IgG4- related disease: an orphan disease with many faces

Immunoglobulin G4- related disease (IgG4-RD) is a rare systemic fibro-inflammatory disorder (ORPHA284264). Although patients have been described more than 100 years ago, the systemic nature of this disease has been recognized in the 21(st) century only. Type 1 autoimmune pancreatitis is the most frequent manifestation of IgG4-RD. However, IgG4-RD can affect any organ such as salivary glands, orbits, retroperitoneum and many others. Recent research enabled a clear clinical and histopathological description of IgG4-RD. Typically, lymphoplasmacellular inflammation, storiform fibrosis and obliterative phlebitis are found in IgG4-RD biopsies and the tissue invading plasma cells largely produce IgG4. Elevated serum IgG4 levels are found in many but not all patients. Consequently, diagnostic criteria for IgG4-RD have been proposed recently. Treatment is largely based on clinical experience and retrospective case series. Glucocorticoids are the mainstay of therapy, although adjunctive immunosuppressive agents are used in relapsing patients. This review summarizes current knowledge on clinical manifestations, pathophysiology and treatment of IgG4-RD

Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma

Background Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types. Methods We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas. Results Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident. Conclusion TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastom

Evaluation of the Temporal Muscle Thickness as an Independent Prognostic Biomarker in Patients with Primary Central Nervous System Lymphoma.

In this study, we assessed the prognostic relevance of temporal muscle thickness (TMT), likely reflecting patient's frailty, in patients with primary central nervous system lymphoma (PCNSL). In 128 newly diagnosed PCNSL patients TMT was analyzed on cranial magnetic resonance images. Predefined sex-specific TMT cutoff values were used to categorize the patient cohort. Survival analyses, using a log-rank test as well as Cox models adjusted for further prognostic parameters, were performed. The risk of death was significantly increased for PCNSL patients with reduced muscle thickness (hazard ratio of 3.189, 95% CI: 2-097-4.848, p < 0.001). Importantly, the results confirmed that TMT could be used as an independent prognostic marker upon multivariate Cox modeling (hazard ratio of 2.504, 95% CI: 1.608-3.911, p < 0.001) adjusting for sex, age at time of diagnosis, deep brain involvement of the PCNSL lesions, Eastern Cooperative Oncology Group (ECOG) performance status, and methotrexate-based chemotherapy. A TMT value below the sex-related cutoff value at the time of diagnosis is an independent adverse marker in patients with PCNSL. Thus, our results suggest the systematic inclusion of TMT in further translational and clinical studies designed to help validate its role as a prognostic biomarker

Brain tumour epidemiology in Austria and the Austrian brain tumour registry

Krebsregister erheben Inzidenz- und Mortalitätsdaten zu Krebserkrankungen, die in einer definierten Population (populations-basiert) auftreten. Die Erfassung beschränkt sich meist auf die Gruppe der malignen Neoplasien, während gutartige oder intermediäre Neubildungen nicht regelmäßig erfasst werden. Hirntumore unterscheiden sich von anderen Krebserkrankungen durch 1., ihr außerordentlich großes Spektrum an verschiedenen Tumorentitäten und 2., ihre Lokalisation im Zentralen Nervensystem in Nähe zu eloquenten Arealen und der damit verbundenen neurologischen Komorbidität und Mortalität, unabhängig von ihrem intrinsischen biologischen Verhalten. Um ein komplettes Bild zum tatsächlichen Krankheitsaufkommen zu erhalten, sind in mehreren Ländern spezialisierte Hirntumorregister entstanden, die epidemiologische Daten zu allen Hirntumor-Typen zur Verfügung stellen. Innerhalb dieser Arbeit fassen wir die Erfahrungen mit der Gründung eines derartigen Registers in Österreich zusammen - das Österreichische Hirntumorregister (ABTR). Wir beschreiben die ersten Schritte - von der Zustimmung und Konsensfindung innerhalb der Österreichischen Gesellschaft für Neuropathologie, der Bildung eines interdisziplinären Expertengremiums, der Infrastrukturentwicklung einschließlich Datenschutz-rechtlich relevanter Fragestellungen, bis hin zur kontinuierlichen Unterstützung durch die nationale Neuroonkologie-Gemeinschaft und der Zusammenarbeit mit dem Österreichischen Nationalen Krebsregister. Einer der wesentlichen Punkte, in denen sich ABTR von anderen Registern seiner Art unterscheidet, ist sein wissenschaftliches, neuropathologisch geprägtes Umfeld, das diagnostische Expertise und Erfahrung mit gewebsbasierten Untersuchungen einbringt. Auf diese Art wird ABTR auch zu einer populations-basierten, virtuellen Hirntumor-Biobank. Nachdem die Grundvoraussetzungen geschaffen worden sind, zeigen wir weiter, dass ABTR qualitativ hochwertige populations-basierte Daten generiert, die erstmals umfassende Analysen zum Auftreten und Überleben von Hirntumorpatienten in Österreich zulassen. Die ersten wissenschaftlichen Beiträge von ABTR adressieren unterschiedliche neuroepidemiologische Fragestellungen von nationaler und internationaler Bedeutung. Wir erheben erstmals exakte Inzidenzdaten zu seltenen Tumortypen, präzisieren diagnostische Kriterien von neu vorgeschlagenen Tumorentitäten, schlagen einheitliche Standards zur molekulargenetischen Testung von Biomarkern vor, und zeigen durch populations-basierte Überlebensanalysen den medizinischen Fortschritt im Zeitverlauf auf. Die unterschiedlichen wissenschaftlichen Beiträge illustrieren das enorme wissenschaftliche Potential von ABTR für weiterführende künftige wissenschaftliche Tätigkeit.Cancer registries provide incidence and mortality data on patients with cancer at the population-level. Cancer registration is most often restricted to the group of malignant neoplasms, whereas information on benign and intermediate tumours is generally not available. Brain tumours however differ from other sites by 1., the large spectrum of different tumour types, and 2., the exclusive localisation in proximity to eloquent areas with considerable neurological comorbidity and mortality irrespective of their biological behaviour. In order to obtain a comprehensive overview of the brain tumour burden specialised brain tumour registries, which provide information on all brain tumours types, have emerged in several countries. Within the frame of this thesis we summarise the Austrian experience on the establishment of such a specialised brain tumour registry - the Austrian Brain Tumour Registry (ABTR). We report on its initial steps - from consensus and commitment of the Austrian Society of Neuropathology, formation of an interdisciplinary team of experts, setup of the infrastructure including data confidentiality issues, to the sustained support of the Austrian neurooncology community and major cooperation with the Austrian National Cancer Registry. ABTR differs from other registries by its scientific setting and neuropathological background warranting strong expertise in brain tumour typing and tissue-based research. Thereby, ABTR constitutes also a virtual brain tumor biobank. By having achieved these steps we further demonstrate that ABTR provides valid and accurate population-based incidence and survival data for individual brain tumour types. First scientific contributions by ABTR address various neuroepidemiological issues of national and international relevance. We first estimate the exact incidence of rare tumour entities, refine key diagnostic criteria of newly proposed tumour entities, advocate common standards for testing of molecular markers, and assess medical progress via real-life outcome analyses. The diverse scientific contributions highlight the enormous scientific potential of ABTR for continued work.submitted by Adelheid WöhrerAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassung in dt. SpracheWien, Med. Univ., Diss., 2012OeBB(VLID)171509

MGMT assessment in pituitary adenomas : comparison of different immunohistochemistry fixation chemicals

Purpose Despite the established role of O6-methyl-guanine-DNA methyltransferase (MGMT) as a marker for temozolomide response, consensus of the most reliable method to assess MGMT expression in pituitary adenomas is still missing. Currently, immunohistochemistry (IHC) assessment of formaldehyde fixed tissue samples is most widely used in a semiquantitative description. As formaldehyde fails to completely preserve nucleic acids, RCL2, an alcohol-based formaldehyde-free fixative, has been proposed as a more reliable alternative in terms of cell stability. Furthermore, as the current method of IHC is semiquantitative and observer-dependent, pyrosequencing, an objective tool to evaluate the methylation status of the MGMT promoter, has emerged as a reliable and accurate alternative. The aim of this study was to validate the current IHC method for assessment of MGMT protein expression in pituitary adenomas. Methods The tissue samples of 8 macroadenomas with positive IHC MGMT expression (>50%) were investigated: first, we compared the time dependent stability of MGMT protein expression after pituitary adenoma removal between formaldehyde vs. RCL2. Then, we compared positive IHC MGMT expression with methylated promoter status using pyrosequencing. Results In the first 12 h after adenoma removal, tissue samples remained MGMT positive in significantly more samples when fixated with formaldehyde than with RCL2, respectively (96 vs. 81%, p=0.025). Conclusion Our data confirm that the current method using formaldehyde tissue fixation and IHC reveals stable and reliable results of MGMT assessment in pituitary adenomas.(VLID)358034

SRPX Emerges as a Potential Tumor Marker in the Extracellular Vesicles of Glioblastoma

Extracellular vesicles (EVs) may be used as a non-invasive screening platform to discover markers associated with early diagnosis, prognosis, and treatment response. Such an approach is invaluable for diseases such as glioblastoma, for which only a few non-invasive diagnostic or prognostic markers are available. We used mass spectrometry to analyze proteomics profiles of EVs derived from four glioblastoma cell lines and human primary astrocytes (HPAs) and found that SRPX is the only protein enriched in the majority of glioblastoma EVs that was absent in the HPA-derived EVs. Then, we evaluated the relationship between SRPX protein expression and tumor grade using immunohistochemical staining (IHC) and performed colony formation and viability assays to analyze the possible function of SRPX in glioblastoma. SRPX mRNA and protein expression were associated with tumor grade. Moreover, temozolomide (TMZ)-resistant tumor tissues showed highly positive SRPX staining, compared to all other tumor grades. Additionally, glioblastoma cells displayed enhanced SRPX gene expression when exposed to TMZ. Knockdown of SRPX gene expression via siRNA inhibited cell viability. Taken together, the results of this study suggest that SRPX can be used as a novel tumor marker for diagnostic and prognostic purposes and can also be a therapeutic target for glioblastomas

AN EXPERIMENTAL STUDY ON REGISTRATION THREE-DIMENSIONAL RANGE IMAGES USING RANGE AND INTENSITY DATA

Laser scanner is noncontact instrument to measurement of spatial data. It measures object surfaces as point series and visualize as point cloud. One of the important steps on processes of laser scanning data is the registration of point clouds relation to common coordinate system. Many interactive and automatic methods have been developed for point cloud registration so far. The automatic methods are applied with range data of laser scanner or image data of sensor combination camera. The registration by range data is mostly depend object geometry. If scan surface is deprived from geometrical details, conjugate points can not be found to compute registration parameters between point clouds. In that case, intensity data of laser points can be used for registration. In this study, intensity image was created from laser scanner data and the registration parameters were computed with keypoints extracted by SIFT method from these images. The results were also compared with the iterative closest point (ICP) method.

Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series

Neurodegenerative diseases are characterised by neuronal loss and cerebral deposition of proteins with altered physicochemical properties. The major proteins are amyloid-β (Aβ), tau, α-synuclein, and TDP-43. Although neuropathological studies on elderly individuals have emphasised the importance of mixed pathologies, there have been few observations on the full spectrum of proteinopathies in the ageing brain. During a community-based study we performed comprehensive mapping of neurodegeneration-related proteins and vascular pathology in the brains of 233 individuals (age at death 77-87; 73 examined clinically in detail). While all brains (from individuals with and without dementia) showed some degree of neurofibrillary degeneration, Aβ deposits were observed only in 160 (68.7 %). Further pathologies included α-synucleinopathies (24.9 %), non-Alzheimer tauopathies (23.2 %; including novel forms), TDP-43 proteinopathy (13.3 %), vascular lesions (48.9 %), and others (15.1 %; inflammation, metabolic encephalopathy, and tumours). TDP-43 proteinopathy correlated with hippocampal sclerosis (p < 0.001) and Alzheimer-related pathology (CERAD score and Braak and Braak stages, p = 0.001). The presence of one specific variable (cerebral amyloid angiopathy, Aβ parenchymal deposits, TDP-43 proteinopathy, α-synucleinopathy, vascular lesions, non-Alzheimer type tauopathy) did not increase the probability of the co-occurrence of others (p = 0.24). The number of observed pathologies correlated with AD-neuropathologic change (p < 0.0001). In addition to AD-neuropathologic change, tauopathies associated well with dementia, while TDP-43 pathology and α-synucleinopathy showed strong effects but lost significance when evaluated together with AD-neuropathologic change. Non-AD neurodegenerative pathologies and their combinations have been underestimated, but are frequent in reality as demonstrated here. This should be considered in diagnostic evaluation of biomarkers, and for better clinical stratification of patients

Noninvasive Differentiation of Meningiomas and Dural Metastases Using Intratumoral Vascularity Obtained by Arterial Spin Labeling.

PURPOSE: Using conventional magnetic resonance imaging (MRI) techniques, the imaging features of meningiomas and dural metastases overlap and a differentiation between these tumor entities therefore remains difficult, particularly in patients with a known primary neoplasm. The purpose of this study was to explore the potential role of normalized vascular intratumoral signal intensity values (nVITS) obtained from pulsed arterial spin labeling (PASL) to differentiate between meningiomas and dural metastases. METHODS: In this study PASL was performed in 46 patients with meningiomas (n = 30) and dural metastases (n = 16) on a 3T scanner, in addition to the routine diagnostic imaging protocol. The ratio between the vascular signal intensity of the tumor and the contralateral normal white matter obtained by PASL images was defined as nVITS. RESULTS: Meningiomas showed significantly higher nVITS values compared to dural metastases (p < 0.001). The optimal nVITS cut-off value to differentiate between the 2 tumor entities was 1.989, with 100% sensitivity and 81.2% specificity. CONCLUSION: The nVITS values obtained by PASL provide a fast and noninvasive MRI technique with which to differentiate between meningiomas and dural metastases in a routine clinical setting based on tumor vascularity