this entity, particularly from the low-middle income countries (LMICs) is lacking. We report outcomes of pediatric histone-mutant diffuse midline gliomas treated between 2014-2021 at our comprehensive cancer centre in India. METHODS: Children (&lt;16 years) with biopsy-proven diffuse midline glioma demonstrating histone mutation (H3K27M) on gene expression profiling were identified through electronic search of neuro-pathology database. Clinico-demographic characteristics, histo-molecular features, treatment details, and survival outcomes were retrieved retrospectively from institutional records. All children had undergone biopsy and occasionally debulking surgery prior to definitive radiotherapy (RT). Upfront temozolomide (TMZ) either concurrent and/or adjuvant was at the discretion of treating oncologist. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods and expressed as point estimates with 95% confidence interval (CI). RESULTS: Median age of the study cohort (N=51) was 11 years (inter-quartile range 6-14 years) with no gender predilection. Metastatic disease (leptomeningeal dissemination, sub-ependymal spread, or distant brain involvement) was seen at presentation in 7 (13.7%) patients and at first progression after definitive RT in 10 (19.6%) patients. At a median follow up of 10.3 months, 1-year Kaplan-Meier estimates of PFS and OS were 21.5% (95%CI: 12.2-37.9%) and 45.6% (33.1-62%) yielding median PFS and OS of 7.8 months (95%CI: 5.6-11 months) and 11.3 months (95%CI: 9.4-14.9 months) respectively. CONCLUSIONS: We report aggressive biological course and dismal outcomes in pediatric histone-mutant diffuse midline gliomas (H3K27M) treated in a LMIC setting. High incidence of metastatic CNS failure in our cohort suggests a potential role for testing neuraxial irradiation and aggressive systemic therapy to improve survival.
DIPG-41. Multi-omic profiling of patient-derived subclones identifies aggressive cellular subpopulations in paediatric diffuse high-grade gliomas (PDHGGs)
Authors: Kessler Ketty , Grabovska Yura , Burford Anna , Temelso Sara , Tari Haider , Molinari Valeria , Crampsie Shauna , Yu Lu , Choudhary Jyoti , Proszek Paula , Hubank Michael , Mackay Alan , Jones Chris 
Published: June 2022

Abstract
Paediatric-type diffuse high-grade gliomas are classified into distinct subgroups based upon their location and defining molecular alterations, with very poor clinical outcomes in patients &gt;3yrs. This extensive inter-tumour heterogeneity is further complicated by a wide diversity of genotypically- and phenotypically-distinct subclonal populations within individual tumours, providing a substantial barrier to developing effective treatments. We have sought to understand the dynamic cellular make-up of PDHGGs such that novel strategies aimed at targeting specific subpopulations based upon their contribution to disease progression as whole may be employed. Two complementary approaches have been undertaken to address this – first by carrying out single-cell profiling of bulk specimens, and the second isolation and propagation of single-cell-derived stem cell-like cultures in vitro. To-date we have studied 10 cases and a total of 218 subclonal colonies from both DMG-H3K27 and DHG-WT. In a spinal metastatic case of DMG-H3K27, lpWGS-FISH highlighted subpopulations driven by mis-segregation of amplified oncogenic ecDNA, and mutually exclusive subpopulations defined by MYCN, PDGFRA and CCND1. Through integrated analysis of scRNA-seq and scATAC-seq, we show distinct chromatin accessibility profiles to underlie gene expression signatures defining unique subpopulations of cells. In addition to cycling populations and those associated with lineage-specificity, we identified ‘aggressive’ subpopulations defined by significant upregulation of immediate early response genes such as FOS/FOSL1/JUN, those associated with promotion of invasion-migration such as SERPINs and MMPs. These subpopulations could be mapped to isolated single-cell-derived subclones with highly proliferative or motile phenotypes, defined by comprehensive profiling of expressed and secreted proteins. Differential cis-regulation driving cell identity-tumorigenesis was found in one example to occur via a trans-histone mechanism mediated by an H4-lysine-methyltransferase, KMT5B. Application of functionally-defined interventional strategies aimed at disrupting the interactions between these subpopulations based upon evolutionary biology principles may offer a novel approach to treat these otherwise incurable tumours in children and young adults.
DIPG-53. Long-term survival from a Phase 1 dose-escalation trial using convection-enhanced delivery (CED) of radioimmunotherapeutic124I-omburtamab for treatment of diffuse intrinsic pontine glioma (DIPG).
Authors: Souweidane Mark M , Kramer Kim , Pandit-Tasker Neeta , Haque Sofia , Zanzonico Pat , Carrasquillo Jorge , Lyashchenko Serge K , Thakur Sunitha B , Khakoo Yasmin , Dunkel Ira J , Donzelli Maria , Lewis Jason S , Cheung Nai-Kong V , Larson Steve M , Reiner Anne S , Panageas Katherine S , Manino Nicole , Nielsen John Rømer 
Published: June 2022

Abstract
BACKGROUND: Median survival from DIPG is less than one year. In a phase 1 dose escalation study (clinicaltrials.gov NCT01502917) 124I-omburtamab targeting B7-H3 was administered intratumorally using CED. METHODS: CED was performed between 4-14 weeks post radiation therapy. Using a 3 + 3 design, 124I-omburtamab was escalated from 0.25-10.0 mCi and infusion volumes (Vi) from 250-10,000 µl with serial 124I PET/CT performed up to ~1 week post-administration. Toxicities were assessed for 30 days. Dose escalation safety was evaluated. Survival was calculated using Kaplan-Meier statistics. RESULTS: 46 children were treated and evaluable for toxicity and survival;4 patients received partial doses and were evaluable for toxicity only. Three patients experienced dose limiting toxicities. Eleven patients had transient treatment related grade 3 toxicities with no grade 4 or 5 toxicities. Grade 3 nervous system toxicities included: muscular weakness(n=8), dysarthria(n=4), ataxia(n=3), dysphagia(n=3), and gait disturbance(n=1). Lesion absorbed doses ranged from 1,000-1,500cGy/mCi, with lesion-to-whole body radiation absorbed-dose ratios of ~900. A dose of 8mCi and infusion volume of 8,000 µl is safe and may provide a distribution volume up to 20cm3. Median survival was 15.3 months (n =46, 95% CI 12.7, 17.3). Survival rate estimates (95% CI) at 1, 2, 3 and 5 years were 0.67 (0.55;0.82); 0.18 (0.09;0.35); 0.10 (0.04;0.26); and 0.05 (0.01;0.20). Four patients survived &gt;3 years; two remain alive (61+ and 106+ months);two have died (44 and 53 month) with distant CNS disease and one with extra-CNS metastasis. CONCLUSION: Administration of escalating doses and volumes of 124I-omburtamab via CED was a viable option for this patient subgroup. The median overall survival was increased 3-4 months compared to historical controls. Anecdotal long-term survival if validated with a planned phase 2 trial would support the concept of whole neuroaxis treatment in combination with CED in a subset of DIPG patients.
DIPG-61. Preclinical efficacy of combined radiotherapy with venetoclax treatment in targeting diffuse midline gliomas
Authors: Madhavan Krishna , Balakrishnan Ilango , Lakshmanachetty Senthilnath , Pierce Angela , Sanford Bridget , Fosmire Susan , Elajaili Hanan , Walker Faye , Wang Dong , Nozik-Grayck Eva , Mitra Siddhartha , Dahl Nathan , Vibhakar Rajeev , Venkataraman Sujatha 
Published: June 2022

Abstract
BACKGROUND: H3K27M diffuse midline gliomas (DMGs) are highly aggressive pediatric tumors of pons, thalamus or spinal cord. The only standard-of-care for DMGs is radiation therapy (RT) since the anatomical location of such tumors does not allow surgical resection. Tumor response to RT is at best transient as tumor becomes refractory due to radioresistance. Tumor relapse after RT is a major hurdle in treating DMGs. The mechanism of development of radioresistance due to RT-induced stress has not been studied in DMGs yet. METHODS: We performed an integrated genomic analysis to determine genes responsible for radioresistance and a targeted drug screen to identify drugs synergizing with radiation in DMG. Effect of venetoclax on radiation-naïve and 6Gy radiated DMG cells was evaluated by studying cell death and apoptosis. The efficacy of combining venetoclax with radiation was evaluated in vivo using orthotopic xenograft models. RESULTS: We identified that BCL2 as a key regulator of tumor growth in DMGs after radiation. Radiation sensitizes DMGs to venetoclax treatment. While venetoclax as a monotherapy was not cytotoxic to DMG cells, post-radiation venetoclax significantly increased cell death and apoptosis. Combining venetoclax with RT significantly enhanced the survival of mice with DMG tumors in vivo. Further, we found that the mechanism of radiation-induced cytotoxic effect of venetoclax is p53-independent in DMGs. CONCLUSIONS: This study shows that venetoclax impedes the anti-apoptotic function of radiation-induced BCL2 in DMG leading to apoptosis. Our results are encouraging because, in clinical settings, majority of the DMG patients, irrespective of the tumor p53 status, will benefit from combining RT with venetoclax treatment. Since venetoclax either alone or in combination with chemotherapy drugs are currently in clinical trials for other pediatric cancers, a phase 1b trial is imminent for treating DMGs with venetoclax in combination with radiation therapy.