HGG-03. THE GLYCOSPHINGOLIPIDS METABOLISM IS A NOVEL TARGET IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA

H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) is a rare malignant brain tumour entity in children and adults with a median overall survival of around 12 months. Genomic and proteomic analysis may help to identify new target structures, however not all relevant targets are covered by these analyses. Glycosphingolipids and particularly gangliosides play a major role in brain development and have been involved in the pathology of brain tumours. The conversion of ceramide to glucosylceramide via glucosylceramide synthase (GCS) is one of the first steps in the synthesis of glycosphingolipids. Therefore, targeting GCS will inhibit their synthesis. Here we analysed the glycosphingolipids composition and tested GCS inhibitors in an in vitro model of H3K27M-mutant DMG. Methods: H3K27M-mutant DMG primary cells were established from needle biopsies of two paediatric patients and characterised by immunohistochemistry. Glycosphingolipids were analysed by thin layer chromatography, liquid chromatography-coupled tandem mass spectrometry and flow cytometry. The effect of the GCS inhibitor eliglustat on the cell proliferation was examined. Results. The primary cells maintained the features of the tumour of origin, including the H3K27M mutation. Neutral glycosphingolipids with 1 to 4 monosaccharides and the ganglioside GD2 were expressed at high concentration. Eliglustat completely abrogated the proliferation of the H3K27M-mutant DMG primary cells. Conclusions. The glycosphingolipids oncometabolism represents a novel target in H3K27M-mutant DMG. The GCS inhibitors eliglusat and miglustat are already used to treat paediatric patients with the lysosomal storage disorders Niemann Pick’s and Gaucher′s disease and miglustat can cross the blood-brain barrier. Thus, our finding may accelerate the access of H3K27M-mutant DMG patients to novel innovative clinical studies based on the inhibition of the glycosphingolipids metabolism.

POS0293 TRheuMa REGISTRY PROVIDES FIRST EVIDENCE OF DIFFERENT COURSE OF RHEUMATIC IMMUNE-RELATED ADVERSE EVENTS AND TUMOUR RESPONSE RATES DEPENDING ON THE TUMOUR ENTITY

Background:Rheumatic immune-related adverse events (irAE) are associated with a better tumour response to immune checkpoint inhibitors (ICI). In contrast to other irAEs, their potentially chronic course may require long-term immunosuppressive treatment.Objectives:Our registry-based study analyses real-world data on the characteristics and outcome of rheumatic irAEs and underlying malignancy. Herein, we present first evidence that these parameters and the optimal clinical management may differ depending on the tumour entity.Methods:The TRheuMa registry is a prospective long-term observational study of a patient cohort suffering from rheumatic side effects of cancer therapies with focus on ICI. It is part of the MalheuR project initiated in July 2018 at the University Hospital Heidelberg to explore interrelations of malignancies and RMDs.Results:64 patients were recruited due to a rheumatic irAE under ICI treatment (nivolumab n=30, pembrolizumab n=33, ipilimumab n=12, PD-L1i n=5, ipi/nivo n=10) with a follow-up of up to 30 months. Of these, 47% had NSCLC and 41% melanoma. In local cohorts of patients receiving ICI, 4% of NSCLC (n total=888) and 13% of melanoma (n total=195) developed a rheumatic irAE. 7% of NSCLC and 23% of melanoma patients experienced a flare of a pre-existing RMD. De novo irAE mostly resembled phenotypes of spondyloarthritis both in NSCLC (43%) as well as in melanoma patients (33%). CRP levels were increased in 83% of NSCLC and 71% of melanoma patients. Almost all irAE patients showed autoantibody negativity and signs of inflammation in ultrasound examination (96%). Comparison of best responses to treatment in patients with and without rheumatic irAE in melanoma and without any irAE in NSCLC patients were as following: Complete remission (CR) in 48% vs. 4% of melanoma patients and partial remission (PR) in 68% vs. 41% of NSCLC patients. In accordance with our severity-based treatment algorithm, 25% of the melanoma patients in CR and 16% of the NSCLC patients in PR needed add-on DMARDs for sufficient irAE-treatment. ICI-treatment was discontinued in 7 cases (17% NSCLC, 8% melanoma)Conclusion:Prospective real-world data from the TRheuMa-registry provide first evidence that rheumatic irAE have distinct characteristics depending on the underlying malignancy. Oncological outcome was better with rheumatic irAE than in their absence and this effect was more pronounced in melanoma patients despite a larger use of immunosuppressants for irAE-treatment.Disclosure of Interests:Leonore Diekmann: None declared, Lea Daniello: None declared, Julia Kunz: None declared, Jan Leipe Consultant of: Pfizer; Novartis; Honoraria (self), Abbvie; Astra Zeneca; BMS; Celgene; Hospira; Janssen-Cilag; Gilead; LEO Pharma; Lilly; MSD; Roche; Sanofi; UCB., Grant/research support from: Research grant/Funding (self): Pfizer; Novartis; Honoraria (self), Hanns-Martin Lorenz Consultant of: Abbvie; BMS; MSD; Pfizer; Celgene; Roche; Chugai; Medac; GSK; Honoraria (self), Novartis; UCB; Janssen-Cilag; Astra Zeneca; Lilly, Grant/research support from: Research grant/Funding (institution): Abbvie; BMS; MSD; Pfizer; Celgene; Roche; Chugai; Medac; GSK; Honoraria (self), Research grant/Funding (institution), Novartis; UCB; Janssen-Cilag; Astra Zeneca; Lilly; Research grant/Funding (institution): Baxter; SOBI; Biogen; Actelion; Mundipharma; Bayer Vital; Octapharm; Sanofi; Hexal; Thermo Fischer; Shire., Jessica Hassel Consultant of: MDS; Honoraria (self): Roche; Novartis; Pierre Fabre., Grant/research support from: BMS; Honoraria (self), Karin Jordan Consultant of: Advisory/Consultancy: Amgen; Merck; MSD; Riemser; Helsinn; Tesaro; Kreussler; Voluntis; Pfizer; Pomme-med; Hexal., Petros Christopoulos Consultant of: advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim, Chugai, Novartis, Pfizer, Roche, Takeda., Grant/research support from: research funding from AstraZeneca, Novartis, Roche, Takeda, Karolina Benesova Grant/research support from: Foundations and Awards” commission of the University of Heidelberg: University of Heidelberg; AbbVie; Novartis; Rheumaliga Baden-Württemberg e.V

Adenocarcinoma of an ileal conduit developing 8 years after cystoprostatectomy for locally advanced prostate carcinoma

A 70-year-old patient was treated in September 2017 for a malignancy in an ileal conduit (IC) which he received in 2009 for the treatment of prostate cancer. The tumour was found incidentally during a routine sonography. A CT scan revealed a mass near the IC. An endoscopy with biopsies showed an intraepithelial neoplasia of the ileal mucosa in the IC. We performed a segmental ileal resection. Histological findings revealed an ileal adenocarcinoma. The postoperative course was uneventful. The patient has remained alive without tumour recurrence up to the most recent negative CT screening in April 2019. Secondary malignancies after urinary diversions are a well-known complication, including procedures using small bowel parts for the urinary diversion. Adenocarcinomas arising in an IC are rarely described in literature. Concerning said tumour entity, surgical removal is often recommended. There is no evidence for the success of chemotherapy or radiation due to insufficient clinical trials. When diagnosing a mass in an IC, a secondary malignancy should be taken under consideration.

Unusual presentation of a large GIST in an extraintestinal site: a challenging diagnosis dilemma

Gastrointestinal stromal tumour (GIST) is a recent recognised tumour entity. In the past, those tumours were classified as leiomyomas, leiomyosarcomas and leiomyoblastomas, but it is now evident that GIST is a separate tumour entity and is the most common sarcoma of the gastrointestinal tract especially with advances in immunohistochemical staining techniques and improvements in microscopic structural imaging. We present a case of GIST of unusual location and presentation pattern, with an overview over current GISTs’ diagnosis and management strategies. The precise incidence and tumour behaviour of rare extragastrointestinal stromal tumour (EGIST) remain to be clarified. Further research is needed in large series with long duration of follow-up and modified risk stratification assessment tailored for EGISTs.

Chordoid Glioma as a Differential Diagnosis of Anterior Third Ventricle Tumours: A Rare Case Report and Five-Year Follow-Up

Chordoid glioma is a rare and relatively recently defined tumour entity. Worldwide there have only been around 90 cases described until now. A chordoid glioma comprises a low-grade suprasellar neuroepithelial neoplasm originating in the anterior part of the third ventricle, with consistent radiological features on MRI. This lesion should be considered as a differential of third ventricle tumours. The patient described in this paper is quite unique in the sense that despite only partial tumour resection was obtained, the residual tumour was not progressive during several years of follow-up. Preoperative recognition of this disease entity is crucial to modify the treatment approach and improve patient outcome.

Novel prognostic histopathological grading system in oral squamous cell carcinoma based on tumour budding and cell nest size shows high interobserver and intraobserver concordance

AimsSquamous cell carcinoma of the oral cavity (OSCC) is a common tumour entity with a variable, partially highly aggressive clinical course. Recently, we proposed a novel (three-tiered) clinically useful grading scheme strongly associated with patient outcome in OSCC, consisting of a sum score of the histomorphological patterns tumour budding and cell nest size which outperforms WHO based grading algorithms currently in use. The aim of our study was to probe for interobserver and intraobserver reliability of this novel grading system.Methods108 OSCC were retrospectively scored according to the proposed grading scheme by three independent pathologists—two experienced head and neck pathologists and one pathologist in training—blinded to each other’s scoring results.ResultsThe Cohen’s Kappa (κ) values for concordance rates between experienced pathologists were κ=0.97 for the overall grade, κ=0.97 for budding activity and κ=0.91 for cell nest size, indicating a strong interobserver reliability of our proposed grading system. Initial interobserver agreement was markedly lower with the pathologist in training (κ=0.55 for overall grade) but improved significantly after a training session (κ=0.87 for overall grade). Intraobserver concordance was high (κ=0.95 for overall grade), indicating a high reproducibility of the algorithm.ConclusionsIn conclusion, our study indicates that OSCC grading based on our proposed novel scheme yields an excellent inter-reader and intrareader agreement, further supporting the suitability of this grading system for routine pathological practice.

PCF11 links alternative polyadenylation to formation and spontaneous regression of neuroblastoma

Diversification at the transcriptome 3’end is an important and evolutionarily conserved layer of gene regulation associated with differentiation and dedifferentiation processes. However the underlying mechanisms and functional consequences are poorly defined. Here, we identify extensive transcriptome-3’end-alterations in neuroblastoma, a tumour entity with a paucity of recurrent somatic mutations and an unusually high frequency of spontaneous regression. Utilising extensive RNAi-screening we reveal the landscape and drivers of transcriptome-3’end-diversification, discovering PCF11 as critical regulator, directing alternative polyadenylation (APA) of hundreds of transcripts including a differentiation RNA-operon. PCF11 shapes inputs converging on WNT-signalling, and governs cell cycle, proliferation, apoptosis and neurodifferentiation. Postnatal PCF11 down-regulation induces a neurodifferentiation program, and low-level PCF11 in neuroblastoma associates with favourable outcome and spontaneous tumour regression. Our findings document a critical role for APA in tumourigenesis and describe a novel mechanism for cell fate reprogramming in neuroblastoma with important clinical implications. An interactive data repository of transcriptome-wide APA covering >170 RNAis, and an APA-network map with regulatory hubs is provided.