Medulloblastoma in adults: evaluation of the Dutch society for neuro-oncology treatment protocol.

PURPOSE: Medulloblastoma is a rare tumor in adults. The objective of this nationwide, multicenter study was to evaluate the toxicity and efficacy of the Dutch treatment protocol for adult medulloblastoma patients. METHODS: Adult medulloblastoma patients diagnosed between 2010 and 2018 were identified in the Dutch rare tumors registry or nationwide pathology database. Patients with intention to treat according to the national treatment protocol were included. Risk stratification was performed based on residual disease, histological subtype and extent of disease. All patients received postoperative radiotherapy [craniospinal axis 36 Gy/fossa posterior boost 19.8 Gy (14.4 Gy in case of metastases)]. High-risk patients received additional neoadjuvant (carboplatin-etoposide), concomitant (vincristine) and adjuvant chemotherapy (carboplatin-vincristine-cyclophosphamide) as far as feasible by toxicity. Methylation profiling, and additional next-generation sequencing in case of SHH-activated medulloblastomas, were performed. RESULTS: Forty-seven medulloblastoma patients were identified, of whom 32 were treated according to the protocol. Clinical information and tumor material was available for 28 and 20 patients, respectively. The histological variants were mainly classic (43%) and desmoplastic medulloblastoma (36%). Sixteen patients (57%) were considered standard-risk and 60% were SHH-activated medulloblastomas. Considerable treatment reductions and delays in treatment occurred due to especially hematological and neurotoxicity. Only one high-risk patient could complete all chemotherapy courses. 5-years progression-free survival (PFS) and overall survival (OS) for standard-risk patients appeared worse than for high-risk patients (PFS 69% vs. 90%, OS 81% vs. 90% respectively), although this wasn't statistically significant. CONCLUSION: Combined chemo-radiotherapy is a toxic regimen for adult medulloblastoma patients that may result in improved survival.

The value of prognostic and predictive parameters in early-stage lung adenocarcinomas: A comparison between biopsies and resections.

INTRODUCTION: Since lung adenocarcinoma (LUAD) biopsies are usually small, it is questionable if their prognostic and predictive information is comparable to what is offered by large resection specimens. This study compares LUAD biopsies and resection specimens for their ability to provide prognostic and predictive parameters. METHODS: We selected 187 biopsy specimens with stage I and II LUAD. In 123 cases, subsequent resection specimens were also available. All specimens were evaluated for growth pattern, nuclear grade, fibrosis, inflammation, and genomic alterations. Findings were compared using non-parametric testing for categorical variables. Model performance was assessed using the area under the curve for both biopsies and resection specimens, and overall (OS) and disease-free survival (DFS) was calculated. RESULTS: The overall growth pattern concordance between biopsies and resections was 73.9%. The dominant growth pattern correlated with OS and DFS in resected adenocarcinomas and for high-grade growth pattern in biopsies. Multivariate analysis of biopsy specimens revealed that T2-tumors, N1-status, KRAS mutations and a lack of other driver mutations were associated with poorer survival. Model performance using clinical, histological and genetic data from biopsy specimens for predicting OS and DSF demonstrated an AUC of 0.72 and 0.69, respectively. CONCLUSIONS: Our data demonstrated the prognostic relevance of a high-grade growth pattern in biopsy specimens of LUAD. Combining clinical, histological and genetic information in one model demonstrated a suboptimal performance for DFS prediction and good performance for OS prediction. However, for daily practice, more robust (bio)markers are required to predict prognosis and stratify patients for therapy and follow-up.

Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy.

BACKGROUND: New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles have failed to direct treatment strategies. We hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision immunotherapy treatment strategies. MATERIALS AND METHODS: A refined and validated microenvironment cell population (MCP) counter method was applied to >800 GBM patient tumours (GBM-MCP-counter). Specifically, partition around medoids (PAM) clustering of GBM-MCP-counter scores in the GLIOTRAIN discovery cohort identified three novel patient clusters, uniquely characterised by TME composition, functional orientation markers and immune checkpoint proteins. Validation was carried out in three independent GBM-RNA-seq datasets. Neoantigen, mutational and gene ontology analysis identified mutations and uniquely altered pathways across subtypes. The longitudinal Glioma Longitudinal AnalySiS (GLASS) cohort and three immunotherapy clinical trial cohorts [treatment with neoadjuvant/adjuvant anti-programmed cell death protein 1 (PD-1) or PSVRIPO] were further interrogated to assess subtype alterations between primary and recurrent tumours and to assess the utility of TME classifiers as immunotherapy biomarkers. RESULTS: TMEHigh tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TMEHigh/mesenchymal+ patients featured tertiary lymphoid structures. TMEMed (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TMELow (24%) tumours were manifest as an 'immune-desert' group. TME subtype transitions upon recurrence were identified in the longitudinal GLASS cohort. Assessment of GBM immunotherapy trial datasets revealed that TMEHigh patients receiving neoadjuvant anti-PD-1 had significantly increased overall survival (P = 0.04). Moreover, TMEHigh patients treated with adjuvant anti-PD-1 or oncolytic virus (PVSRIPO) showed a trend towards improved survival. CONCLUSIONS: We have established a novel TME-based classification system for application in intracranial malignancies. TME subtypes represent canonical 'termini a quo' (starting points) to support an improved precision immunotherapy treatment approach.

Spinal meningiomas: Treatment outcome and long-term follow-up.

BACKGROUND: Spinal intradural tumors can be classified as intradural extramedullary or intramedullary tumors. Spinal meningiomas are among the most frequent intradural, extramedullary tumors (IDEMs), representing 12 % of all meningiomas and 25-45 % of all intradural spinal tumors. OBJECTIVE: To evaluate postoperative outcome, defined by mortality, tumor recurrence and modified Rankin Scale in patients with spinal meningiomas. Furthermore, to identify factors related to these outcome measures and define possible prognosticators. METHODS: A large single center retrospective analysis of 166 consecutive spinal meningioma patients during a 29-year period (1989-2018). RESULTS: Female to male ratio was 5.15 to 1. Of all 166 resected tumors, 159 were WHO grade I and seven were WHO grade II. Histopathologically, the psammomatous type was most common (42.8 %). The thoracic region was the most frequent location (71.1 %), followed by cervical and lumbar locations. A complete resection (Simpson I-III) was achieved in 88.7 %. In 12 cases (7.2 %) recurrences of a spinal meningioma occurred after an interval of 0.70-13.78 years. Postoperative complications consisted of CSF leakage and wound healing problems. Three patients died of direct postoperative complications (1.8 %), nine patients died in follow-up due to unrelated causes. Post-operative complications were related to the overall outcome (p = 0.029). Clinical outcome showed improvement in 117 patients out of 148 (79.1 %) according to modified Rankin Scale; 24 patients remained stable and 7 patients deteriorated. Patients with pre-existing bladder/bowel problems and incomplete resections had higher chance of recurrences. Younger patients also had a higher recurrence rate. Follow-up ranged from 0 to 23 years, median of 0.77 years, most were discontinued after 2 years. CONCLUSIONS: The primary treatment of spinal meningiomas remains surgery. Complete resection of spinal meningiomas is achieved in most of the cases, however preserving and improving neurological status has priority over complete tumor resection. Morbidity and mortality is relatively low. Longer follow-up periods are recommended, since recurrences can occur after 10-15 years.

The complement system in glioblastoma multiforme.

The human complement system is represents the main effector arm of innate immunity and its ambivalent function in cancer has been subject of ongoing dispute. Glioma stem-like cells (GSC) residing in specific niches within glioblastomas (GBM) are capable of self-renewal and tumor proliferation. Recent data are indicative of the influence of the complement system on the maintenance of these cells. It appears that the role of the complement system in glial tumorigenesis, particularly its influence on GSC niches and GSC maintenance, is significant and warrants further exploration for therapeutic interventions.

Expression-based intrinsic glioma subtypes are prognostic in low-grade gliomas of the EORTC22033-26033 clinical trial.

INTRODUCTION: The European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 clinical trial (NCT00182819) investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared with radiotherapy (RT) in low-grade glioma (LGG) patients. In this study, we performed gene expression profiling on tissues from this trial to identify markers associated with progression-free survival (PFS) and treatment response. METHODS: Gene expression profiling, performed on 195 samples, was used to assign tumours to one of six intrinsic glioma subtypes (IGSs; molecularly similar tumours as previously defined using unsupervised expression analysis) and to determine the composition of immune infiltrate. DNA copy number changes were determined using OncoScan arrays. RESULTS: We confirm that IGSs are prognostic in the EORTC22033-26033 clinical trial. Specific genetic changes segregate in distinct IGSs: most samples assigned to IGS-9 have IDH-mutations and 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations without 1p19q codeletion and samples assigned to other intrinsic subtypes often are IDH-wildtype. A trend towards benefit from RT was observed for samples assigned to IGS-9 (hazard ratio [HR] for TMZ is 1.90, P = 0.065) but not for samples assigned to IGS-17 (HR 0.87, P = 0.62). We did not identify genes significantly associated with PFS within intrinsic subtypes, although follow-up time is limited. We also show that LGGs and glioblastomas differ in their immune infiltrate, which suggests that LGGs are less amenable to checkpoint inhibitor-type immune therapies. Gene expression analysis also allows identification of relatively rare subtypes. Indeed, one patient with a pilocytic astrocytoma was identified. CONCLUSION: IGSs are prognostic for PFS in EORTC22033-26033 clinical trial samples.

A rare missense variant in RCL1 segregates with depression in extended families.

Depression is the most prevalent psychiatric disorder with a complex and elusive etiology that is moderately heritable. Identification of genes would greatly facilitate the elucidation of the biological mechanisms underlying depression, however, its complex etiology has proved to be a major bottleneck in the identification of its genetic risk factors, especially in genome-wide association-like studies. In this study, we exploit the properties of a genetic isolate and its family-based structure to explore whether relatively rare exonic variants influence the burden of depressive symptoms in families. Using a multistep approach involving linkage and haplotype analyses followed by exome sequencing in the Erasmus Rucphen Family (ERF) study, we identified a rare (minor allele frequency (MAF)=1%) missense c.1114C>T mutation (rs115482041) in the RCL1 gene segregating with depression across multiple generations. Rs115482041 showed significant association with depressive symptoms (N=2393, ßT-allele=2.33, P-value=1 × 10-4) and explained 2.9% of the estimated genetic variance of depressive symptoms (22%) in ERF. Despite being twice as rare (MAF<0.5%), c.1114C>T showed similar effect and significant association with depressive symptoms in samples from the independent population-based Rotterdam study (N=1604, ßT-allele=3.60, P-value=3 × 10-2). A comparison of RCL1 expression in human and mouse brain revealed a striking co-localization of RCL1 with the layer 1 interlaminar subclass of astrocytes found exclusively in higher-order primates. Our findings identify RCL1 as a novel candidate gene for depression and offer insights into mechanisms through which RCL1 may be relevant for depression.

CECR1-mediated cross talk between macrophages and vascular mural cells promotes neovascularization in malignant glioma.

Glioblastomas (glioblastoma multiforme, GBM) are most malignant brain tumors characterized by profound vascularization. The activation of macrophages strongly contributes to tumor angiogenesis during GBM development. Previously, we showed that extracellular adenosine deaminase protein Cat Eye Syndrome Critical Region Protein 1 (CECR1) is highly expressed by M2-like macrophages in GBM where it defines macrophage M2 polarization and contributes to tumor expansion. In this study, the effect of CECR1 in macrophages on tumor angiogenesis was investigated. Immunohistochemical evaluation of GBM tissue samples showed that the expression of CECR1 correlates with microvascular density in the tumors, confirming data from the TCGA set. In a three-dimensional co-culture system consisting of human pericytes, human umbilical vein endothelial cells and THP1-derived macrophages, CECR1 knockdown by siRNA and CECR1 stimulation of macrophages inhibited and promoted new vessel formation, respectively. Loss and gain of function studies demonstrated that PDGFB mRNA and protein levels in macrophages are modulated by CECR1. The proangiogenic properties of CECR1 in macrophages were partially mediated via paracrine activation of pericytes by PDGFB-PDGFRß signaling. CECR1-PDGFB-PDGFRß cross-activation between macrophages and pericytes promoted pericyte migration, shown by transwell migration assay, and enhanced expression and deposition of periostin, a matrix component with proangiogenic properties. CECR1 function in (M2-like) macrophages mediates cross talk between macrophages and pericytes in GBM via paracrine PDGFB-PDGFRß signaling, promoting pericyte recruitment and migration, and tumor angiogenesis. Therefore, CECR1 offers a new portent target for anti-angiogenic therapy in GBM via immune modulation.

The importance of microsurgery in childhood meningioma: a case report.

INTRODUCTION: Although meningiomas are frequently diagnosed in adults, it is a rare (intracranial) tumor in the pediatric population, with an incidence of 0.06/100,000. The pathology and treatment of meningiomas in adulthood has been a topic of increasing investigation. So far, the treatment of pediatric meningiomas has been extrapolated from these results. The question remains, however, whether translation of adult meningioma data into the childhood population is legitimate. METHODS: We present the case of a 3-year-old girl diagnosed with an intraventricular malignant meningioma and type 2 neurofibromatosis. She was operated on multiple times to achieve complete resection and received adjuvant chemotherapy. Since, she has been stable with no neurological sequelae and/or recurrence of the meningioma. CONCLUSION: Pediatric meningiomas are rare tumors and differ from their adult counterparts in various aspects. We believe that gross total resection of meningioma in the pediatric population, when possible, is the treatment of choice. In the event of a subtotal resection, repeat resection is recommended. Any adjuvant treatment with chemotherapy or radiation therapy should be carefully considered during multidisciplinary meetings.

Preoperative normalization of cortisol levels in Cushing's disease after medical treatment: consequences for somatostatin and dopamine receptor subtype expression and in vitro response to somatostatin analogs and dopamine agonists.

CONTEXT: Corticotroph pituitary adenomas often highly express the dopamine 2 receptor (D2R) and somatostatin receptor subtype 5 (sst5). The sst2 expression is relatively low, likely resulting from downregulating effects of high cortisol levels. This may explain why the sst2-preferring somatostatin analog octreotide, compared with the multi-receptor-targeting somatostatin analog pasireotide, is generally ineffective in Cushing's disease. OBJECTIVE: Our objective was to compare sst and D2R expression levels between adenomas from patients with elevated and normalized preoperative urinary free cortisol excretion. PATIENTS AND DESIGN: Corticotroph adenoma tissue was examined from patients from group 1 (n = 22; elevated preoperative urinary free cortisol) and group 2 (n = 11; mean duration of preoperative normocortisolism 10 weeks). Somatotroph adenoma tissue from 10 acromegalic patients was examined to compare receptor expression profiles. MAIN OUTCOME MEASURES: We evaluated receptor mRNA and protein expression levels and effects of octreotide, pasireotide, and cabergoline on ACTH secretion by cultured human corticotroph adenoma cells. RESULTS: The sst2 mRNA expression in group 2 was 10-fold higher than in group 1 (P < .01), even comparable to that in somatotroph adenomas. There were no statistically significant differences in sst5 and D2R mRNA expression or in sst2, sst5, and D2R protein expression between both groups of corticotroph adenomas. In responders, octreotide (n = 2 out of 4; -30.5% ± 10.4%) was less potent than pasireotide (n = 5 out of 6; -47.0% ± 4.2%) and cabergoline (n = 3 out of 4; -41.9% ± 3.1%) with respect to inhibition of ACTH secretion by adenomas from group 2. CONCLUSIONS: After achieving normocortisolism induced by medical therapy, cortisol-mediated sst2 downregulation on corticotroph adenomas appears to be a reversible process at the mRNA but not at the protein level. Octreotide remains less potent than pasireotide and cabergoline with respect to in vitro inhibition of ACTH secretion. Whether sustained normocortisolism induced by medical therapy induces re-expression of functional sst2 protein in corticotroph adenomas and whether this increases the ACTH-lowering potency of octreotide remains to be established.

FISH-based detection of 1p 19q codeletion in oligodendroglial tumors: procedures and protocols for neuropathological practice - a publication under the auspices of the Research Committee of the European Confederation of Neuropathological Societies (Euro-CNS).

The codeletion of chromosomal arms 1p 19q is a characteristic and early genetic event in oligodendroglial tumors, that is associated with a better prognosis and enhanced response to therapy. Over the last years, the increasing clinical demand to determine the 1p 19q status has led to the implementation of its testing in many neuropathology laboratories. Several different methods for 1p 19q testing are available: PCR-based loss of heterozygosity analysis, multiplex ligation-dependent probe amplification, array comparative genomic hybridization, and fluorescence in situ hybridization (FISH). Herein, we focus and critically discuss the latter method because a detailed description of procedures and protocols for FISH-based 1p 19q testing in practice is lacking. We present a practical approach to the FISH-based assessment of the 1p 19q status in oligodendroglial tumors, from commonly used locus-specific probes and technical protocols to the neuropathological interpretation of results. Thereby, we aim to facilitate the implementation of FISH-based 1p 19q testing for clinical purposes in standard neuropathology laboratories without special focus on brain tumor research.

A primary extraosseous Ewing sarcoma in the cerebellopontine angle of a child: review of relevant literature and case report.

BACKGROUND AND IMPORTANCE: We report the occurrence of a primary intracranial extraosseous Ewing sarcoma/peripheral primitive neuroectodermal tumor (EES/pPNET) in the cerebellopontine angle in a child. CLINICAL PRESENTATION: A 10-year-old girl presented with symptoms and signs of an infratentorial space-occupying lesion that was confirmed by magnetic resonance imaging and followed up by subtotal surgical resection. Tumor cells displayed membranous expression of CD99, and one of the typical translocations of EES/pPNET (chromosome 22) was demonstrated by cytogenetic analysis. CONCLUSION: The literature regarding the histopathological, molecular, radiological, prognostic, and therapeutic features of intracranial EES/pPNET is reviewed, emphasizing the distinction of this entity from the central PNET. Although exceptionally rare, intracranial EES/pPNET should be considered in the differential diagnosis of lesions in the cerebellopontine angle.

The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma.

Genomic translocations have been implicated in cancer. In this study, we performed a screen for genetic translocations in gliomas based on exon-level expression profiles. We identified a translocation in the contactin-associated protein-like 2 (CASPR2) gene, encoding a cell adhesion molecule. CASPR2 mRNA was fused to an expressed sequence tag that likely is part of the nuclear receptor coactivator 1 gene. Despite high mRNA expression levels, no CASPR2 fusion protein was detected. In a set of 25 glioblastomas and 22 oligodendrogliomas, mutation analysis identified two additional samples with genetic alterations in the CASPR2 gene and all three identified genetic alterations are likely to reduce CASPR2 protein expression levels. Methylation of the CASPR2 gene was also observed in gliomas and glioma cell lines. CASPR2-overexpressing cells showed decreased proliferation rates, likely because of an increase in apoptosis. Moreover, high CASPR2 mRNA expression level is positively correlated with survival and is an independent prognostic factor. These results indicate that CASPR2 acts as a tumor suppressor gene in glioma.

IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide.

BACKGROUND: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) have been implicated in tumorigenesis of gliomas. Patients with high-grade astrocytomas with IDH1 or IDH2 mutations were reported to have a better survival, but it is unknown if this improved survival also holds for low-grade astrocytoma and whether these mutations predict outcome to specific treatment. METHODS: We retrospectively investigated the correlation of IDH1 and IDH2 mutations with overall survival and response to temozolomide in a cohort of patients with dedifferentiated low-grade astrocytomas treated with temozolomide at the time of progression after radiotherapy. RESULTS: IDH1 mutations were present in 86% of the 49 progressive astrocytomas. No mutations in IDH2 were found. Presence of IDH1 mutations were early events and significantly improved overall survival (median survival 48 vs 98 months), but did not affect outcome of temozolomide treatment. CONCLUSION: These results indicate that IDH1 mutations identify a subgroup of gliomas with an improved survival, but are unrelated to the temozolomide response.

Filamin A mutation, a common cause for periventricular heterotopia, aneurysms and cardiac defects.

Filamin A is an important gene involved in the development of the brain, heart, connective tissue and blood vessels. A case is presented illustrating the challenge in recognising patients with filamin A mutations. The patient, a 71-year-old woman, was known to have heart valve disease and bilateral periventricular nodular heterotopia when she died of a subarachnoid haemorrhage. Autopsy showed typical cerebral bilateral periventricular heterotopia and vascular abnormalities. Postmortally, the diagnosis of a filamin A mutation was confirmed. Recognition during life may prevent cardiovascular problems and provide possibilities for genetic counselling.

Safety and efficacy of frameless and frame-based intracranial biopsy techniques.

BACKGROUND: Frameless stereotaxy or neuronavigation has evolved into a feasible technology to acquire intracranial biopsies with good accuracy and little mortality. However, few studies have evaluated the diagnostic yield, morbidity, and mortality of this technique as compared to the established standard of frame-based stereotactic brain biopsy. We report our experience of a large number of procedures performed with one or other technique. PATIENTS AND METHODS: We retrospectively assessed 465 consecutive biopsies done over a ten-year time span; Data from 391 biopsies (227 frame-based and 164 frameless) were available for analysis. Patient demographics, peri-operative characteristics, and histological diagnosis were reviewed and then information was analysed to identify factors associated with the biopsy not yielding a diagnosis and of it being followed by death. RESULTS: On average, nine tissue samples were taken with either stereotaxy technique. Overall, the biopsy led to a diagnosis on 89.4% of occasions. No differences were found between the two biopsy procedures. In a multiple regression analysis, it was found that left-sided lesions were less likely to result in a non-diagnostic tissue sample (p = 0.023), and cerebellar lesions showed a high risk of negative histology (p = 0.006). Postoperative complications were seen after 12.1% of biopsies, including 15 symptomatic haemorrhages (3.8%). There was not a difference between the rates of complication after either a frame-based or a frameless biopsy. Overall, peri-operative complications (p = 0.030) and deep-seated lesions (p = 0.060) increased the risk of biopsy-related death. Symptomatic haemorrhages resulting in death (1.5% of all biopsies) were more frequently seen after biopsy of a fronto-temporally located lesion (p = 0.007) and in patients with a histologically confirmed lymphoma (p = 0.039). CONCLUSIONS: The diagnostic yield, complication rates, and biopsy-related mortality did not differ between a frameless biopsy technique and the established frame-based technique. The site of the lesion and the occurrence of a peri-operative complication were associated with the likelihood of failure to achieve a diagnosis and with death after biopsy. We believe that using intraoperative frozen section or cytologic smear histology is essential during a stereotactic biopsy in order to increase the diagnostic yield and to limit the number of biopsy specimens that need to be taken.

From expert opinion to evidence-based: changes in the gold standard of primary brain tumour diagnosis.

Since 1997, significant progress has been made in the WHO guidelines for the diagnosis of primary tumours of the central nervous system. A large group of international experts was involved in editing the content; consensus on definitions and classifications was sought; and updated findings of genomic investigations were included. Nevertheless, significant inter-observer variability still exists in the histopathological diagnosis of several tumour types. The challenge for the near future is to identify histological and genotypic characteristics with prognostic or predictive value. With that aim, testing histological or molecular parameters in prospective clinical studies is indicated.

[Three patients with a paraneoplastic neurological syndrome: the significance of paraneoplastic antibodies]. / Drie patiënten met een paraneoplastisch neurologisch syndroom; de betekenis van paraneoplastische antistoffen.

Establishing the presence of paraneoplastic antibodies is important in identifying an often severe neurological syndrome as paraneoplastic and hence directing the search for an underlying neoplasm. A paraneoplastic neurological syndrome was diagnosed in 3 patients. The first was a 64-year-old woman in whom paraneoplastic encephalomyelitis was diagnosed. The diagnosis was strongly supported by a high titre of serum anti-Hu antibodies, despite three negative biopsies from a mediastinal mass. The patient died of a non-convulsive status epilepticus; autopsy revealed not only paraneoplastic encephalomyelitis but also small-cell lung cancer. The second patient was a 55-year-old woman with metastatic breast cancer. After a three-year period of progressive neurological deterioration, a high titre of anti-CV2/CRMP5 antibodies was detected, on the basis of which the clinical syndrome was diagnosed as paraneoplastic. She received immunotherapy and her condition stabilised. The third patient, a 41-year-old man, presented with severe limbic encephalitis. Biopsy from a paraaortic mass was positive for undifferentiated carcinoma. The patient had a high titre ofanti-Ma2 antibodies and was subsequently tested positive for serum alpha-foetoprotein (AFP) and beta-human-chorionic gonadotrophin (bta-HCG). During chemotherapy for a non seminoma testicular cancer, the limbic encephalitis improved both clinically and radiologically, but the patient died as a result of the toxicity of the treatment.

Raman spectroscopic characterization of porcine brain tissue using a single fiber-optic probe.

Accurate targeting of diseased and healthy tissue has significantly been improved by MRI/CT-based navigation systems. Recently, intraoperative MRI navigation systems have proven to be powerful tools for the guidance of the neurosurgical operations. However, the widespread use of such systems is held back by the costs, the time consumption during operation, and the need for MR-compatible surgical devices. Raman spectroscopy is a nondestructive optical technique that enables real-time tissue identification and classification and has proved to be a powerful diagnostic tool in a large number of studies. In the present report, we have investigated the possibility of distinguishing different brain structures by using a single fiber-optic probe to collect Raman scattered light in the high-wavenumber region of the spectrum. For the Raman measurements, 7 pig brains were sliced in the coronal plain and Raman spectra were obtained of 11-19 anatomical structures. Adjacent brain structures could be distinguished based on their Raman spectra, reflecting the differences in their biochemical composition and illustrating the potential Raman spectroscopy holds as a guidance tool during neurosurgical procedures.