An unexpected intracerebral lesion - case report of a superinfected aspergillosis mimicking a brain metastasis

BACKGROUND: Invasive aspergillosis of the central nervous system is a rare but increasingly prevalent disease. We present the unusual case of an immunosuppressed patient suffering from unexpected superinfected invasive aspergillosis with cerebral, pulmonal, and adrenal manifestations, mimicking a metastasized bronchial carcinoma. This report reveals the importance of including aspergillosis in the differential diagnosis of a cerebral mass lesion in the light of unspecific clinical findings. CASE PRESENTATION: A 58-year-old immunocompromised female presented to our emergency department with a single tonic-clonic seizure. Imaging showed a ring enhancing cerebral mass with perifocal edema and evidence of two smaller additional hemorrhagic cerebral lesions. In the setting of a mass lesion in the lung, and additional nodular lesions in the left adrenal gland the diagnosis of a metastasized bronchus carcinoma was suspected and the cerebral mass resected. However, histology did not reveal any evidence for a neoplastic lesion but septate hyphae consistent with aspergillus instead and microbiological cultures confirmed concomitant staphylococcal infection. CONCLUSIONS: A high index of suspicion for aspergillus infection should be maintained in the setting of immunosuppression. Clinical and radiological findings are often unspecific and even misleading. Definite confirmation usually relies on tissue diagnosis with histochemical stains. Surgical resection is crucial for establishing the diagnosis and guiding therapy with targeted antifungal medications

Anaplastic ganglioglioma-A diagnosis comprising several distinct tumour types

AIMS Anaplastic ganglioglioma is a rare tumour, and diagnosis has been based on histological criteria. The 5th edition of the World Health Organization Classification of Tumours of the Central Nervous System (CNS WHO) does not list anaplastic ganglioglioma as a distinct diagnosis due to lack of molecular data in previous publications. We retrospectively compiled a cohort of 54 histologically diagnosed anaplastic gangliogliomas to explore whether the molecular profiles of these tumours represent a separate type or resolve into other entities. METHODS Samples were subjected to histological review, desoxyribonucleic acid (DNA) methylation profiling and next-generation sequencing. Morphological and molecular data were summarised to an integrated diagnosis. RESULTS The majority of tumours designated as anaplastic gangliogliomas resolved into other CNS WHO diagnoses, most commonly pleomorphic xanthoastrocytoma (16/54), glioblastoma, isocitrate dehydrogenase protein (IDH) wild type and diffuse paediatric-type high-grade glioma, H3 wild type and IDH wild type (11 and 2/54), followed by low-grade glial or glioneuronal tumours including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumour and diffuse leptomeningeal glioneuronal tumour (5/54), IDH mutant astrocytoma (4/54) and others (6/54). A subset of tumours (10/54) was not assignable to a CNS WHO diagnosis, and common molecular profiles pointing to a separate entity were not evident. CONCLUSIONS In summary, we show that tumours histologically diagnosed as anaplastic ganglioglioma comprise a wide spectrum of CNS WHO tumour types with different prognostic and therapeutic implications. We therefore suggest assigning this designation with caution and recommend comprehensive molecular workup

Mutational Landscape and Expression of PD-L1 in Patients with Non-Small Cell Lung Cancer Harboring Genomic Alterations of the MET gene

BACKGROUND Mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations and MET gene amplification occur in 3-5% of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) targeting MET alterations have shown promising results in these patients. OBJECTIVE The aim of this study was to describe the genomic profile, PD-L1 expression and clinicopathological features of MET dysregulated NSCLC. PATIENTS AND METHODS We identified 188 patients with advanced-stage NSCLC with data on MET expression by immunohistochemistry (IHC). IHC for PD-L1 expression was performed in 131 patient samples, and next-generation sequencing (NGS) analysis was performed in 109 patient samples. RESULTS MET exon 14 skipping alterations were identified in 16 (14.7%) samples, MET amplifications with cut-off ≥4 copy number variations were identified in 11 (10.1%) samples, and an oncogenic MET mutation (MET p.D1228N) was identified in 1 (0.9%) sample. 12/15 tumors (80.0%) harboring MET exon 14 alterations and 7/11 (63.6%) MET-amplified tumors expressed PD-L1 in ≥1% of tumor cells. Tumors harboring MET exon 14 skipping alterations expressed PD-L1 more frequently than MET wild-type IHC-positive tumors (p = 0.045). Twenty-five percent of MET exon 14-altered cases and 33% of MET-amplified cases harbored potentially targetable oncogenic co-mutations in KRAS, BRAF, and EGFR. The most frequent co-occurring mutations in all MET-altered tumors were TP53, KRAS, BRAF, and CDK4. CONCLUSIONS We demonstrated that MET exon 14 skipping alterations and MET amplification are not mutually exclusive to other oncogenic co-mutations, and report the association of genomic MET alterations with PD-L1 expression. Since genomic MET alterations are emerging targets requiring upfront treatment, optimal understanding of the co-mutational landscape for this patient population is needed

Association of pre- and postoperative αKlotho levels with long-term remission after pituitary surgery for acromegaly

Soluble αKlotho (sKl) is a disease-specific biomarker that is elevated in patients with acromegaly and declines after surgery for pituitary adenoma. Approximately 25% of patients do not achieve remission after surgery, therefore a risk stratification for patients early in the course of their disease may allow for the identification of patients requiring adjuvant treatment. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have been assessed as biomarker for disease activity, however the value of sKl as a predictive biomarker of surgical success has not been evaluated yet. In this study, we measured serum biomarkers before and after transsphenoidal pituitary surgery in 55 treatment-naïve patients. Based on biochemical findings at follow-up (7-16 years), we divided patients into three groups: (A) long-term cure (defined by normal IGF-1 and random low GH (< 1 μg/l) or a suppressed GH nadir (< 0.4/μg/l) on oral glucose testing); (B) initial remission with later disease activity; (C) persistent clinical and/or biochemical disease activity. sKl levels positively related to GH, IGF-1 levels and tumor volume. Interestingly, there was a statistically significant difference in pre- and postoperative levels of sKl between the long-term cure group and the group with persistent disease activity. This study provides first evidence that sKl may serve as an additional marker for surgical success, decreasing substantially in all patients with initial clinical remission while remaining high after surgery in patients with persistent disease activity

A prognostic model for tumor recurrence and progression after meningioma surgery: preselection for further molecular work-up

PurposeThe selection of patients for further therapy after meningioma surgery remains a challenge. Progress has been made in this setting in selecting patients that are more likely to have an aggressive disease course by using molecular tests such as gene panel sequencing and DNA methylation profiling. The aim of this study was to create a preselection tool warranting further molecular work-up.MethodsAll patients undergoing surgery for resection or biopsy of a cranial meningioma from January 2013 until December 2018 at the University Hospital Zurich with available tumor histology were included. Various prospectively collected clinical, radiological, histological and immunohistochemical variables were analyzed and used to train a logistic regression model to predict tumor recurrence or progression. Regression coefficients were used to generate a scoring system grading every patient into low, intermediate, and high-risk group for tumor progression or recurrence.ResultsOut of a total of 13 variables preselected for this study, previous meningioma surgery, Simpson grade, progesterone receptor staining as well as presence of necrosis and patternless growth on histopathological analysis of 378 patients were included into the final model. Discrimination showed an AUC of 0.81 (95% CI 0.73 – 0.88), the model was well-calibrated. Recurrence-free survival was significantly decreased in patients in intermediate and high-risk score groups (p-value &lt; 0.001).ConclusionThe proposed prediction model showed good discrimination and calibration. This prediction model is based on easily obtainable information and can be used as an adjunct for patient selection for further molecular work-up in a tertiary hospital setting

A T-cell antigen atlas for meningioma: novel options for immunotherapy

Meningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is located outside the blood-brain barrier, they might be an accessible target for immunotherapy. However, the landscape of naturally presented tumor antigens in meningioma is unknown. We here provide a T-cell antigen atlas for meningioma by in-depth profiling of the naturally presented immunopeptidome using LC-MS/MS. Candidate target antigens were selected based on a comparative approach using an extensive immunopeptidome data set of normal tissues. Meningioma-exclusive antigens for HLA class I and II are described here for the first time. Top-ranking targets were further functionally characterized by showing their immunogenicity through in vitro T-cell priming assays. Thus, we provide an atlas of meningioma T-cell antigens which will be publicly available for further research. In addition, we have identified novel actionable targets that warrant further investigation as an immunotherapy option for meningioma

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology

Neurofibromatosis type 1 (NF1) with an unusually severe phenotype due to digeny for NF1 and ryanodine receptor 1 associated myopathy

We describe a 5-year-old girl with marked hypotonia, poor feeding and reduced facial expression since birth. Congenital myopathy was suspected; muscle biopsy showed unspecific type 1 fibre predominance. The possibility of a ryanodine receptor 1 gene (RYR1)-associated myopathy was considered, but not further investigated. At the age of 2 years, she presented with exophthalmos. Brain MRI revealed optic pathway glioma. On clinical examination, she had six café-au-lait spots, thus fulfilling the diagnostic criteria for neurofibromatosis type 1 (NF1). The hypotonia was then attributed to NF1. At the age of 3 years, she developed scoliosis and had an unusually severe motor delay for NF1, as she was not able to walk independently. Dual pathology was suspected, and muscle MRI showed the typical pattern for RYR1-related myopathy. This was genetically confirmed with the discovery of two heterozygous mutations. CONCLUSION: NF1 is one of the most frequent genetic diseases in children. RYR1-related myopathy is one of the most frequent causes of congenital myopathy. The combination of these two pathologies has not yet been described. In cases of unusual presentations or clinical course, the possibility of genetic "double trouble" should be considered