The utility of multiparametric MRI in reducing diagnostic uncertainty for primary central nervous system lymphoma.

AIM: A key limitation in the early treatment initiation in primary central nervous system lymphoma (PCNSL) is the diagnostic delay caused by lack of recognition of a lesion as a possible lymphoma, steroid initiation, and lesion involution, often resulting in inconclusive biopsy. We highlight the importance of multiparametric MRI (MPMRI), which incorporates diffusion weighted imaging (DWI), dynamic susceptibility contrast-enhanced perfusion weighted imaging (DSC-PWI) and proton magnetic resonance spectroscopy (1H-MRS) in addition to standard MRI sequences in resolving diagnostic uncertainty for PCNSL. MATERIALS AND METHODS: We present a consecutive series of 10 patients at our centre with histology-proven PCNSL (specifically, diffuse large B-cell lymphoma of the CNS) who underwent multiparametric MRI. We retrospectively analyse the qualitative and semi-quantitative parameters and assess their radiological concordance for this diagnosis. RESULTS: We note overall low apparent diffusion coefficient on DWI (mean ADCmin of 0.74), high percentage signal recovery on perfusion weighted imaging (mean 170%), a high choline-creatine ratio and a high-grade lipid peak on MRS giving a "twin-tower" appearance. Nine of ten patients had MRMRI findings concordant for PCNSL, defined as at least 3 of 4 parameters being consistent for PCNSL. CONCLUSION: We propose that concordance between these imaging multiparametric modalities could be used as a radiological predictor of PCNSL, reducing diagnostic delays, providing a more accurate biopsy target, and resulting in quicker treatment initiation.

A Case of Bing-Neel Syndrome Presenting Like Giant Cell Arteritis.

ABSTRACT: A 55-year-old woman presented with new-onset headache, scalp tenderness, shoulder arthralgias, night sweats, and loss of appetite. She was diagnosed with giant cell arteritis by her primary care physician and commenced on oral corticosteroids. However, her headache, scalp tenderness, and night sweats persisted. She then developed right Horner syndrome and trigeminal hypoesthesia. Extensive blood work-up revealed mildly elevated inflammatory markers and a paraproteinemia. Subsequent bone marrow biopsy showed lymphoplasmacytic lymphoma, with 10% of hemopoiesis, and staging led to the diagnosis of Waldenstrom macroglobulinemia without nodal or central nervous system (CNS) lesions. Immunohistochemical staining of a temporal artery biopsy showed perivascular lymphoplasmacytic cells and paraprotein deposits. She was diagnosed with CNS involvement of her macroglobulinemia-Bing-Neel syndrome (BNS). Identification of rare CNS involvement of lymphoma is challenging when a patient is already on steroid immunosuppression. In the absence of clear diagnostic criteria, the rare and heterogenous BNS remains a clinical diagnosis.

Protocol for the Tessa Jowell BRAIN MATRIX Platform Study.

INTRODUCTION: Gliomas are the most common primary tumour of the central nervous system (CNS), with an estimated annual incidence of 6.6 per 100 000 individuals in the USA and around 14 deaths per day from brain tumours in the UK. The genomic and biological landscape of brain tumours has been increasingly defined and, since 2016, the WHO classification of tumours of the CNS incorporates molecular data, along with morphology, to define tumour subtypes more accurately. The Tessa Jowell BRAIN MATRIX Platform (TJBM) study aims to create a transformative clinical research infrastructure that leverages UK National Health Service resources to support research that is patient centric and attractive to both academic and commercial investors. METHODS AND ANALYSIS: The TJBM study is a programme of work with the principal purpose to improve the knowledge of glioma and treatment for patients with glioma. The programme includes a platform study and subsequent interventional clinical trials (as separate protocols). The platform study described here is the backbone data-repository of disease, treatment and outcome data from clinical, imaging and pathology data being collected in patients with glioma from secondary care hospitals. The primary outcome measure of the platform is time from biopsy to integrated histological-molecular diagnosis using whole-genome sequencing and epigenomic classification. Secondary outcome measures include those that are process centred, patient centred and framework based. Target recruitment for the study is 1000 patients with interim analyses at 100 and 500 patients. ETHICS AND DISSEMINATION: The study will be performed in accordance with the recommendations guiding physicians in biomedical research involving human subjects, adopted by the 18th World Medical Association General Assembly, Helsinki, Finland and stated in the respective participating countries' laws governing human research, and Good Clinical Practice. The protocol was initially approved on 18 February 2020 by West Midlands - Edgbaston Research Ethics Committee; the current protocol (v3.0) was approved on 15 June 2022. Participants will be required to provide written informed consent. A meeting will be held after the end of the study to allow discussion of the main results among the collaborators prior to publication. The results of this study will be disseminated through national and international presentations and peer-reviewed publications. Manuscripts will be prepared by the Study Management Group and authorship will be determined by mutual agreement. TRIAL REGISTRATION NUMBER: NCT04274283, 18-Feb-2020; ISRCTN14218060, 03-Feb-2020.

Rathke's Cleft Cyst Abscess with a Very Unusual Course.

Infected Rathke's cleft cysts (RCC) are extremely rare with only a few published cases. We report the case of a 31-year-old man who presented with headaches, visual disturbance, and hypopituitarism secondary to an infected RCC with extension of abscesses along the optic tract. Magnetic resonance imaging showed ring enhancing cystic lesions within an expanded sella with suprasellar and intraparenchymal extension. The radiological appearance suggested a high-grade optic glioma, but an endoscopic transsphenoidal biopsy revealed frank pus in the pituitary fossa, which subsequently grew Staphylococcus aureus . Pathological examination of the cyst wall showed an inflamed RCC. Following a prolonged course of intravenous antibiotics, the infection resolved and vision improved. RCC abscesses are rare and the intracranial extension of the infection in our case makes it unique.

Reconfiguration from emergency to urgent elective neurosurgery for glioblastoma patients improves length of stay, surgical adjunct use, and extent of resective surgery.

Background: Glioblastoma (GB) is the most common intrinsic brain cancer and is notorious for its aggressive nature. Despite widespread research and optimization of clinical management, the improvement in overall survival has been limited. The aim of this study was to characterize the impact of service reconfiguration on GB outcomes in a single centre. Methods: Patients with a histopathological confirmation of a diagnosis of GB between 01/01/2014 and 31/12/2019 were retrospectively identified. Demographic and tumour characteristics, survival, treatment (surgical and oncological), admission status, use of surgical adjunct (5-aminolevulinic acid, intra-operative neuro-monitoring), the length of stay, extent of resection, and surgical complications were recorded from the hospital databases. Results: From August 2018 the neurosurgical oncology service was reconfigured to manage high-grade tumours on an urgent outpatient basis by surgeons specializing in oncology. We demonstrate that these changes resulted in an increase in elective admissions, greater use of intra-operative adjuncts resulting in the improved extent of tumour resection, and a reduction in median length of stay and associated cost-savings. Conclusions: Optimizing neuro-oncology patient management through service reconfiguration resulted in increased use of intra-operative adjuncts, improved surgical outcomes, and reduced hospital costs. These changes also have the potential to improve survival and disease-free progression for patients with GB.

Multisystem screening reveals SARS-CoV-2 in neurons of the myenteric plexus and in megakaryocytes.

SARS-CoV-2, the causative agent of COVID-19, typically manifests as a respiratory illness, although extrapulmonary involvement, such as in the gastrointestinal tract and nervous system, as well as frequent thrombotic events, are increasingly recognised. How this maps onto SARS-CoV-2 organ tropism at the histological level, however, remains unclear. Here, we perform a comprehensive validation of a monoclonal antibody against the SARS-CoV-2 nucleocapsid protein (NP) followed by systematic multisystem organ immunohistochemistry analysis of the viral cellular tropism in tissue from 36 patients, 16 postmortem cases and 16 biopsies with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 status from the peaks of the pandemic in 2020 and four pre-COVID postmortem controls. SARS-CoV-2 anti-NP staining in the postmortem cases revealed broad multiorgan involvement of the respiratory, digestive, haematopoietic, genitourinary and nervous systems, with a typical pattern of staining characterised by punctate paranuclear and apical cytoplasmic labelling. The average time from symptom onset to time of death was shorter in positively versus negatively stained postmortem cases (mean = 10.3 days versus mean = 20.3 days, p = 0.0416, with no cases showing definitive staining if the interval exceeded 15 days). One striking finding was the widespread presence of SARS-CoV-2 NP in neurons of the myenteric plexus, a site of high ACE2 expression, the entry receptor for SARS-CoV-2, and one of the earliest affected cells in Parkinson's disease. In the bone marrow, we observed viral SARS-CoV-2 NP within megakaryocytes, key cells in platelet production and thrombus formation. In 15 tracheal biopsies performed in patients requiring ventilation, there was a near complete concordance between immunohistochemistry and PCR swab results. Going forward, our findings have relevance to correlating clinical symptoms with the organ tropism of SARS-CoV-2 in contemporary cases as well as providing insights into potential long-term complications of COVID-19. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Oligosarcomas, IDH-mutant are distinct and aggressive.

Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c) TERT promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.

Failed Acellular Nerve Allografts: A Critical Review.

BACKGROUND: Acellular nerve allograft (ANA) occupies an increasingly prominent role in the treatment of peripheral nerve reconstruction. There is demonstrable efficacy; however, some grafts fail to support axonal regrowth and the reasons for this are unclear. This study examines the ANA experience in a specialized peripheral nerve surgery department to discuss the clinical and histological findings in failed cases. METHOD: Failed ANA grafts were identified from a prospective database using Medical Research Council Classification (MRCC) S3 and M3 as thresholds for success. Cases in which ANA grafting was indicated for nerve related pain and dysesthesia but where no subjective improvement in symptoms occurred were also included. Patients requiring revision surgery after ANA grafting were also considered failures. Cases were then examined in conjunction with a literature review to identify possible mechanisms of failure, including detailed histological analysis in 2 cases. RESULTS: Eight failed procedures were identified from a database of 99 separate allograft records on 74 patients. This included procedures for 2 tibial nerves, 2 superficial radial nerves, 2 median nerves, 1 digital nerve and a lateral cord brachial plexus injury (male/female, 5:3; age range, 24-54 years). Allograft length range 25 to 120 mm. One postoperative infection was identified. Histological findings in 2 cases included adequate vascularization of allograft material without subsequent axonal regeneration, a reduction of large myelinated fibers proximal to a tibial nerve allograft in the setting of a chronic injury, and a preference for small rather than large fiber regeneration. CONCLUSIONS: This article reports instances of ANA graft failure in a variety of contexts, for which the primary reasons for failure remain unclear. The etiology is likely to be multifactorial with both patient, graft and surgeon factors contributing to failure. Further clinical and histological analysis of ANA failures will improve our understanding of the mechanisms of graft failure.

Development of an Affordable, Sustainable and Efficacious Plant-Based Immunomodulatory Food Ingredient Based on Bell Pepper or Carrot RG-I Pectic Polysaccharides.

The prevalence of acute respiratory infections and their impact on quality of life underlies the need for efficacious solutions that are safe, sustainable and economically viable. Polysaccharides in several (traditional) plant extracts have been shown to be immunostimulatory, and some studies suggest beneficial effects against respiratory infections. The aim of this study was to (i) identify the active polysaccharide constituents from affordable and renewable crops (bell pepper and carrot) using activity-guided fractionation, (ii) evaluate in vitro effects on innate immune responses (phagocytosis and cytokine secretion), microbiota modulation and production of short chain fatty acids, followed by (iii) the evaluation of effects of a bell pepper extract enriched for the active component in a human proof of concept study. We identified rhamnogalacturonan-I (RG-I) as the nutricophore responsible for the immunostimulatory activity with substantial structural and functional equivalence between bell pepper (bp) and carrot (c). The in vitro studies showed that bpRG-I and cRG-I comprise similar immune- and microbiota modulatory potential and the human study demonstrated that bpRG-I was well tolerated and enhanced innate immune responsiveness in vivo. This is an important step towards testing the efficacy of RG-I from bpRG-I or cRG-I in an infection trial in humans.

Advances in Research of Adult Gliomas.

Diffuse gliomas are the most frequent brain tumours, representing 75% of all primary malignant brain tumours in adults. Because of their locally aggressive behaviour and the fact that they cannot be cured by current therapies, they represent one of the most devastating cancers. The present review summarises recent advances in our understanding of glioma development and progression by use of various in vitro and in vivo models, as well as more complex techniques including cultures of 3D organoids and organotypic slices. We discuss the progress that has been made in understanding glioma heterogeneity, alteration in gene expression and DNA methylation, as well as advances in various in silico models. Lastly current treatment options and future clinical trials, which aim to improve early diagnosis and disease monitoring, are also discussed.

Investigation of the natural supplement IQP-AS-119 for the prevention of upper respiratory tract infections in marathon race participants: A randomized, double-blind, placebo-controlled pilot study.

Intense and prolonged exercise leads to immune suppression, causing upper respiratory tract infections (URTI). A proprietary standardized dietary supplement, IQP-AS-119 has been previously developed to aid immune responses under such conditions. The current randomized, double-blind, placebo-controlled pilot study aimed to investigate the effects of IQP-AS-119 on marathon runners. A total of 80 participants were randomized equally into groups receiving either placebo (P group) or IQP-AS-119 (V group) treatment, starting 3 weeks before and for 14 days after the marathon. Benefit assessment was performed using different questionnaires. Post-marathon, the V and P groups reported 1±2.38 and 2.11±3.25 days with upper respiratory tract symptoms (URTS), respectively (P=0.038). During the 14 days post-marathon, 20.0% of the participants in the V group compared with 44.4% in the P group reported URTS (P=0.042). The V group reported significantly milder URTS compared with the P group on Days 9, 12, 13 and 14 post-marathon (P<0.05). The total Perceived Stress Questionnaire-20 score on days 2-14 were significantly lower for the V group compared with the P group (P=0.035). In the Short Form 12 Health Survey, the V group exhibited significant improvement in mental composite score on days -5 to 14 compared with the P group (P=0.038). In the overall treatment effect assessment, there were no statistically significant differences between the groups. The IQP-AS-119 was rated 'very good' or 'good' by investigators and participants, respectively, for 71 and 65% of the participants. The tolerability of IQP-AS-119 was rated as 'very good' or 'good' by both investigators and 95% of participants. No clinically relevant differences were observed between groups regarding adverse events or other safety parameters. Therefore, IQP-AS-119 was demonstrated to reduce the incidence and severity of URTI in marathon runners. Given its good tolerability profile, IQP-AS-119 may be a good nutritional supplement for the reduction of URTS in susceptible individuals.

Statin-induced autoimmune necrotizing myositis-A single-center case series highlighting this potentially life-threatening but treatable condition.

Statin-induced autoimmune necrotizing myositis is a rare but important cause muscle weakness. Withdrawal of the statin and steroid treatment alone may be insufficient treatment for SIANM. Targeted immunosuppression may be needed and can be effective.

Extramedullary malignant melanotic schwannoma of the spine: Case report and an up to date systematic review of the literature.

BACKGROUND: Melanotic schwannoma is a rare variant of schwannoma. Extramedullary melanotic schwannoma originates in the vicinity of nerve roots mimicking other intervertebral disc disorders. Therefore, T1 and T2-weighted MRI sequences become an essential tool for diagnosis. Aside from case reports, no large studies exist to provide consensus on the signal intensities in T1 and T2-weighted MR imaging. Moreover, no clear evidence is available to delineate prognosis. Here, a case report is presented together with a subsequent systematic review of the literature regarding this rare entity. CASE DESCRIPTION: A 45-year old female presented with a one-year history of insidious onset of neck pain and paraesthesia. Magnetic resonance imaging confirmed an extramedullary lesion along the C6 nerve root with T1-weighted hyperintensity and T2-weighted hypointensity. Despite two surgical decompressions and adjuvant immunotherapy, the patient unfortunately passed away due to metastatic progression. DISCUSSION: According to the systematic review conducted, in over half of the cases of extramedullary melanotic schwannoma, there is local reoccurrence and/or distal metastasis. Moreover, in 64.7% and 70.6% of the cases, the T1-weighted image of the lesion appears hyperintense and hypointense on a T2-weighted image, respectively. It is an aggressive variant of schwannoma, one of the most commonly observed extramedullary tumours presenting to neurosurgical practice. CONCLUSION: Our results highlight that specific T1 and T2-weighted imaging findings can provide valuable information, enabling early suspicion, influencing the surgical aims and strategy and the timely commencement of relevant immunotherapy. Considering the poor prognosis, early adjuvant therapy with other modalities should be considered.

Multiparametric MRI: practical approach and pictorial review of a useful tool in the evaluation of brain tumours and tumour-like lesions.

MRI has a vital role in the assessment of intracranial lesions. Conventional MRI has limited specificity and multiparametric MRI using diffusion-weighted imaging, perfusion-weighted imaging and magnetic resonance spectroscopy allows more accurate assessment of the tissue microenvironment. The purpose of this educational pictorial review is to demonstrate the role of multiparametric MRI for diagnosis, treatment planning and for assessing treatment response, as well as providing a practical approach for performing and interpreting multiparametric MRI in the clinical setting. A variety of cases are presented to demonstrate how multiparametric MRI can help differentiate neoplastic from non-neoplastic lesions compared to conventional MRI alone.

Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course.

The "isomorphic subtype of diffuse astrocytoma" was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1 and MYB alterations and a specific DNA methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA methylation profiling very helpful for their identification.

Tumors diagnosed as cerebellar glioblastoma comprise distinct molecular entities.

In this multi-institutional study we compiled a retrospective cohort of 86 posterior fossa tumors having received the diagnosis of cerebellar glioblastoma (cGBM). All tumors were reviewed histologically and subjected to array-based methylation analysis followed by algorithm-based classification into distinct methylation classes (MCs). The single MC containing the largest proportion of 25 tumors diagnosed as cGBM was MC anaplastic astrocytoma with piloid features representing a recently-described molecular tumor entity not yet included in the WHO Classification of Tumours of the Central Nervous System (WHO classification). Twenty-nine tumors molecularly corresponded to either of 6 methylation subclasses subsumed in the MC family GBM IDH wildtype. Further we identified 6 tumors belonging to the MC diffuse midline glioma H3 K27 M mutant and 6 tumors allotted to the MC IDH mutant glioma subclass astrocytoma. Two tumors were classified as MC pilocytic astrocytoma of the posterior fossa, one as MC CNS high grade neuroepithelial tumor with BCOR alteration and one as MC control tissue, inflammatory tumor microenvironment. The methylation profiles of 16 tumors could not clearly be assigned to one distinct MC. In comparison to supratentorial localization, the MC GBM IDH wildtype subclass midline was overrepresented, whereas the MCs GBM IDH wildtype subclass mesenchymal and subclass RTK II were underrepresented in the cerebellum. Based on the integration of molecular and histological findings all tumors received an integrated diagnosis in line with the WHO classification 2016. In conclusion, cGBM does not represent a molecularly uniform tumor entity, but rather comprises different brain tumor entities with diverse prognosis and therapeutic options. Distinction of these molecular tumor classes requires molecular analysis. More than 30% of tumors diagnosed as cGBM belong to the recently described molecular entity of anaplastic astrocytoma with piloid features.

The local thermal effect of using monopolar electrosurgery in the presence of a deep brain stimulator: Cadaveric studies on a lamb brain.

In 2001, a patient with a deep brain stimulator (DBS) died following treatment with medical diathermy. Manufacturers have since advised against all forms of diathermy except bipolar electrosurgery in DBS patients. This effective ban on monopolar electrosurgery has an impact on the 150,000 patients treated with DBS to date, a number that is set to progressively increase. Analysis of the events, technical specifications, and literature suggests that the original ban was based on extrapolation from medical diathermy to electrosurgery, two very different treatment modalities. This prompted novel work exploring the impact of electrosurgery on DBS systems. Monopolar electrosurgery was employed on an animal cadaveric model with a DBS system paired with a thermocouple at the brain implant site. Prolonged use of monopolar, including at settings higher than normal surgical practice, resulted in a maximum mean temperature increase of only 2.6 °C. Microscopic post-event analysis showed no evidence of thermal injury at the implant site. The implication is that there may be limits within which monopolar electrosurgery use is safe in patients with DBS.

Reviewing the Pathophysiology Behind the Advances in the Management of Giant Cell Arteritis.

Improving understanding of the underlying pathophysiology of giant cell arteritis (GCA) is transforming clinical management by identifying novel avenues for targeted therapies. One key area of concern for both clinicians and patients with GCA is glucocorticoid (GC) morbidity. The first randomised controlled trials of targeted treatment to reduce cumulative GC use in GCA have been published, with tocilizumab, an interleukin (IL)-6 receptor inhibitor, now the first ever licensed treatment for GCA. Further potential therapies are emerging owing to our enhanced understanding of the pathophysiology of the disease. Other improvements in the care of our patients are rapid access pathways and imaging techniques, such as ultrasound, which are becoming part of modern rheumatology practice in the UK, Europe and beyond. These have been highlighted in the literature to reduce delay in diagnosis and improve long-term outcomes for those investigated for GCA.

Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations.

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.