Refined Functional Magnetic Resonance Imaging and Magnetoencephalography Mapping Reveals Reorganization in Language-Relevant Areas of Lesioned Brains.

BACKGROUND: Neurosurgical decisions regarding interventions close to brain areas with language-related functions remain highly challenging because of the risk of postoperative dysfunction. To minimize these risks, improvements in the preoperative mapping of language-related regions are required, especially as space-occupying lesions often lead to altered cortical topography and language area reorganization. METHODS: The degree of deviation and language area reorganization were investigated in 26 functional magnetic resonance imaging- and magnetoencephalography-dissociable cortical sub-areas displaying language-related activations in each of 18 patients with brain lesions and 3 healthy volunteers (during visual language tasks). RESULTS: Both modalities showed good congruency of the language areas. The mean spatial distance of the centroids and maxima was 9.06 mm and 10.58 mm, respectively, allowing us to define more specific anatomical positions. Postoperatively, language abilities increased in 11% (2 of 18) of the patients, remained unchanged in 83% (15 of 18) of the patients, and decreased in 6% (1 of 18) of the patients, respectively. Signs of language function reorganization detected on both functional magnetic resonance imaging and magnetoencephalography were present in 29% (5 of 17) of the patients. Attenuation of neurovascular coupling was found postoperatively in 17% (3 of 18) of the patients. Monohemispheric language processing cannot be assumed always in patients with brain lesions. CONCLUSIONS: The more detailed subdivision of language-relevant brain areas shown in this study can help to achieve more radical tumor resection without postoperative language deficits.

Comparative fMRI and MEG localization of cortical sensorimotor function: Bimodal mapping supports motor area reorganization in glioma patients.

INTRODUCTION: Preoperative functional mapping in the vicinity of brain lesion is of high importance for avoiding complications in surgical management. However, space-occupying lesions may lead to functional reorganization or decreased BOLD activity. METHODS: Therefore in 13 patients with cerebral gliomas or brain arterio-venous malformations/ hemangioma fMRI- and MEG-based cortical localizations of motor and somatosensory cortical activation pattern were compared in order to investigate their congruency. RESULTS: Localization of cortical sensorimotor areas with fMRI and MEG showed good congruency with a mean spatial distance of around 10 mm, with differences depending on the localization method. The smallest mean differences for the centroids were found for MEF with MNE 8 mm and SEF with sLORETA 8 mm. Primary motor area (M1) reorganization was found in 5 of 12 patients in fMRI and confirmed with MEG data. In these 5 patients with M1-reorganization the distance between the border of the fMRI-based cortical M1-localization and the tumor border on T1w MR images varied between 0-4 mm, which was significant (P = 0.025) different to the distance in glioma patients without M1-reorganization (5-26 mm). CONCLUSION: Our multimodal preoperative mapping approach combining fMRI and MEG reveals a high degree of spatial congruence and provided high evidence for the presence of motor cortex reorganization.

A web-based diagnostic reference centre for the European Reference Network "EpiCare": recommendations of the eNeuropathology working group.

Epilepsy surgery is a valuable treatment strategy for a selected group of patients with drug-resistant focal epilepsy. While reliable disease classification is essential for the optimal management of patients in general and crucial for the development of more personalized therapies in the future, arriving at a precise diagnosis often poses considerable difficulties due to the broad and variant-rich spectrum of epilepsy-associated brain lesions. Given the scarcity of European institutions diagnostically focusing on the histopathology of epilepsy surgery cases, the provision of subspecialty expertise as well as training opportunities remains logistically and financially challenging. To improve this situation, the European Reference Network's (ERN) epilepsy care program (EpiCare, http://epi-care.eu) has set out to develop a web-based microscopy referral and teaching framework. This paper reviews the aspects of digital microscopy, data storage, and image analysis technology relevant to the practice of neuropathology. Cognizant of the European data security requirements and regulations, we propose a collaborative, diagnostic network initiative (the eNeuropathology reference centre) and delineate a roadmap for its implementation favouring open-source, vendor-independent browser platforms.

Reelin depletion is an early phenomenon of Alzheimer's pathology.

Alterations in the expression of Reelin (RELN) have been implicated in the pathology of Alzheimer's disease (AD). However, whether these changes are cause or consequence of AD remains to be resolved. To better understand the role of RELN pathway in the development of AD, we examined the expression profile of RELN and its downstream signaling members APOER2, VLDLR, and DAB1 in AD-vulnerable regions of transgenic and wildtype mice as well as in AD patients and controls across disease stages and/or aging. We show that both AD pathology and aging are associated with perturbation of the RELN pathway in a species-, region-, and molecule-specific manner. Further, we show that depletion of RELN, but not its downstream signaling molecules, is detectable long before the onset of amyloid-ß pathology in the murine hippocampus and in a pre-clinical AD stage in the human frontal cortex. This early event hints at a possible causative role of RELN decline in the precipitation of AD pathology and supports RELN's potential as a pre-clinical marker for AD.

Spontaneous haemoptysis as a late complication of plombage in a tuberculosis patient.

The endemic spread of tuberculosis after World War II and the deficiency of appropriate antituberculous drugs had led to a renaissance of the surgical tuberculosis therapy until the early 1950s. Late complications of plombage performed decades before are rare and are mainly related to infection and/or migration of the inserted foreign material and are scarcely recognized today. We report on a 73-year-old male patient, who was admitted to the emergency room of our hospital with acute massive haemoptysis for four days. On physical examination the patient presented with decreased breath sounds over the left lung and an old left-sided thoracotomy scar. Radiological findings and bronchoscopy revealed an empyema and a fistula as late complications 53 years after collapse therapy with insertion of a plombage for the treatment of pulmonary tuberculosis. The endobronchial nylon threads in the left bronchial tree and the fistula ending in the left lower bronchus confirmed our diagnosis. The patient was successfully treated by resection of the affected lower lobe. The present casuistic demonstrates a rare cause of spontaneous haemoptysis: late complications after extrapleural pneumolysis and plombage for cavitary tuberculosis over 50 years after the initial operation.

Prostate cancer detection and dutasteride: utility and limitations of prostate-specific antigen in men with previous negative biopsies.

CONTEXT: We addressed the question whether the change of serum prostate-specific antigen (PSA) in men who use 5α-reductase inhibitor (5-ARI) dutasteride is sensitive for the detection of aggressive prostate cancer (PCa). OBJECTIVE: The case of a man using dutasteride diagnosed with Gleason 7 transition zone cancer at biopsy indicated by a rising PSA is described. The following issues are discussed: (1) Is a rise of PSA in patients using dutasteride predictive of aggressive PCa in men with prior negative biopsies? (2) Is it safe not to biopsy men using dutasteride who do not show a rising PSA? (3) How can we avoid potentially unnecessary biopsies in men using dutasteride without a rising PSA? EVIDENCE ACQUISITION: We reviewed the recent literature addressing our objective that relates to two studies: the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events trial. EVIDENCE SYNTHESIS: In men using dutasteride, the positive predictive value/detection rate of Gleason 7-10 PCa is 13.2% and 4.0% for men with and without a rising PSA, respectively. However, a substantial proportion of Gleason 7-10 cases (42.9%) would be missed if a rising PSA was used as the only biopsy indication. Currently available data do not provide selective mechanisms to diagnose these cancers. CONCLUSIONS: A rising PSA for a patient using dutasteride should be an indication for prostate biopsies. Currently, in the case of stable PSA a biopsy may still be considered. Options for a selective approach are therefore suggested in this review to avoid unnecessary biopsies and to achieve a more selective PCa detection in men on 5-ARI treatment.

Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1.

Heterozygous germline mutations in mismatch repair (MMR) genes MLH1, PMS2, MSH2, and MSH6 cause Lynch syndrome. New studies have indicated that biallelic mutations lead to a distinctive syndrome, childhood cancer syndrome (CCS), with haematological malignancies and tumours of brain and bowel early in childhood, often associated with signs of neurofibromatosis type 1. We provide further evidence for CCS reporting on six children from two consanguineous families carrying homozygous PMS2 germline mutations. In family 1, all four children had the homozygous p.I590Xfs mutation. Two had a glioblastoma at the age of 6 years and one of them had three additional Lynch-syndrome associated tumours at 15. Another sibling suffered from a glioblastoma at age 9, and the fourth sibling had infantile myofibromatosis at 1. In family 2, two of four siblings were homozygous for the p.G271V mutation. One had two colorectal cancers diagnosed at ages 13 and 14, the other had a Non-Hodgkin's lymphoma and a colorectal cancer at ages 10 and 11, respectively. All children with malignancies had multiple café-au-lait spots. After reviewing published cases of biallelic MMR gene mutations, we provide a concise description of CCS, revealing similarities in age distribution with carriers of heterozygous MMR gene mutations.

Morphological detection of hormone and growth factor receptors in breast cancer.

In the multidisciplinary effort of today's clinical oncology, histopathology has to deal increasingly with the genetic and proteomic profiles of neoplastic cells obtained in ever smaller samples via various diagnostic routes. None of the numerous molecular markers available has surpassed hormone and growth factor receptors in their relevance for the selection of targeted therapies. In the following, morphologic concepts and histopathologic methods pertinent to the clinically most important receptors are discussed with a focus on tumors of the breast.

Absence of microsatellite instability and lack of evidence for subclone diversification in the pathogenesis and progression of mycosis fungoides.

Mutator phenotypes with microsatellite instability (MSI) correlated with defects in the mismatch repair system are characteristic for a subset of solid neoplasms, but are rare in non-Hodgkin lymphomas. In mismatch repair-deficient mice, however, mutator-type non-Hodgkin lymphomas are the most frequent tumors. To determine the role of MSI in mycosis fungoides, we compared the states of the eight dinucleotide microsatellite loci DXS418, DXS453, DXS556, DXS1060, D1S201, D6S260, D9S162, and D10S215 in tumor cells of 12 well-characterized patients at early- and advanced-stage diseases to matched healthy tissue. We did not find any MSI, although all but one patient had progressed to advanced-stage disease within the timeframe of the study. Concordantly, the expression of mismatch repair genes was normal. These results suggest that progressive accumulation of mutations as detected by MS analysis does not play a major role in the pathogenesis or in the progression of mycosis fungoides.

Gene expression in macrophage-rich inflammatory cell infiltrates in human atherosclerotic lesions as studied by laser microdissection and DNA array: overexpression of HMG-CoA reductase, colony stimulating factor receptors, CD11A/CD18 integrins, and interleukin receptors.

OBJECTIVE: Inflammatory cells play an important role in atherogenesis. However, more information is needed about their gene expression profiles in human lesions. METHODS AND RESULTS: We used laser microdissection (LMD) to isolate macrophage-rich shoulder areas from human lesions. Gene expression profiles in isolated cells were analyzed by cDNA array and compared with expression patterns in normal intima and THP-1 macrophages. Upregulation of 72 genes was detected with LMD and included 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, interferon regulatory factor-5 (IRF-5), colony stimulating factor (CSF) receptors, CD11a/CD18 integrins, interleukin receptors, CD43, calmodulin, nitric oxide synthase (NOS), and extracellular superoxide dismutase (SOD). Several of these changes were also present in PMA-stimulated THP-1 macrophages in vitro. On the other hand, expression of several genes, such as VEGF, tissue factor pathway inhibitor 2, and apolipoproteins C-I and C-II, decreased. CONCLUSIONS: Overexpression of HMG-CoA reductase in macrophage-rich lesion areas may explain some beneficial effects of statins, which can also modulate increased expression of CD11a/CD18 and CD43 found in microdissected cells. We also found increased expression of CSF receptors, IRF-5, and interleukin receptors, which could become useful therapeutic targets for the treatment of atherosclerotic diseases.

hTERT gene dosage correlates with telomerase activity in human lung cancer cell lines.

Maintenance of telomeres, most often by telomerase, is a necessary prerequisite for immortality of eukaryotic cells. To better understand the mechanisms of telomerase up-regulation during tumorigenesis, we analysed the gene dosage of hTERT on chromosome 5p15, a region known to be overrepresented in a variety of malignancies, in 20 lung cancer cell lines by Southern blotting, fluorescence in-situ hybridization, and comparative genomic hybridization. We found a significant correlation between hTERT gene dosage, hTERT mRNA expression and telomerase activity. Imbalances of chromosome 5p may exert functionally relevant hTERT gene dosage effects in human lung cancer.