Search

Objective Pain depicts a severe physical symptom but its relationship to mental health problems is not well studied in cancer patients. The aim of this study was to investigate the prevalence of pain and its correlation with symptoms of post-traumatic stress disorder (PTSD), depression, anxiety, and psychological distress in a large sample of cancer patients. Methods From 2010 to 2019, cancer patients who received outpatient treatment at the Medical University of Vienna, were assessed with the Post-Traumatic Symptom Scale (PTSS-10) and the Hospital Anxiety and Depression Scales (HADS). A visual analogue scale was used to assess pain perception. For statistical analysis, linear regression models were applied to log-transformed data. Results Of the 846 cancer patients included in the study, 63.5% experienced pain (mild 43.5%, moderate 13.6%, severe 6.4%). About a third (31,2%) of the total sample presented with significant PTSD symptoms. Significant symptoms of depression, anxiety, and distress were present in 13.9%, 15.1%, and 25.3%, respectively. Women more often reported symptoms of PTSD, anxiety, and distress. Pain scores were significantly related to symptoms of PTSD, depression and psychological distress (all with p Conclusions Results show a high prevalence of experienced pain and indicate a clear association of elevated pain levels with psychiatric symptoms in oncological patients in a large Austrian sample. In order to decrease experienced pain and to enable better treatment of mental health problems in cancer patients, diagnostic procedures and interventions based on a biopsychosocial model need to be intensified. This article is protected by copyright. All rights reserved.

Background Brain metastases (BM) are a frequent complication of advanced cancer and are characterized by a variety of neurological symptoms. Although the presence of neurological symptoms is included in the response assessment in patients with primary brain tumors, to the authors' knowledge little is known regarding the prognostic impact of neurological symptoms in patients with BM. Methods Patients with newly diagnosed BM from non–small cell lung cancer were identified from the Vienna Brain Metastasis Registry and were evaluated according to the incidence, distribution, and prognostic impact of neurological symptoms at the time of diagnosis of BM. Results A total of 1608 patients (57.3% male and 42.7% female; median age, 62 years) were available for further analyses. Neurological symptoms including focal deficits (985 patients; 61.3%), signs of increased intracranial pressure (483 patients; 30.0%), epileptic seizures (224 patients; 13.9%), and neuropsychological symptoms (233 patients; 14.5%) were documented in 1186 of the 1608 patients (73.8%). Patients with asymptomatic BM presented with a longer median overall survival after the diagnosis of BM compared with patients with symptomatic BM (11 months vs 7 months; P, Neurological symptoms at the time of diagnosis of brain metastases demonstrate a strong, independent prognostic impact on prognosis. The current study highlights the integration of neurological symptom burden into the prognostic assessment of patients with brain metastases from non–small cell lung cancer.

Background We investigated the influence of population‐wide COVID‐19 lockdown measures implemented on 16, March 2020 on routine and emergency care of cancer outpatients at a tertiary care cancer centre in Vienna, Austria. Methods We compared the number/visits of cancer outpatients receiving oncological therapies at the oncologic day clinic (DC) and admissions at the emergency department (ED) of our institution in time periods before (pre‐lockdown period: 1 January – 15 March 2020) and after (post‐lockdown period: 16 March– 31 May 2020) lockdown implementation with the respective reference periods of 2018 and 2019. Additionally, we analysed Emergency Severity Index (ESI) score of unplanned cancer patient presentations to the ED in the same post‐lockdown time periods. Patient outcome was described as 3‐month mortality rate (3‐MM). Results In total, 16 703 visits at the DC and 2664 patient visits for the respective time periods were recorded at the ED. No decrease in patient visits was observed at the DC after lockdown implementation (P = .351), whereas a substantial decrease in patient visits at the ED was seen (P

Objective Post‐traumatic stress disorder (PTSD) is a severe psychiatric disorder, which might develop after a traumatic event, like cancer diagnosis, and threatens the patient's psychological and/or physiological integrity. Anxiety, depression, and mental distress are known to be common in cancer patients; however, the frequency of PTSD was not investigated thoroughly in this patient group so far. Here, we aim to screen cancer patients for PTSD symptoms and determine a possible correlation with anxiety, depression, and distress. Methods The study was performed at the Divisions of Hematology and Oncology of the Medical University of Vienna from 2010 to 2018. Following written consent, patients were asked to fill out the validated self‐assessment questionnaire for PTSS‐10 and HADS. The study was approved by the institutional ethics committee of the Medical University of Vienna (EC Nr: 2255/2016). Results A total of 1017 adult cancer patients (513 male, 504 female) were included in a cross‐sectional single‐center study. Mean age was 57.6 years (SD 14.4 years); 31.7%, 14.6%, 13.2%, and 27.4% of patients outscored the predefined thresholds for self‐assessed cases of PTSD, anxiety, depression, and distress, respectively. Compared with men, women showed a higher prevalence of symptoms for PTSD (38.9% vs 24.5%; P

Aims Expression profiles and clinical impact of programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) expressing tumour infiltrating lymphocytes (TILs) in head and neck squamous cell carcinoma (HNSCC) are not elucidated fully. This study evaluates expression patterns in primary HNSCC and related lymph node metastasis and the impact on patients' clinical outcome. Methods and results Immunohistochemical staining patterns of PD-L1 and PD-1 were evaluated in 129 specimens of primary HNSCC and 77 lymph node metastases. Results were correlated with patients' clinical data. PD-L1 expression was observed in 36% of primary carcinoma and 33% of lymph node metastasis, and correlates significantly with decreased overall survival (OS) (P = 0.01) and disease-free survival (DFS) (P = 0.001) in oral cavity squamous cell carcinoma patients. PD-L1 expression was associated with presence of lymph node metastasis (P = 0.0223). Infiltration of PD-1-expressing lymphocytes correlates significantly with favourable OS (P = 0.001) and DFS (P = 0.001) in oropharyngeal cancer and hypopharyngeal cancer patients OS (P = 0.007) and DFS (P = 0.001). Presence of PD-1 TILs also correlates significantly with better OS (P = 0.005) and DFS (P = 0) in the human papilloma virus (HPV)-negative cohort. Cox regression multivariate analysis revealed PD-1 TIL expression as an independent prognostic marker for OS (P = 0.004) and DFS (P = 0.001) and T stage was validated as negative prognostic marker for OS (P = 0.011). PD-1-expressing lymphocytes (P = 0.0412) and PD-L1 expression (P = 0.0022) patterns correlate significantly in primary cancers and matched lymph node metastases. Conclusions Our results characterise the expression profiles of PD-1 axis proteins in HNSCC which might serve as possible clinical prognostic markers.

Aim We aimed to characterize angiogenesis and proliferation and their correlation with clinical characteristics in a large brain metastasis (BM) series. Methods Ki67 proliferation index, microvascular density (MVD) and hypoxia-inducible factor 1 alpha (HIF-1 alpha) index were determined by immunohistochemistry in BM and primary tumour specimens. Results Six hundred thirty-nine BM specimens of 639 patients with lung cancer (344/639; 53.8%), breast cancer (105/639; 16.4%), melanoma (67/639; 10.5%), renal cell carcinoma (RCC; 52/639; 8.1%) or colorectal cancer (CRC; 71/639; 11.1%) were available. Specimens of the corresponding primary tumour were available in 113/639 (17.7%) cases. Median Ki67 index was highest in CRC BM and lowest in RCC BM (P

In this study we aimed to characterize immune infiltrates and expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) in a series of melanoma BM to provide a basis for experimental therapy using immune checkpoint inhibitors.We investigated expression of PD-1, PD-L1, CD3, CD8, CD45RO, forkhead box protein 3 (FoxP3), CD20 and BRAF V600E by immunohistochemistry in melanoma BM samples. Forty-three specimens [27 of which (62.8%) were BRAF V600E-positive] were available. CD3(+) tumour-infiltrating lymphocytes (TILs) were evident in 33 specimens (76.7%), CD8(+) in 39 (90.7%), CD45RO(+) in 32 (74.4%), PD-1(+) in 27 (62.8%), FoxP3(+) in 21 (48.8%) and CD20(+) TILs in 19 (44.2%). Tumour PD-L1 expression was observed in 22 specimens (51.1%), and in nine of these (40.9%) expression was observed in more than 5% of tumour cells. PD-L1 expression was associated with higher density of PD-1(+) (P0.001), CD3(+) (P = 0.014) and FoxP3(+) (P0.001) TIL infiltration. Density of CD3(+) TILs was associated with density of CD8(+) (P0.001), PD-1(+) (P0.001) and CD45RO(+) (P0.001) TILs. PD-L1 expression or PD-1(+) , CD3(+) , CD8(+) or CD45RO(+) TILs density did not correlate with BRAF V600E status, previous systemic therapy or survival (P0.05).Melanoma BM showed considerable lymphocytic infiltrates and expression of PD-L1 in the majority of investigated specimens, with high PD-L1 expression found predominantly in regions of abundant inflammation. Our data indicate that clinical studies should investigate the value of checkpoint inhibitors in patients with melanoma BMs.

Background CMET represents an emerging therapy target for monoclonal antibodies and tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). Methods We investigated CMET gene amplification status by fluorescence in-situ hybridization (FISH) and CMET protein expression by immunohistochemistry in a large series of 209 NSCLC brain metastases (BM; 165 adenocarcinoma, 20 squamous cell carcinoma, 11 adenosquamous carcinomas, 11 large cell carcinomas and two large cell neuroendocrine carcinomas) and correlated our results to clinic-pathological parameters and molecular data from previous studies. Results We found CMET gene amplification in 36/167 (21.6%) and CMET protein expression in 87/196 (44.4%) of evaluable BM. There was a strong correlation between the presence of CMET gene amplification and CMET protein expression (P

Anaplastic lymphoma kinase (ALK) gene aberrations are found in several tumor types including anaplastic large cell lymphoma (ALCL) and non-small cell lung cancer (NSCLC). Crizotinib, an inhibitor of ALK-fusion proteins, has shown clinical activity, but resistance mechanisms limit long-lasting disease control. It has been shown that ALK-NPM fusion upregulates platelet-derived growth factor receptor beta (PDGFRB) via JUN and transcription factor Jun B (JUNB) in ALCL. PDGFRB inhibition has been identified as therapy option for ALK-positive ALCL. Here, we investigated the ALK/JUN/JUNB/transcription factor Jun C (JUNC)/PDGFR axis in metastatic NSCLC with regard to ALK aberrations. We performed immunohistochemical analysis of platelet-derived growth factor receptor alpha (PDGFRA), PDGFRB, JUNB and JUNC expression in formalin-fixed, paraffin-embedded specimens of 15 NSCLC brain metastases (5 ALK translocations, 3 of them involving EML4, 5 ALK amplifications, 5 without ALK aberrations). We did not find a statistically significant difference in expression of PDGFRA, PDGFRB, JUNB or JUNC in tumor samples with normal ALK status, ALK amplification or ALK translocations (Kruskal-Wallis test p > 0.05). Interestingly, PDGFRB was not expressed in tumor cells (but in vascular and stromal cells) in any of our cases. Our data argue against PDGFRB activation in association with ALK gene aberrations in metastatic NSCLC and thus seem to imply differential pathobiological roles of ALK alterations in lung cancer and lymphoma, possibly depending on different fusion partner genes. These results may be relevant for targeted therapies, as they indicate that inhibition of PDGFRB in ALK translocated NSCLC seems to be no therapeutic opportunity.

BRAF V600E mutation and homozygous deletion of CDKN2A (p16) are frequent molecular alterations in pleomorphic xanthoastrocytomas (PXAs). We investigated 49 PXAs for clinical, histological and immunohistochemical characteristics related to BRAF mutation status. BRAF mutation was detected by immunohistochemical assay and DNA sequencing in 38/49 (78%) tumors. All but one PXA located in the temporal lobe harbored a BRAF V600E mutation (23/24; 96%) compared with 10/19 nontemporal PXAs (53%; P = 0.0009). Histological and immunohistochemical analysis demonstrated increased reticulin deposition (76% vs. 27%; P = 0.003) and a more frequent expression of CD34 in BRAF-mutant PXAs (76% vs. 27%; P = 0.003). We further investigated the utility of combined BRAF V600E (VE1) and p16 analysis by immunohistochemistry to distinguish PXAs from relevant histological mimics like giant-cell glioblastoma. Among PXAs, 38/49 (78%) were VE1-positive, and 30/49 (61%) had a loss of p16 expression. The combined features (VE1 positivity/p16 loss) were observed in 25/49 PXAs (51%) but were not observed in giant-cell glioblastoma (VE1 0/28, p16 loss 14/28). We demonstrate that temporal location, reticulin deposition and CD34 expression are associated with BRAF mutation in PXA. Combined VE1 positivity and p16 loss represents a frequent immunoprofile of PXA and may therefore constitute an additional diagnostic tool for its differential diagnosis.

BACKGROUND: Meningiomas are common intracranial tumors arising from the meninges and usually are benign. However, a few meningiomas have aggressive behavior and, for such patients, effective treatment options are needed. Trabectedin is a novel, marine-derived, antineoplastic agent that has been approved and is used routinely as therapy for advanced soft tissue sarcoma and ovarian cancer. METHODS: The authors investigated the in vitro effects of trabectedin alone and in combination with hydroxyurea, cisplatin, and doxorubicin in primary cell cultures of benign (n = 9), atypical (n = 6), and anaplastic (n = 4) meningiomas using chemosensitivity assays (3-[4,5dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide [MTT]), Western blot analysis, cell cycle analysis, and immunofluorescent staining. RESULTS: Strong antimeningioma activity of trabectedin was observed and was characterized by distinct cell cycle arrest, down-regulation of multiple cyclins, deregulated expression of cell death-regulatory genes, and massive apoptosis induction. Cytotoxic activity was especially intense in higher grade meningiomas with a half-maximal inhibitory concentration

Preusser M, Hoeftberger R, Woehrer A, Gelpi E, Kouwenhoven M, Kros J M, Sanson M, Idbaih A, Brandes A A, Heinzl H, Gorlia T, Hainfellner J A & van den Bent M (2012) Histopathology 60, 885–894 Prognostic value of Ki67 index in anaplastic oligodendroglial tumours – a translational study of the European Organization for Research and Treatment of Cancer Brain Tumor Group Aims: To evaluate the prognostic value and clinical utility of Ki67 tumour cell proliferation index in anaplastic oligodendroglial tumours (AOT). Methods and results: We performed anti-Ki67 immunostaining (MIB-1 antibody) of formalin-fixed and paraffin-embedded tumour tissue specimens of 128 patients with newly diagnosed AOT that were treated in a randomized Phase III trial. Ki67 index was assessed by three independent observers and was correlated to clinical, histopathological and molecular features (including 1p/19q co-deletion, epithelial growth factor receptor gene (EGFR) amplification, isocitrate dehydrogenase (IDH1) mutations, O6-methylguanine-DNA methyltransferase gene (MGMT) promoter methylation, and patient survival times. Intra- and inter-observer agreement of Ki67 index assessment was excellent. Univariable analysis (n = 79) showed that patients with a low Ki67 index had significantly more favourable progression-free survival (PFS) (P-value = 0.004, log-rank test) and overall survival (OS) (P-value = 0.003, log-rank test) than patients with a high Ki67 index, respectively. On multivariable analysis (n = 43), Ki67 index showed no independent association with PFS or OS. Conclusions: In AOT the Ki67 index has a strong prognostic impact on univariable analysis, but no independent influence on multivariable analysis. However, further prospective studies including larger numbers of cases and standardized evaluation of Ki67 index in conjunction with other relevant prognostic parameters are needed to draw definitive conclusions.

Eur J Clin Invest 2011; 41 (5): 539–545 Abstract Background Temozolomide (TMZ) is commonly used for the therapy of malignant glioma and induces thrombocytopenia in a fraction of patients. Currently, no biomarkers predicting TMZ-induced thrombocytopenia are available. In this study, we investigated whether changes in platelet count (PLT) or the immature platelet fraction (IPF) may serve as predictor of TMZ-induced thrombocytopenia in malignant glioma patients. Methods We prospectively included 52 malignant glioma patients receiving TMZ-containing therapy regimens in this study. Platelet counts and IPF were determined at each clinical follow-up visit (weekly during concomitant radiochemotherapy or at least monthly during TMZ monotherapy) using the Sysmex XE-2100 system. We explored the diagnostic utility of PLT change/day and IPF change/day from the last to the current follow-up visit for the prediction of clinically relevant thrombocytopenia (PLT

RCL2 is an alcohol-based fixative reported to preserve histomorphology and nucleic acids in non-CNS neoplasms. We compared histomorphology, immunohistochemistry, DNA and RNA in brain tumor specimens preserved frozen at -80°C, and after formalin or RCL2 fixation. RCL2-fixed and paraffin-embedded (RCLPE) samples showed well-preserved histomorphology and specific immunoreactivity comparable to formalin-fixed and paraffin-embedded (FFPE) specimens testing a broad panel of antibodies. In all the analyzed cases, high-molecular weight DNA (up to a fragment length of 600 bp) was amplifyable from RCLPE samples, even after prolonged fixation times. Beta-actin (ACTB) and 06-methylguanine-methyltransferase (MGMT) gene concentrations were significantly higher in DNA isolated from RCLPE specimens as compared with FFPE specimens. Testing of MGMT promoter methylation status using methylation-specific polymerase-chain reaction (MSP) yielded conclusive results in 8/8 analyses in RCLPE and 6/8 analyses in FFPE material, respectively. Amplification of three reference genes (ABL, RAR-alpha, BCR-1) from cDNA showed good RNA preservation in frozen and RCLPE tissue specimens and significant RNA degradation in all FFPE samples. In conclusion, RCL2 fixation of brain tumor biopsies does not seem to significantly compromise histological tumor typing or immunohistochemistry and preserves nucleic acids (DNA and RNA) at a better quality than formalin fixation.

BACKGROUND: Currently, no effective alternative treatment exists for progressive, regrowing, nonfunctioning pituitary adenomas (NFPA) that are resistant to conventional multimodality therapy. Temozolomide (TMZ) was proposed as a treatment option for pituitary carcinomas and aggressive pituitary adenomas. Recently, it was suggested that the responsiveness of pituitary tumors to TMZ depends on the immunoexpression of O6-methylguanine DNA methyltransferase (MGMT). Therefore, the authors of this report assessed MGMT expression in a series of patients with progressive, regrowing NFPAs to evaluate whether TMZ may serve as alternative treatment option. METHODS: On the basis of postoperative magnetic resonance imaging, 45 patients with NFPAs were allocated to either a group with progressive, regrowing tumors (n = 24) or a tumor-free group (n = 21), which served as a control. MGMT expression was assessed semiquantitatively by immunohistochemistry (low expression was defined as ≤50% immunostained adenoma cells, and high expression was defined as >50% immunostained adenoma cells) and was compared between the 2 groups. RESULTS: At the time of initial surgery, low MGMT expression was observed in 12 of 24 patients (50%) in the study group with progressive, regrowing NFPAs. In the control group of tumor-free patients, only 5 of 21 patients (24%) exhibited low MGMT expression. A comparable distribution of MGMT expression was observed in the specimens from repeat surgeries. A shorter interval to second surgery was observed in patients who had low MGMT expression. CONCLUSIONS: The current data has suggested that half of the patients with progressive, regrowing NFPAs exhibit low MGMT expression and are potential candidates for treatment with TMZ. These findings provide a rationale for the use of TMZ as an alternative treatment approach in this subgroup if conventional therapy, including reoperation, radiosurgery, and radiotherapy, fails. Cancer 2009. © 2009 American Cancer Society.

Recently, a family with idiopathic brain calcification was reported, in which one family member was diagnosed with multiple system atrophy (MSA) at autopsy. We report here a case showing similar neuropathological features in a patient with longstanding hypoparathyroidism. Our female patient had a history of hypoparathyroidism with hypocalcaemia and tetany since the age of 9 years. In her 50s she developed dementia and parkinsonism. She died of myocardial infarction aged 65 years. Neuropathology showed severe brain calcifications of the Fahr type in the basal ganglia, thalami, cerebral and cerebellar white matter and dentate nuclei. Additionally, there was prominent alpha-synucleinopathy of the multiple system atrophy type (MSA). The patient has a healthy identical twin and there is no family history of hypoparathyroidism or neurological disease. Data on alpha-synuclein accumulation in various cases of Fahr's syndrome are needed to establish the correlation between alpha-synucleinopathy and bilateral striopallidodentate calcification.

Papillary glioneuronal tumor (PGNT) is a rare, recently recognized tumor type histologically characterized by pseudopapillary architecture associated with compact areas composed of neuronal elements in different maturation states. The histogenesis of this tumor type is still unclear. The immunophenotype of PGNT comprises expression of several glial and neuronal proteins. Recently, immunohistochemical expression of Olig2 in a fraction of tumor cells has been reported, suggesting an additional oligodendroglial or at least oligodendroglia-like tumor cell component. We report a further case of papillary glioneuronal tumor in a 12-year-old boy with immunohistochemical expression of PDGFRalpha, Olig2 and Nestin in support of a postulated origin of this tumor type from common progenitor cells in the subependymal plate. Nevertheless, further studies are needed to clarify the histogenesis of PGNT.

Secretagogin is a recently described calcium-binding protein, which is expressed in some neurons of the human brain. In this study we systematically investigated secretagogin expression in 245 tumours of the human brain and its coverings using immunohistochemistry. We found focal or widespread secretagogin expression in tumour cells in 1/18 oligoastrocytomas, 1/19 oligodendrogliomas, 2/20 anaplastic oligodendrogliomas, 2/9 ependymomas, 2/11 anaplastic ependymomas, 2/10 glioblastomas, 3/11 gangliogliomas and 1/2 anaplastic gangliogliomas, 10/10 central neurocytomas, 5/10 classic medulloblastomas, 4/5 desmoplastic medulloblastomas, 3/5 large cell/anaplastic medulloblastomas, 3/5 neuroblastomas, 3/10 meningiomas, 2/10 haemangioblastomas, and 13/19 pituitary adenomas. Further, we observed secretagogin expression in endothelial cells in 5/10 meningiomas, 2/5 haemangiopericytomas, and 2/10 haemangioblastomas. We detected no secretagogin expression in fibrillary astrocytoma, pilocytic astrocytoma, DNT, pineocytoma, pineoblastoma, subependymal giant cell astrocytoma (SEGA), atypical teratoid/rhabdoid tumour (AT/RT), or primary central nervous system lymphoma (PCNSL). We conclude that secretagogin is differentially expressed in human neuronal, glial, and embryonal brain tumours, meningial neoplasms and pituitary adenomas. Our findings indicate that secretagogin is involved in the calcium metabolism of tumour cells and endothelial cells in a subset of neoplasms of the brain and its coverings. Anti-secretagogin immunohistochemistry does not seem to be helpful in most differential diagnostic situations in surgical neuropathology.

Aims : NeuN is considered to be a marker of neuronal differentiation in brain tumours. Our aim was to perform, for the first time, a systematic and comparative analysis of NeuN expression in all major brain tumour subtypes to provide guidance for the rational use of NeuN immunohistochemistry in diagnostic histopathology. Methods and results : Anti-NeuN immunohistochemistry was performed on paraffin-embedded biopsy specimens of 106 diffuse astrocytomas, 100 pilocytic astrocytomas, 107 ependymomas, 59 1p-aberrant oligodendroglial neoplasms, 115 glioblastomas, 115 medulloblastomas, 14 gangliogliomas/gangliocytomas and 10 central neurocytomas. We found no NeuN expression in pilocytic astrocytoma, whereas all other investigated tumour subtypes showed focal or widespread expression in varying proportions of cases. Comparing NeuN expression in clear cell tumours, widespread NeuN expression had a positive predictive value of 76.9% (95% confidence interval 46.2, 95.0) for central neurocytoma. Lack of NeuN expression had a positive predictive value of 87.3% (76.5, 94.4) for oligodendroglioma. Conclusions : Immunohistochemistry can detect NeuN expression in all major brain tumour subtypes except pilocytic astrocytoma. In the individual case, assessment of NeuN expression may be helpful in the differential diagnosis of clear cell primary brain tumours but does not seem to be useful for the differential diagnosis of other brain tumour subtypes.

BACKGROUND Hot-spot microvessel density (MVD) and vascular patterns have been reported as histopathologic factors that influence prognosis in retrospective series of malignant gliomas. To investigate clinical utility, the authors systematically studied observer agreement on MVD and vascular patterns and the influence of repeatedly assessed data on patient outcomes in 2 independent glioblastoma series. METHODS MVD and vascular patterns were assessed retrospectively by 5 observers in 1) a retrospectively compiled glioblastoma series that included 110 patients and 2) a glioblastoma series that included 233 patients who were treated within a randomized trial. MVD was determined in the field of greatest density (“hot-spot”). Predominantly classic or bizarre vascular patterns were determined by using a previously defined algorithm. RESULTS Observer agreement on MVD was highly variable (range of κ values, 0.464-0.901). The worst observer agreement was achieved when both the selection of hot-spots and MVD counts were performed independently. Survival analysis did not show a consistent association between repeatedly assessed MVD and patient outcome. Observer agreement on vascular patterns was poor (κ = 0.297). Survival analysis did not show a consistent association between repeatedly assessed vascular patterns and patient outcome. CONCLUSIONS Observer agreement on hot-spot MVD and vascular patterns in patients with glioblastoma was poor in independent assessments. MVD and vascular patterns were not associated consistently with patient outcome. Based on these findings, the authors concluded that poor observer agreement limits the clinical utility of histopathologically assessed hot-spot MVD and vascular patterns as prognostic factors in patients with glioblastoma. Improved methodologies for morphologic assessment of glioblastoma vascularization need to be identified. Cancer 2006. © 2006 American Cancer Society.

Monoclonal antibody D110 has recently been described as a novel marker of hypoxic tissue damage, reacting with a so far unknown antigen with preferential expression in the central nervous system. The aim of the study was to investigate D110 immunoreactivity in glioblastoma, its association with the expression of hypoxia-related proteins and its impact on patient outcome. A total of 114 consecutive adult patients who underwent first operation of primary glioblastoma were included in this study. We evaluated D110 immunoreactivity qualitatively and semi-quantitatively and correlated it with expression of hypoxia inducible factor 1 alpha (HIF-1alpha), expression of vascular endothelial growth factor (VEGF), and with patient survival using univariate and multivariate statistical analysis. We observed D110 immunolabelling in 85.1% of the cases. D110 immunoreactivity was detectable in infiltrating HLA-DR and CD68 expressing cells, most likely microglial cells or haematogenous cells of monocyte/macrophage lineage. In the peripheral lymphoreticular system, immunohistochemistry disclosed selective D110 labelling of Langerhans cells and of dendritic cells of the thymic medulla. Univariate statistical analysis revealed significantly longer survival of patients whose glioblastomas contained D110 immunoreactive infiltrating cells. There was no association between presence of D110 immunoreactive cells and expression of HIF-1alpha and VEGF. We conclude that D110 immunoreactivity in glioblastoma does not seem to be related to tissue hypoxia. D110 identifies immunocompetent cells, which positively influence survival of glioblastoma patients.

Silencing of O6‐methylguanine‐DNA methyltransferase (MGMT) protein expression because of MGMT gene promoter hypermethylation is considered to be associated with postoperative chemoradiotherapy benefits in glioblastoma multiforme (GBM) patients. The objective of this study was to clarify the usability of MGMT immunohistochemistry (IHC) as a clinical biomarker. We immunostained a tissue microarray containing biopsy samples of 164 GBM patients from the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada (EORTC/NCIC) trial 26981/22981 using two commercial anti‐MGMT antibodies (clones MT3.1 and MT23.2). Immunostaining results were semiquantitatively evaluated by four observers from three neuropathological laboratories using a predefined algorithm. We analyzed (i) inter‐ and intraobserver agreement on MGMT expression (kappa statistics); (ii) correlation of MGMT expression with MGMT promoter methylation status (kappa statistics); and (iii) correlation of MGMT expression with patient outcome (log‐rank test). Interobserver agreement on MGMT expression varied from slight to almost perfect, whereas intraobserver agreement ranged from substantial to almost perfect. MGMT expression showed poor to moderate correlation with MGMT promoter methylation status. We found no significant association of MGMT expression with patient outcome. In our hands, observer variability as well as lack of association with the MGMT promoter methylation status and patient survival impeded the use of anti‐MGMT immunohistochemistry as a clinical biomarker for routine diagnostic purposes.

The pathological findings in Alzheimer's disease (AD) are partly attributed to alterations in calcium-binding protein (CBP) functions. We showed previously that immunoreactivity of secretagogin, a recently cloned CBP, in the human hippocampus is restricted to pyramidal neurones and that the amount of immunoreactive neurones does not differ between AD cases and controls. In this study we investigate the influence of hippocampal tau pathology on secretagogin expression in more details. The study group consisted of 26 cases with different degrees of neuropathologically confirmed AD pathology. Sections were incubated separately with secretagogin- and tau-specific antibodies, respectively. The amount of immunoreactive neurones and integral optical densities were assessed. In addition, double immunofluorescence for both secretagogin and tau was performed. No difference with respect to secretagogin immunoreactivity was observed in different stages of AD pathology, and similarly no significant associations were seen between the amount of secretagogin and tau immunoreactivity in the different hippocampal subfields. Double immunofluorescence revealed that both proteins rarely colocalize because only 5.3% of tau and 2.9% of secretagogin immunoreactive neurones, respectively, showed colocalization. Because there are no differences in the amount of hippocampal secretagogin expression between AD cases and controls (as we have shown previously), the lack of an association between the amount of secretagogin expression and tau burden together with the low frequency of colocalization of tau and secretagogin in the human hippocampus, suggest that secretagogin-expressing neurones are largely resistant to neurodegeneration in AD.