bluuebunny/crossref_metadata_2025_split huggingface dataset:
RARE-30. Novel collision tumor of craniopharyngioma and ependymoma in a pediatric patient: a case study
Authors: Gray Rachel , Chien Franklin , Vega Jose Velazquez , Patteson Brooke , Wrubel David , Eaton Bree , Schniederjan Matthew , Mazewski Claire 
Published: June 2022

Abstract
Collision tumors are rare tumors comprised of two distinct histologies. In this case report, we discuss a suprasellar collision tumor consisting of adamantinomatous craniopharyngioma and supratentorial ependymoma in a pediatric patient. Case Presentation: Our patient was a two-year-old female with progressive craniopharyngioma status post cyst decompression with Ommaya reservoir placement, subcutaneous peginterferon, Ommaya taps, and subtotal resection. An MRI three months post-resection showed progression and treatment was started with subcutaneous interferon alfa. After eight weeks, she presented with new onset headaches and vomiting. MRI demonstrated tumor progression with associated obstructive hydrocephalus. She underwent a subtotal resection. Pathology revealed recurrent adamantinomatous craniopharyngioma and a 0.5cm ependymoma with classic histomorphology lacking anaplasia features. The ependymoma was positive for GFAP immunostain and EMA immunohistochemistry highlighted a ‘dot-like’ reaction. The Ki-67 proliferation index was very low (&lt;1%). The limited diagnostic material precluded further genomic characterization of the ependymoma. The previous pathology was reviewed and no ependymoma was identified. Spine MRI was negative for metastatic disease. CSF cytology was negative for malignant cells. Following recovery from surgery, she received 54Gy (RBE) focal proton radiation. Eight months from completion of therapy, surveillance MRI shows stable residual tumor. Genetic work-up for cancer predisposition syndrome is in process despite no strong family history of cancer. Discussion: Due to the patient’s young age at diagnosis, our initial treatment strategy was to delay radiotherapy and utilize other treatment options. Following diagnosis with a collision tumor, the patient proceeded to radiotherapy to manage both tumor components. The role of interferon in the development of a collision tumor in this patient in unknown, but we suspect it to be unrelated. Conclusion: To our knowledge, this is the first documented case of a suprasellar collision tumor comprised of craniopharyngioma and ependymoma. Discovery of the collision tumor impacted the patient’s treatment plan.
DIPG-02. Role of a Bevacizumab-based regime in the treatment of children with diffuse intrinsic pontine glioma (DIPG): a systematic review
Authors: Evans Mia , Gill Ria , Bull Kim 
Published: June 2022

Abstract
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is an aggressive paediatric brainstem tumour. There are no effective treatments and median survival is 11.2 months, therefore maintaining quality of life (QOL) is a priority for many families. Bevacizumab, an anti-VEGF IgG antibody, has the potential to improve QOL and survival in DIPG, but has never been evaluated systematically. AIM: To collate the evidence and assess the role of this drug, in the treatment of DIPG. METHODS: MEDLINE, EMBASE, Scopus and Web of Science were searched for relevant studies using terms developed from PICO criteria, including alternatives for Bevacizumab and DIPG. One reviewer screened titles and abstracts, then two reviewers screened full texts. Data were extracted into tables and study quality assessed using MINORS and JBI tools. RESULTS: Searching revealed 1,001 papers; after deduplication 851 remained. After screening of titles and abstracts, 28 full texts were screened, resulting in the inclusion of 11 studies. All studies evaluated more than one outcome. Four studies reported a median overall survival longer than historical data, however, two determined no significant impact. Five studies reported a radiological response in a proportion of participants and two reported no response. Three studies evaluating clinical response, reported improvement in a proportion of patients. Three studies evaluating QOL reported stability or improvement. Four studies evaluating steroid use reported reductions in the proportion of patients receiving steroids. In the treatment of radiation necrosis, Bevacizumab led to clinical improvement in 6/12 patients in 2 studies and permitted a reduction in steroid use in the majority of patients. CONCLUSION: Insufficient evidence means the role of Bevacizumab in the treatment of DIPG is unclear. However, Bevacizumab may be beneficial to some patients. The review highlights the need for further research in this area, particularly randomised controlled trials. More effective therapies are desperately needed.
DIPG-18. Evaluating drug distribution in children with diffuse intrinsic pontine glioma (DIPG) treated with convection-enhanced drug delivery
Authors: Szychot Elwira , Bhagawati Dolin , Gill Steven , Walker David , Hyare Harpreet 
Published: June 2022

Abstract
BACKGROUND: There is currently no method for evaluating drug distribution and tumour coverage using the convection-enhanced drug delivery (CED) technique in diffuse midline glioma of the pons (previous DIPG). AIMS: To determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED of carboplatin and sodium valproate. METHODS: 12 children with DIPG received between 4–18ml of infusate, through 2 pairs of catheters to encompass tumour volume on 2 days. Volumetric T2W and Diffusion Weighted Imaging (DWI) MRI sequences were performed before and after the first cycle of CED therapy and Apparent Diffusion Coefficient (ADC) maps were calculated. The tumour volume pre and post CED was automatically segmented (ITKSnap) on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were registered and subtracted (FSL) to visualize the infusate distribution. RESULTS: ADC and T2W demonstrated a significant (&lt;0.001) change in mean tumour volume post-infusion (mean ADC volume pre: 19.8ml, post 24.4ml; mean T2W volume pre 19.4ml, post 23.4ml). A significant correlation (p&lt;0.001) was observed for the difference in tumour volume and the actual infused volume (ADC, r=0.76, T2W, r=0.70). There was a significant increase (p&lt;0.001) in mean ADC and mean T2W signal intensity ratio post-infusion, no significant correlation with infusion volume. Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion visually demonstrated high signal intensity, presumed infusate coverage of the tumour. CONCLUSIONS: Our study provides the preliminary evidence that measurement of change in tumour ADC and T2W MR sequences, has a potential value for quantifying the distribution of infusate delivered by the intermittent CED, which will facilitate the use of CED in future clinical trials.
DIPG-20. Copper chelation therapy targets S-adenosylmethionine (SAM) metabolism and epigenetic regulators in diffuse intrinsic pontine glioma (DIPG)
Authors: Michniewicz Filip , Bell Jessica , Saletta Federica , Watkinson Tayla , Mercatelli Daniele , Giorgi Federico M , Barlow Christopher K , Faridi Pouya , Tsoli Maria , Ziegler David , Vittorio Orazio 
Published: June 2022

Abstract
DIPG is an incurable pediatric brain cancer of the ventral pons characterized by its complex epigenetic profile. Up to 81% of patients present with mutation H3K27M, resulting in the global reduction of H3K27 trimethylation and increased H3K27 acetylation, deregulating gene expression through an aberrant pattern of epigenetic modification. These alterations affect many cellular and metabolic mechanisms, complicating the search for effective targeted therapeutic strategies. Copper is highly abundant in the pons and is essential for normal brain function and development. However, excess copper accumulation is implicated in several neurological diseases and cancers. Incidentally, recent investigations have indicated the H3-H4 dimer can interact with copper acting as a reductase enzyme. Copper chelation therapy is clinically approved for pediatric patients with Wilson’s Disease, improving their neurological symptoms, and is being trialed in several cancers. We therefore hypothesized copper chelation may represent an effective therapeutic strategy for DIPG. Copper chelator tetraethylenepentamine (TEPA) decreased cell growth and induced apoptosis in DIPG cell lines. To understand these results, unbiased RNA-seq and metabolomics analyses were performed, revealing downregulation of EZH2, DNMT1 and DNMT3B, upregulation of KDM6B and the disruption of key enzymes in the S-adenosylmethionine (SAM)-cycle. Importantly, TEPA downregulated SAM, which donates methyl groups for methylation, S-adenosylhomocysteine, its post-methylation product and α-ketoglutarate, a co-factor for KDM6B. Western blots confirmed the reduced expression of EZH2, DNMT1 and DNMT3B, with further blots examining the chromatin cell fraction revealing modulation of H3K27 trimethylation through copper or TEPA stimulation, and reduction of H3K27 acetylation by TEPA. Importantly, in vitro combinations with Panobinostat were synergistic, while in vivo investigations demonstrated TEPA improved survival in an orthotopic patient derived xenograft (PDX) model, showing complete tumor regression in 25% of treated mice. This study indicates a novel use for copper chelators as epigenetic drugs, and their potential as therapeutics for DIPG.
DIPG-21. DIPG cells alter the permeability of the blood-brain barrier in the brainstem leading to treatment failure.
Authors: Ung Caitlin , Upton Dannielle H , Venkat Pooja , Pandher Ruby , Curnis Flavio , Corti Angelo , Nicolazzo Joesph , Mayoh Chelsea , Tsoli Maria , Ziegler David S 
Published: June 2022

Abstract
Diffuse Intrinsic Pontine Glioma (DIPG) is an aggressive paediatric high-grade glioma with no effective therapies. The blood-brain barrier (BBB) presents a significant obstacle for delivery of therapeutics into the brain, especially in the brainstem. This study aims to investigate the effect of DIPG cells on the BBB in the brainstem. We hypothesized that the location of DIPG may result in a less permeable BBB than other brain regions. We compared two independent orthotopic models with the same DIPG cells injected in the cortical region or brainstem. We found that treatment with mTOR inhibitor, temsirolimus, significantly extended survival for cortical tumors compared with the same tumor in the brainstem (p=0.0097). Immunohistochemical analysis showed significant reduction of mTOR target, P-p70S6K, in the cortical region compared to brainstem in treated animals, with pharmacokinetic analysis confirming significantly higher temsirolimus levels in the cortical region. These findings suggest that cortical tumors respond better than brainstem tumors, and that a less permeable BBB in brainstem tumors contributes to treatment failure. To understand whether DIPG cells affect the BBB in the brainstem, single-cell RNA sequencing experiments were conducted on vasculature isolated from DIPG and matrigel-injected mice. Gene-ontology overrepresentation analyses identified downregulation in the P38MAPK pathway in endothelial cells from DIPG-injected mice, suggesting the potential for therapeutic manipulation with cytokines. Treatment with SNGR-TNFα, a derivative of an agent successfully used in improving drug penetration in CNS lymphoma patients, in an in vitro BBB/DIPG model significantly reduced transendothelial resistance, and further exploration into the effects on the BBB in vivo is currently being undertaken. Our studies indicate that the intact BBB in the brainstem in DIPG is a major reason for treatment failure, and DIPG cells directly influence the vasculature and response to treatment. This may lead to a novel DIPG treatment strategy and for other brain tumors.
DIPG-22. Modifying the tumor microenvironment with a TIM-3 monoclonal antibody as a therapeutic strategy for DIPGs
Authors: Ausejo-Mauleon Iker , Labiano Sara , De la Nava Daniel , Garcia-Moure Marc , Laspidea Virginia , Becher Oren J , Jiang Li , Filbin Mariella G , Pastor Fernando , Alonso Marta M 
Published: June 2022

Abstract
Diffuse Midline Glioma, encompassing Diffuse Intrinsic Pontine Gliomas (DIPGs), are the most aggressive pediatric brain tumors. Their meager survival has not changed despite the combination of radiotherapy with targeted therapies emphasizing the urgent need for effective treatments. TIM-3 (HAVCR2) is a member of the T-cell immunoglobulin and mucin domain protein family. It is expressed on multiple immune cell types, including T cells, NK cells, myeloid populations, and microglia, regulating adaptive and innate immunity. In silico assessment of TIM-3 expression in DIPG datasets showed a robust expression of this gene. Single-cell sequencing analyses of DIPG biopsies uncover TIM-3 expression, especially in microglia. In vivo efficacy studies showed that treatment with AbTIM-3 significantly increased overall survival in two DIPG immunocompetent orthotopic models, led to long-term survivors (50%), and showed immune memory. TIM-3 treatment led to a significant increase in the tumor microenvironment of microglia, granulocytes, NK, and CD8+ cells and higher levels of IFNγ, GrzB and TNFα corresponding with an NK and T-cell activate phenotypes. Interestingly, there was a decrease in the Treg population which causes an increase in the pro-inflammatory CD8/Treg ratio. CD4, CD8 or NK cell depletion leads to a significant but not a total loss of treatment efficacy. CD4+ and CD8+ cells were aumented in treated draining lymph nodes and expressed higher amounts of pro-inflamattory cytokines than control-mice. Population analysis and depletion experiments demonstrated the relevance of NK, CD4, CD8 and myeloid populations in the response to anti-TIM-3 therapy. Interestingly, the depletion of the different immune populations combined or using immunodeficient Rag2 mice, did not completely abrogate the treatment efficacy. These results suggest the concurrence of an additional mechanism of action that together with the immune response leads to a robust anti-DIPG effect. In conclusion, these data demonstrate that TIM-3 is a potential target for the treatment of DIPG.
DIPG-24. Neurological symptom improvement after re-irradiation in patients with diffuse intrinsic pontine glioma (DIPG): A retrospective analysis of the SIOP-E-HGG/DIPG project.
Authors: Chavaz Lara , Janssens Geert O , Bolle Stephanie , Mandeville Henry , Ramos-Albiac Monica , van Beek Karen , Benghiat Helen , Hoeben Bianca , La Madrid Andres Morales , Seidel Clemens , Kortmann Rolf-Dieter , Hargrave Darren , Gandola Lorenza , Pecori Emilia , van Vuurden Dannis G , Biassoni Veronica , Massimino Maura , Kramm Christof , von Bueren Andre O 
Published: June 2022

Abstract
PURPOSE: To investigate the spectrum of neurological triad improvement in patients with diffuse intrinsic pontine glioma (DIPG) treated by re-irradiation (re-RT) at first progression. METHODS: Re-analysis of the SIOP-E retrospective DIPG cohort by investigating clinical benefits after re-RT with focus on the neurological triad. Patients were divided as "responding" or "non-responding" to re-RT. To assess the interdependence between patients’ characteristics and clinical benefits we used a Chi-Square or Fisher’s Exact test. Survival according to clinical response to re-RT was calculated by the Kaplan-Meier method. RESULTS: As earlier reported, 77% (n = 24/31) of patients had any clinical benefit after re-RT. Among 25/31 well documented patients, 44% (n=11/25) had improvement in cranial nerve palsies, 40% (n=10/25) in long-tract signs, 44% (11/25) in cerebellar signs. Clinical benefits were observed in at least 1, 2 or 3 out of 3 symptoms of the DIPG triad, in 64%, 40% and 24% respectively. Patients irradiated with a dose ≥ 20 Gy versus &lt; 20 Gy may improve slightly better with regards of ataxia (67% versus 23%; P-value = 0.028). The survival from the start of re-RT to death was not different between responding and non-responding DIPG patients (P-value = 0.871). CONCLUSION: A median re-irradiation dose of 20 Gy provides a neurological benefit in two-third of patients with an improvement of at least one symptom of the triad. DIPG patients receiving ≥20 Gy appear to improve slightly better with regards of ataxia, however we need more data to determine whether dose escalation up to 30 Gy provides additional benefit.
DIPG-28. IndolentH3 K27M-mutant diffuse midline glioma
Authors: Damodharan Sudarshawn , Bradley Kristin , Stadler Andrew , Rebsamen Susan , Helgager Jeffrey , Puccetti Diane 
Published: June 2022

Abstract
INTRODUCTION: H3 K27M-mutant diffuse midline glioma (DMG) is an aggressive central nervous system tumor that is universally fatal with a median survival of 8-12 months after diagnosis. Here we present a patient who was incidentally found to have a lesion within the right thalamus on brain magnetic resonance imaging (MRI). Twelve years later, she was found to have a brain mass within the same area with pathology consistent with an H3 K27M-mutant DMG. CASE DESCRIPTION: A 14-year-old female presented with new onset left-sided numbness and weakness, blurry vision and a right-sided temporal headache. Her past medical history is significant for severe persistent asthma and anoxic brain injury secondary to a cardiopulmonary arrest at 2-years-of-age due to an asthma exacerbation. She has had multiple MRIs of her brain since her initial insult which initially showed the presence of a T2/FLAIR hyper-intense lesion within the right medial thalamus in addition to chronic central nervous system changes. The right thalamic lesion was stable in size between images obtained at 2-years and 4-years of age. Her current physical exam is significant for decreased strength to her left upper and lower extremities. Brain MRI with and without contrast is obtained with partial effacement of the third ventricle due to mass effect from an enlarging mass from the right thalamus. Biopsy of the lesion demonstrated an H3 K27M-mutant DMG, WHO grade IV. Our patient went on to receive palliative radiation therapy with 59.4 Gy over 33 fractions. DISCUSSION: This case illustrates an unusual presentation of an H3 K27M-mutant DMG with an indolent course, diagnosed twelve years after the initial MRI finding. This proposes the possibility of multiple factors playing a role in the oncogenesis of these aggressive tumors and that further research is warranted.
DIPG-34. Life and End-of-Life after Diffuse Intrinsic Pontine Glioma diagnosis
Authors: Pejenaute Idoya Serrano , López-Almaráz Ricardo , Echebarria Aizpea , Adán Rosa , De Pedro Jimena , Gonzalez Paula , Sanchez Jesús , López-Bayón Julio , Astigarraga Itziar , García-Ariza Miguel 
Published: June 2022

Abstract
INTRODUCTION AND OBJECTIVES: Despite advances in pediatric oncology, Diffuse Intrinsic Pontine Glioma’s (DIPG) life expectancy remains &lt;10% at 2 years, and the mean survival time is 8-10 months from diagnosis. Its location associates multiple symptoms of complex management that condition their quality of life. The aim is to review our experience in the clinical course of the disease and the involvement of palliative care (PC). METHODS: Single-centre retrospective study of patients &lt;18 years diagnosed with DIPG between 2011-2022. A review of the electronic medical record was carried out, recording demographic data, oncological treatments, PC and advance care planning (ACP). RESULTS: We registered 14 patients (2 alive). Median age at diagnosis was 6.4 years (range 3.5-11.9). Median survival from diagnosis was 9.6 months (range 0.5-18) and 3.8 months from progression (range 0.1-12). At diagnosis, 92% received oncological treatment (radiotherapy 75%, chemotherapy 41%, oncolytic viruses 21%, partial resection 8%). After progression, 4 patients received metronomic chemotherapy or re-irradiation and in the last month of life 2 received chemotherapy. In the last 3 months of life, 64% were admitted at least once for progression or end-of-life. In the last month, all received oral dexamethasone. Follow-up by PC team was provided in 64%, with first contact in the last month of life in 36%. ACP was recorded in 4 patients, all of them followed up for PC. Death occurred at home in 33%, hospital in 58%. Palliative sedation was used in 5 patients. CONCLUSIONS: Despite the known prognosis of DIPG, some patients continue receiving oncological treatment after progression and in the last month of life. Contact with PC teams occurred mainly at advanced disease stage. Median survival of children with DIPG is below one year, with multiple symptoms in the progression phase. Therefore, early follow-up by PC teams is recommended.
DIPG-38. Significant tumor regression of H3K27M-mutated diffuse midline glioma of the brainstem with panobinostat: a case report.
Authors: Partap Sonia , Abadilla Natasha , Farahzadi Thrithi , Monje Michelle 
Published: June 2022

Abstract
INTRODUCTION: Diffuse midline glioma is a fatal CNS tumor that chiefly occurs in children. To date, standard of care has been limited to local field radiation. A histone mutation in H3K27M is seen in 80% of diffuse midline gliomas of the brainstem, also called diffuse intrinsic pontine glioma (DIPG). Panobinostat, a potent inhibitor of histone deacetylases, has shown moderate efficacy in DIPG/DMGs in preclinical models, and a dose-finding clinical trial (PBTC-047) is ongoing. We report on a case of a child with biopsy-proven H3K27M-mutated DMG of the brainstem treated off-trial with panobinostat monotherapy after radiation. METHODS: This is a case report of a 12-year-old female with H3K27M-mutated DMG of the medulla and cerebellum that exhibited gadolinium-enhancement on MRI. The patient was treated with 54 Gy focal photon radiation to the tumor field over six weeks after biopsy demonstrating the H3.3K27M mutation (H3F3A), as well as mutations in TP53, PIK3R1 and AXSL1 genes. She was not eligible for PBTC-047 due to uncontrolled hypertension. She received panobinostat as per the ongoing PBTC protocol at a dose of 28 mg/m2 given on Monday, Wednesday, and Friday on alternating weeks. She received three 28-day cycles over three months. RESULTS: The patient tolerated the therapy well, with minimal adverse reactions of low-grade abdominal pain and constipation. MRI imaging after three cycles revealed an 80% reduction in tumor volume. Together with this radiographic response, she exhibited improvement in left-sided motor strength and improved left facial sensation. Due to an unrelated need for oral surgery, panobinostat was held. MRI imaging six weeks after cessation of panobinostat revealed extensive relapse with supratentorial and spinal disease. CONCLUSION: Systemic panobinostat may demonstrate anti-tumor efficacy in some cases of H3K27M-mutated DMG. Future work is required to determine factors predictive of favorable response.