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Children diagnosed with diffuse midline gliomas (DMG) have an extremely poor overall survival: 9-12 months from diagnosis with currently no curative treatment options. Given DMG molecular heterogeneity, surgical biopsies are needed for molecular profiling and as part of enrolment into molecular-based and precision medicine type clinical interventions. In this study, we describe the results of real time profiling and drug testing at the diffuse intrinsic pontine glioma/DMG Research Centre at University Children's Hospital Zurich.Biopsies were taken using a frame based stereotactic robot system (NeuroMate®, Renishaw) at University Children's Hospital Zurich. Tissue samples were evaluated to confirm diagnosis by H3K27M and H3K27 trimethylation loss. Genomic analyses were done using a variety of platforms (INFORM, Oncomine, UCSF500 gene panel). Cell lines were developed by mechanical tissue dissociation and verified by either sequencing or immunofluorescence staining confirming H3K27M mutation and used afterwards for drug testing.Twenty-five robot-assisted primary biopsies were successfully performed. Median hospital stay was 2 days (range 1-4 days). Nine low-passage patient-derived cells were developed, whereas 8 cell lines were used to inform response to clinically relevant drugs. Genome and RNA expression were used to further guide treatment strategies with targeted agents such as dual PI3K/mTOR inhibitor paxalisib.We established a systematic workflow for safe, robot-assisted brainstem biopsies and in-house tissue processing, followed by real-time drug testing. This provides valuable insights into tumour prognostic and individual treatment strategies targeting relevant vulnerabilities in these tumours in a clinically meaningful time frame.

Background Despite recent studies, the effect of chemotherapy on programmed death-ligand 1 (PD-L1) expression remains controversial. In this study, we investigated whether PD-L1 expression is affected by platinum-based chemotherapy. Furthermore, we evaluated correlation of PD-L1 expression with oncogenic driver alterations. Materials and Methods We retrospectively evaluated changes in PD-L1 expression by immunohistochemical (IHC) analysis in resected specimens and in biopsies at non–small cell lung cancer recurrence in patients receiving or not adjuvant chemotherapy after surgical resection. Four IHC score groups were defined: TC0 Results Thirty-six patients with adenocarcinoma were included. Twenty (56%) patients underwent adjuvant chemotherapy, and 16 (44%) patients did not receive adjuvant chemotherapy. PD-L1 expression was present in 10 (28%) of 36 initial tumor specimens. From patients receiving adjuvant chemotherapy, 7 (35%) of 20 tumor biopsies showed significant upregulation in PD-L1 expression at recurrence. In contrast, from patients with no adjuvant therapy, only 2 (12.5%) of 16 showed a change in PD-L1 expression. Six (17%) of 36 patients were PD-L1-negative in the primary tumor and turned positive at recurrence. KRAS mutation was present in 70% of patients expressing PD-L1. Conclusion PD-L1 expression in non–small cell lung cancer can change from primary to recurrence, implicating the need for re-biopsy at recurrence. Moreover, chemotherapy might increase expression of PD-L1, supporting a combinatorial therapy with chemotherapy and anti-PD(L)1 treatment.

Background The addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT → TMZ) did not prolong overall survival (OS) in patients with newly diagnosed glioblastoma in phase III trials. Elderly and frail patients are underrepresented in clinical trials, but early reports suggested preferential benefit in this population. Patients and methods ARTE was a 2 : 1 randomized, multi-center, open-label, non-comparative phase II trial of hypofractionated RT (40 Gy in 15 fractions) with bevacizumab (10 mg/kg×14 days) (arm A, N = 50) or without bevacizumab (arm B, N = 25) in patients with newly diagnosed glioblastoma aged ≥65 years. The primary objective was to obtain evidence for prolongation of median OS by the addition of bevacizumab to RT. Response was assessed by RANO criteria. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Exploratory studies included molecular subtyping by 450k whole methylome and gene expression analyses. Results Median PFS was longer in arm A than in arm B (7.6 and 4.8 months, P = 0.003), but OS was similar (12.1 and 12.2 months, P = 0.77). Clinical deterioration was delayed and more patients came off steroids in arm A. Prolonged PFS in arm A was confined to tumors with the receptor tyrosine kinase (RTK) I methylation subtype (HR 0.25, P = 0.014) and proneural gene expression (HR 0.29, P = 0.025). In a Cox model of OS controlling for established prognostic factors, associations with more favorable outcome were identified for age

Summary Background The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups. Methods In this multicentre, retrospective analysis, we investigated genome-wide DNA methylation patterns of meningiomas from ten European academic neuro-oncology centres to identify distinct methylation classes of meningiomas. The methylation classes were further characterised by DNA copy number analysis, mutational profiling, and RNA sequencing. Methylation classes were analysed for progression-free survival outcomes by the Kaplan-Meier method. The DNA methylation-based and WHO classification schema were compared using the Brier prediction score, analysed in an independent cohort with WHO grading, progression-free survival, and disease-specific survival data available, collected at the Medical University Vienna (Vienna, Austria), assessing methylation patterns with an alternative methylation chip. Findings We retrospectively collected 497 meningiomas along with 309 samples of other extra-axial skull tumours that might histologically mimic meningioma variants. Unsupervised clustering of DNA methylation data clearly segregated all meningiomas from other skull tumours. We generated genome-wide DNA methylation profiles from all 497 meningioma samples. DNA methylation profiling distinguished six distinct clinically relevant methylation classes associated with typical mutational, cytogenetic, and gene expression patterns. Compared with WHO grading, classification by individual and combined methylation classes more accurately identifies patients at high risk of disease progression in tumours with WHO grade I histology, and patients at lower risk of recurrence among WHO grade II tumours (p=0·0096) from the Brier prediction test). We validated this finding in our independent cohort of 140 patients with meningioma. Interpretation DNA methylation-based meningioma classification captures clinically more homogenous groups and has a higher power for predicting tumour recurrence and prognosis than the WHO classification. The approach presented here is potentially very useful for stratifying meningioma patients to observation-only or adjuvant treatment groups. We consider methylation-based tumour classification highly relevant for the future diagnosis and treatment of meningioma. Funding German Cancer Aid, Else Kroner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.

Amyloid myopathy associated with a plasma cell dyscrasia is a rare cause of muscle hypertrophy. It can be a challenging diagnosis, since pathological findings are often elusive. In addition, the mechanism by which immunoglobulin light-chain deposition stimulates muscle overgrowth remains poorly understood. We present a 53-year old female with a 10-year history of progressive generalized muscle overgrowth. Congo-red staining and immunohistochemistry revealed perivascular lambda light chain amyloid deposits, apparent only in a second muscle biopsy. The numbers of central nuclei and satellite cells were increased, suggesting enhanced muscle progenitor cell formation. Despite the chronicity of the light chain disease, the patient showed complete resolution of hematologic findings and significant improvement of her muscle symptoms following autologous bone marrow transplantation. This case highlights the importance of early diagnosis and therapy for this treatable cause of a chronic myopathy with muscle hypertrophy.

Menkes disease is a lethal infantile neurodegenerative disorder of copper metabolism caused by mutations in a P-type ATPase, ATP7A. Currently available treatment (daily subcutaneous copper injections) is not entirely effective in the majority of affected individuals. The mottled-brindled (mo-br) mouse recapitulates the Menkes phenotype, including abnormal copper transport to the brain owing to mutation in the murine homolog, Atp7a, and dies by 14 days of age. We documented that mo-br mice on C57BL/6 background were not rescued by peripheral copper administration, and used this model to evaluate brain-directed therapies. Neonatal mo-br mice received lateral ventricle injections of either adeno-associated virus serotype 5 (AAV5) harboring a reduced-size human ATP7A (rsATP7A) complementary DNA (cDNA), copper chloride, or both. AAV5-rsATP7A showed selective transduction of choroid plexus epithelia and AAV5-rsATP7A plus copper combination treatment rescued mo-br mice; 86% survived to weaning (21 days), median survival increased to 43 days, 37% lived beyond 100 days, and 22% survived to the study end point (300 days). This synergistic treatment effect correlated with increased brain copper levels, enhanced activity of dopamine-β-hydroxylase, a copper-dependent enzyme, and correction of brain pathology. Our findings provide the first definitive evidence that gene therapy may have clinical utility in the treatment of Menkes disease.

The epidemiological, prognostic, and therapeutic features of child and adolescent meningioma are poorly defined. Clinical knowledge has been drawn from small case series and extrapolation from adult studies. This study was done to pool and analyse the clinical evidence on child and adolescent meningioma.Searches of PubMed, Medline, and Embase identified 35 case series of child and adolescent meningioma completed over the past 21 years. Individual patient data were obtained from 30 studies via direct communication with investigators. Primary outcomes were relapse-free survival (RFS) and overall survival. Prognostic variables were extent of initial surgery, use of upfront radiotherapy, age, sex, presence of neurofibromatosis, tumour location, and tumour grade. RFS and overall survival were analysed using Kaplan-Meier survival curves and multivariable Cox regression models.From a total of 677 children and adolescents with meningioma, 518 were eligible for RFS analysis and 547 for overall survival analysis. Multivariable analysis showed that patients who underwent initial gross-total resection had better RFS (hazard ratio 0·16, 95% CI 0·10-0·25; p0·0001) and overall survival (0·21, 0·11-0·39; p0·0001) than those who had subtotal resection. No significant benefit was seen for upfront radiotherapy in terms of RFS (0·59, 0·30-1·16; p=0·128) or overall survival (1·10, 0·53-2·28; p=0·791). Patients with neurofibromatosis type 2 (NF2) had worse RFS than those without neurofibromatosis (2·36, 1·23-4·51; p=0·010). There was a significant change in overall survival with time between patients with NF2 compared with those without neurofibromatosis (1·45, 1·09-1·92; p=0·011); although overall survival was initially better for patients with NF2 than for those without neurofibromatosis, overall survival at 10 years was worse for patients with NF2. Patients with WHO grade III tumours had worse RFS than those with WHO grade I (3·90, 2·10-7·26; p0·0001) and grade II tumours (2·49, 1·11-5·56; p=0·027).Extent of initial surgical resection is the strongest independent prognostic factor for child and adolescent meningioma. No benefit for upfront radiotherapy was noted. Hence, aggressive surgical management, to achieve gross-total resection, is the initial treatment of choice. In the event of a subtotal resection, repeat resection is recommended to achieve maximum extirpation. Close observation is warranted for patients who have a subtotal resection or who have WHO grade III tumours. Patients without neurofibromatosis should have a minimum 10-year follow-up, whereas patients with NF2 should be considered a special risk category, necessitating life-long follow-up.None.

Mesenchymal chondrosarcoma, a rare malignant round cell and hyaline cartilage tumor, is most commonly intraosseous but can occur in extraskeletal sites. We intensively observed the morphology and applied Sox9 (master regulator of chondrogenesis), beta-catenin (involved in bone formation, thought to inhibit chondrogenesis in a Sox9-dependent manner), and osteocalcin (a marker for osteoblastic phenotype) to 22 central nervous system and musculoskeletal mesenchymal chondrosarcoma. Cases of mesenchymal chondrosarcoma were retrieved and reviewed from our files. Immunohistochemistry and follow-up were obtained on mesenchymal chondrosarcoma and tumor controls. Twenty-two mesenchymal chondrosarcomas included 5 central nervous system (all female; mean age, 30.2; mean size, 7.8 cm; in frontal lobe [n = 4] and spinal cord [n = 1]) and 17 musculoskeletal (female-male ratio, 11:6; mean age, 31.1; mean size, 6.2 cm; 3 each of humerus and vertebrae; 2 each of pelvis, rib, tibia, neck soft tissue; one each of femur, unspecified bone, and elbow soft tissue). The hyaline cartilage in most tumors revealed a consistent linear progression of chondrocyte morphology, from resting to proliferating to hypertrophic chondrocytes. Sixty-seven percent of cases demonstrated cell death and acquired osteoblastic phenotype, cells positive for osteocalcin at the site of endochondral ossification. Small round cells of mesenchymal chondrosarcoma were negative for osteocalcin. SOX9 was positive in both components of 21 of 22 cases of mesenchymal chondrosarcoma. beta-Catenin highlighted rare nuclei at the interface between round cells and hyaline cartilage in 35% cases. Control skull and central nervous system cases were compared, including chondrosarcomas and small cell osteosarcoma, the latter positive for osteocalcin in small cells. Mesenchymal chondrosarcoma demonstrates centrally located hyaline cartilage with a linear progression of chondrocytes from resting to proliferative to hypertrophic, which undergoes endochondral ossification, recapitulating growth plate cartilage and suggesting that this component of mesenchymal chondrosarcoma may be a differentiated (benign or metaplastic) component of a malignant metastasizing tumor. This hyaline cartilage component is morphologically different from cartilage of control chondrosarcoma. Mesenchymal chondrosarcoma can be separated from small cell osteosarcoma, using Sox 9 for cartilage and osteocalcin for osteoblastic phenotype. Rare nuclear beta-catenin expression at the interface between hyaline cartilage and small round cells potentially implicates the APC/Wnt pathway during endochondral ossification in morphologically benign hyaline cartilage component of mesenchymal chondrosarcoma.

Background Human herpesvirus-6 (HHV-6) has been associated with a diverse spectrum of central nervous system (CNS) diseases and reported glial tropism. Objective To determine if HHV-6 is present in a series of pediatric brain tumors. Study design Pediatric gliomas from 88 untreated patients represented in a tissue microarray (TMA) were screened for HHV-6 by nested polymerase chain reaction (PCR), in situ hybridization (ISH), and immunohistochemistry (IHC) and compared to non-glial tumors ( N = 22) and control brain ( N = 32). Results were correlated with tumor grade and overall survival. Results HHV-6 U57 was detected by nested PCR in 68/120 (57%) tumors and 7/32 (22%) age-matched non-tumor brain ( P = 0.001). HHV-6 U31 was positive in 73/120 (61%) tumors and 11/32 (34%) controls ( P = 0.019). Seventy-two percent (43/60) of tumors were HHV-6 Variant A. HHV-6 U57 was confirmed by ISH in 83/150 (54%) tumors and 10/32 (31%) controls ( P = 0.021), revealing a non-lymphocytic origin of HHV-6. HHV-6A/B gp116/64/54 late antigen was detected by IHC in 50/124 (40%) tumors and 6/32 (18%) controls ( P = 0.013). Interestingly, 58% of low grade gliomas ( N = 67) were IHC positive compared to 19% of high grade gliomas ( N = 21, P = 0.002) and 25% of non-gliomas ( N = 36, P = 0.001). HHV-6A/B gp116/64/54 antigen co-localized with glial fibrillary acidic protein, confirming the astrocytic origin of antigen. Overall, there was no primary association between HHV-6A/B gp116/64/54 antigen detection and survival ( P = 0.861). Conclusions We provide the first reported series of HHV-6 detection in pediatric brain tumors. The predominance of HHV-6 in glial tumors warrants further investigation into potential neurooncologic disease mechanisms.

The term “tethered cord” refers to any condition in which the spinal cord is rendered partly or completely immobile within the spinal canal. As a clinicopathologic entity, tethered cord generally involves an abnormally low and relatively fixed conus medullaris, often arising in a distal spinal cord and/or vertebral malformation. This article reviews the essentials of etiology, pathogenesis, and neuropathology of tethered cord.

We describe a case of anaplastic astrocytoma in a 14-year-old boy arising at the site of a dysembryoplastic neuroepithelial tumor (DNT) 3 years after combined radiation and chemotherapy. The subtotally excised superficial right temporoparietal tumor was originally diagnosed as mixed oligoastrocytoma in 1974; the patient was treated with radiation therapy postoperatively. One year later he underwent a craniotomy to remove cyst fluid and no change was reported in the size of the residual tumor. Postoperatively, he received a 6-week course of chemotherapy (lovustine, CCNU). He remained clinically and radiographically stable until 3 years later, when seizure activity returned and imaging studies were consistent with tumor recurrence. He was lost to follow-up until 1986, when records showed that he had died. Review of the initial biopsy showed cortical fragments containing abundant calcifications and multinodular structures typical of the complex form of DNT, in addition to specific glioneuronal elements. The Ki-67 labeling index ranged from 0.1% to 3% focally. The specimen from the third surgery showed an anaplastic astrocytoma (Ki-67 up to 12%) and morphologic features characteristic of radiation effect. This is the first documented case of malignant transformation of DNT following radiation and adjuvant chemotherapy. The implications of malignant transformation in subtotally excised complex DNTs and the intriguing issue of the contribution of radiation/chemotherapy are discussed.

Solitary fibrous tumor is a spindle cell tumor first described in the pleura, but also found in multiple extrathoracic sites including the meninges, orbit, nasal and paranasal sinuses. No cases have been previously reported in the cavernous sinus or pituitary fossa. We present the case of a 54-year-old woman who presented with progressive amaurosis. On imaging studies, a widely infiltrative lesion involving the pituitary fossa, sphenoid sinus, cavernous sinus, carotid artery, medial temporal, ethmoid, and pterygoid bones, and extending into the nasopharynx was discovered; impression was a malignant tumor originating in the pituitary fossa. At surgery, the tumor was only partially resectable because of extensive bony invasion and encasement of the carotid artery, and was found to compress but not invade the pituitary gland. Histology showed a spindle cell proliferation with a dense, hyalinized collagenous stroma and dilated vascular spaces, some showing a staghorn-like appearance. Areas of cellular pleomorphism and increased cellularity were present, but few mitoses were identified. Immunohistochemistry showed strong positivity with CD34, factor XIIIa, CD99, and Bcl-2. There was scattered cyclin D1, mib-1, and p53 positivity. Muscle, epithelial, vascular, and melanocytic markers were negative. These results led to the diagnosis of solitary fibrous tumor. The size, extensive invasion, and bony destruction indicated a tumor with at least low malignant potential. The occurrence of solitary fibrous tumors in the pituitary fossa and sinuses of the head and neck is rare, but must be considered in the differential diagnosis of spindle cell lesions in these regions.

Background Craniopharyngiomas are slow-growing, locally invasive intracranial tumors that can generate considerable morbidity, and recurrences are often difficult to manage. Because reliable morphologic criteria for accurately predicting the clinical outcome of these tumors are lacking, we evaluated the growth potential of craniopharyngiomas by measuring their proliferative activity based on MIB-1 immunostaining for the Ki-67 antigen, which is expressed during all phases of the cell cycle except G 0. Methods Paraffin sections from 37 cases of craniopharyngiomas were immunostained with the monoclonal antibody MIB-1, and a labeling index was derived in each case from an the with the highest labeling. Results MIB-1 immunoreactivity was mainly confined to the peripheral palisaded epithelium of craniopharyngiomas. In adult craniopharyngiomas, MIB-1 labeling indices (MIB-LI) varied from 0.1% to 34.6% (mean 8.9%; SD 9.8), and in pediatric tumors the indices ranged from 1.8% to 15.0% (mean 6.3%; SD 3.7). MIB-LI was not found to be an independent predictor of recurrence, although in all the pediatric cases that recurred, MIB-LI in the second specimen was greater. Conclusions The actively proliferating compartment in craniopharyngiomas seems to be the peripheral palisaded epithelium. Low MIB-LI observed in the majority of tumors is in concordance with the slow growth and low-grade invasiveness associated with craniopharyngiomas. However, unlike other intracranial neoplasms, where Ki-67 labeling indices have been useful in predicting tumor behavior, a clear relationship could not be demonstrated between MIB-1 immunoreactivity, morphological features and clinical outcomes in adults or children with craniopharyngiomas.

Background Traumatic intracranial aneurysms (TICAs) may develop following gunshot injuries to the head. Management of these lesions often combines various aspects of microneurosurgical and endovascular techniques to safely repair or obliterate vessel defects. Methods We reviewed our experience over the last 18 years and identified five cases of intracranial aneurysms following gunshot and handgun wounds that were treated surgically and/or endovascularly. Results All patients had successful obliteration of their lesions using a variety of therapeutic modalities aimed at preserving neurologic function while at the same time eliminating the aneurysm from the circulation. Conclusion Both microneurosurgery and endovascular surgery have important roles to play in the management of TICAs. In some cases, both methods can be combined to eliminate lesions and maximize patient recovery in a safe, efficient, and effective fashion.

We studied 35 parenchymal neoplasms arising in the pineal gland, including 11 pineoblastomas, 21 pineocytomas, and three mixed pineocytoma-pineoblastomas. Pineoblastomas were most commonly found in children (mean age, 12.6 years). The median postsurgical length of survival for seven patients, including five with remote metastases, with fatal outcome was 24 months. The 21 pineocytomas were found in older individuals (mean age, 26.8 years). Four patients with pineocytoma died; two before surgery and two in the immediate postoperative period. The remaining 17 patients survived for intervals between 6 and 118 months after surgery. Two mixed pineocytoma-pineoblastomas were found in infants who died a few months after biopsy, whereas a third patient, an adult, was alive at 46 months after excision and irradiation. Both pineoblastoma and pineocytoma exhibited variable immunoreactivity to neurofilament proteins, synaptophysin, glial fibrillary acidic protein, S-100 protein, retinal-S antigen, and rhodopsin; the highest percentages of positive cells stained with synaptophysin. Three pineocytomas exhibited ganglionic differentiation and two of them also showed a glial component. Prognosis could not be correlated with the degree of divergent differentiation. Comparison of silver-stained nucleolar organizer region (AgNOR) counts between pineoblastomas and pineocytomas suggests that the former are more actively proliferative than the latter, with mixed pineocytoma-pineoblastoma showing intermediate activity. There was no correlation between AgNOR score and prognosis within the three tumor groups.

Clinic for Neurology, University Medical Centre Gottingen, Gottingen, Germany; Department of Neuroimmunology, University Medical Centre Gottingen, Gottingen, Germany; Department of Trauma Surgery, University Medical Centre Gottingen, Gottingen, Germany; Department of Neuropathology, University Medical Centre Gottingen, Gottingen, Germany; Friedrich-Baur-Institute, University of Munchen, Munchen, Germany; Department of Neurology, University of Halle, Halle, Germany; Neuroimmunology Unit, Dept. of Pathophysiology, University of Athens Medical School, Athens, Greece; Department of Rheumatology and Clinical Immunology, University Medical Centre Freiburg, Freiburg, Germany

Autoimmune necrotizing myopathies (ANM) represent a well-recognized entity among the so-called idiopathic inflammatory myopathies (IIMs), which also comprise dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (sIBM) and non-specific myositis. The diagnosis of these IIMs is established on the basis of specific clinical symptoms, results derived from muscle biopsy and ancillary data, such as creatine kinase (CK) levels, electromyography (EMG) and modern imaging techniques. Myositis-associated and myositis-specific autoantibodies play an important role and may prove to be clues for understanding details of the pathogenesis of these conditions, which to date remain largely unknown. ANMs probably represent a heterogeneous group of diseases all of which are characterized by the striking presence of necrotic fibres on muscle biopsy. However, additional morphological features as well as certain autoantibodies (e.g. SRP or HMGCR auto-antibodies) may be helpful to define subgroups of ANM. Subclassification of ANMs and definition of specific syndromes with precise and characteristic immunological features is a subject of intense research, especially since clinical trials with anti-inflammatory agents or so called ’biologicals’ should follow universally defined and accepted criteria. We present molecular and morphological data of subgroups within the spectrum of autoimmune necrotizing myopathies.