Interaction of quality of life, mood and depression of patients and their informal caregivers after surgical treatment of high-grade glioma: a prospective study.

INTRODUCTION: Patients who are diagnosed with high-grade gliomas (HGG) have poor prognoses and often experience rapid declines in functional and cognitive status, which makes caring for them particularly stressful. We conducted a prospective study to investigate the factors influencing the quality of life of HGG patients and their informal caregivers and analyzed their reciprocal impacts. Based on our results, we elaborated a screening model to identify patients and caregivers in need of psychooncological support. METHODS: A total of 45 matched HGG patient-caregiver dyads completed the Multidimensional Mood State Questionnaire, the 12-Item Short Form Medical Outcome Questionnaire and the Center for Epidemiology Studies Depression Scale. A subsequent semi-structured interview was performed with each individual. RESULTS: We found a significant relationship between the mood and depression scores of patients and caregivers, with a third of them displaying symptoms of a major depressive episode. Our screening model showed that 73% of the dyads exhibited signs of severe emotional strain with the need of psychooncological support. Beneficial factors that helped patients and caregivers cope with the illness included mutual respect, good communication, caregiver mastery and resilience. CONCLUSIONS: For a more comprehensive understanding of patient-caregiver interactions, we recommend using a combination of standardized psychometric tests and a semi-structured interview. The high percentage of emotional strain and depression found in patients and their caregivers facing HGG highlights the necessity of methodical screening for warning signs and consequent initiation of psycho-oncological interventions.

Two cases of atypical meningioma with pulmonary metastases: a comparative cytogenetic analysis of chromosomes 1p and 22 and a review of the literature.

We present two cases of atypical meningioma WHO grade II with a history of multiple local recurrences and late pulmonary metastases. Comparative cytogenetic analyses on 1p and 22q confirmed clonal origin of the primary intracranial meningiomas and the pulmonary metastases in both cases. These cases illustrate the importance of close neuroradiological follow-up to detect tumor recurrence in patients with atypical meningiomas WHO grade II even with clinically stable disease and should sensitize clinicians to late extracranial metastases of these tumors, especially to the lung. In an effort to elucidate common clinical features of metastatic meningiomas, especially to the lung, the literature was reviewed from 1995 to 2014, identifying a total of 45 published cases.

Three gangliogliomas: results of GTG-banding, SKY, genome-wide high resolution SNP-array, gene expression and review of the literature.

According to the World Health Organization gangliogliomas are classified as well-differentiated and slowly growing neuroepithelial tumors, composed of neoplastic mature ganglion and glial cells. It is the most frequent tumor entity observed in patients with long-term epilepsy. Comprehensive cytogenetic and molecular cytogenetic data including high-resolution genomic profiling (single nucleotide polymorphism (SNP)-array) of gangliogliomas are scarce but necessary for a better oncological understanding of this tumor entity. For a detailed characterization at the single cell and cell population levels, we analyzed genomic alterations of three gangliogliomas using trypsin-Giemsa banding (GTG-banding) and by spectral karyotyping (SKY) in combination with SNP-array and gene expression array experiments. By GTG and SKY, we could confirm frequently detected chromosomal aberrations (losses within chromosomes 10, 13 and 22; gains within chromosomes 5, 7, 8 and 12), and identify so far unknown genetic aberrations like the unbalanced non-reciprocal translocation t(1;18)(q21;q21). Interestingly, we report on the second so far detected ganglioglioma with ring chromosome 1. Analyses of SNP-array data from two of the tumors and respective germline DNA (peripheral blood) identified few small gains and losses and a number of copy-neutral regions with loss of heterozygosity (LOH) in germline and in tumor tissue. In comparison to germline DNA, tumor tissues did not show substantial regions with significant loss or gain or with newly developed LOH. Gene expression analyses of tumor-specific genes revealed similarities in the profile of the analyzed samples regarding different relevant pathways. Taken together, we describe overlapping but also distinct and novel genetic aberrations of three gangliogliomas.

Bortezomib sensitizes primary human esthesioneuroblastoma cells to TRAIL-induced apoptosis.

TNF-related apoptosis-inducing ligand (TRAIL), a promising novel anti-cancer cytokine of the TNF superfamily, and Bortezomib, the first-in-class clinically used proteasome inhibitor, alone or in combination have been shown to efficiently kill numerous tumor cell lines. However, data concerning primary human tumor cells are very rare. Using primary esthesioneuroblastoma cells we analyzed the anti-tumor potential and the mechanism employed by Bortezomib in combination with TRAIL for the treatment of this rare but aggressive tumor. Expression of components of the TRAIL pathway was analyzed in tumor specimens and isolated primary tumor cells at the protein level. Cells were treated with TRAIL, Bortezomib, and a combination thereof, and apoptosis induction was quantified. Clonogenicity assays were performed to elucidate the long-term effect of this treatment. Despite expressing all components of the TRAIL pathway, freshly isolated primary esthesioneuroblastoma cells were completely resistant to TRAIL-induced apoptosis. They could, however, be very efficiently sensitized by subtoxic doses of Bortezomib. The influence of Bortezomib on the TRAIL pathway was analyzed and showed upregulation of TRAIL death receptor expression, enhancement of the TRAIL death-inducing signaling complex (DISC), and downregulation of anti-apoptotic proteins of the TRAIL pathway. Of clinical relevance, TRAIL-resistant primary tumor cells could be repeatedly sensitized by Bortezomib, providing the basis for repeated clinical application schedules. This is the first report on the highly synergistic induction of apoptosis in primary esthesioneuroblastoma cells by Bortezomib and TRAIL. This combination, therefore, represents a promising novel therapeutic option for esthesioneuroblastoma.

Molecular analyses of glioblastoma stem-like cells and glioblastoma tissue.

Glioblastoma is a common, malignant brain tumor whose disease incidence increases with age. Glioblastoma stem-like cells (GSCs) are thought to contribute to cancer therapy resistance and to be responsible for tumor initiation, maintenance, and recurrence. This study utilizes both SNP array and gene expression profiling to better understand GSCs and their relation to malignant disease. Peripheral blood and primary glioblastoma tumor tissue were obtained from patients, the latter of which was used to generate GSCs as well as a CD133pos./CD15pos. subpopulation. The stem cell features of GSCs were confirmed via the immunofluorescent expression of Nestin, SOX2, and CD133. Both tumor tissue and the isolated primary cells shared unique abnormal genomic characteristics, including a gain of chromosome 7 as well as either a partial or complete loss of chromosome 10. Individual genomic differences were also observed, including the loss of chromosome 4 and segmental uniparental disomy of 9p24.3→p21.3 in GSCs. Gene expression profiling revealed 418 genes upregulated in tumor tissue vs. CD133pos./CD15pos. cells and 44 genes upregulated in CD133pos./CD15pos. cells vs. tumor tissue. Pathway analyses demonstrated that upregulated genes in CD133pos./CD15pos. cells are relevant to cell cycle processes and cancerogenesis. In summary, we detected previously undescribed genomic and gene expression differences when comparing tumor tissue and isolated stem-like subpopulations.

Central neurocytoma: SNP array analyses, subtel FISH, and review of the literature.

The central neurocytoma (CN) is a rare brain tumor with a frequency of 0.1-0.5% of all brain tumors. According to the World Health Organization classification, it is a benign grade II tumor with good prognosis. However, some CN occur as histologically "atypical" variant, combined with increasing proliferation and poor clinical outcome. Detailed genetic knowledge could be helpful to characterize a potential atypical behavior in CN. Only few publications on genetics of CN exist in the literature. Therefore, we performed cytogenetic analysis of an intraventricular neurocytoma WHO grade II in a 39-year-old male patient by use of genome-wide high-density single nucleotide polymorphism array (SNP array) and subtelomere FISH. Applying these techniques, we could detect known chromosomal aberrations and identified six not previously described chromosomal aberrations, gains of 1p36.33-p36.31, 2q37.1-q37.3, 6q27, 12p13.33-p13.31, 20q13.31-q13.33, and loss of 19p13.3-p12. Our case report contributes to the genetic knowledge about CN and to increased understanding of "typical" and "atypical" variants.

Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.

PURPOSE: Malignant gliomas are the most aggressive human brain tumors without any curative treatment. The antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in gliomas has thus far only been thoroughly established in tumor cell lines. In the present study, we investigated the therapeutic potential of TRAIL in primary human glioma cells. EXPERIMENTAL DESIGN: We isolated primary tumor cells from 13 astrocytoma and oligoastrocytoma patients of all four WHO grades of malignancy and compared the levels of TRAIL-induced apoptosis induction, long-term tumor cell survival, caspase, and caspase target cleavage. RESULTS: We established a stable culture model for isolated primary human glioma cells. In contrast to cell lines, isolated primary tumor cells from all investigated glioma patients were highly TRAIL resistant. Regardless of the tumor heterogeneity, cotreatment with the proteasome inhibitor bortezomib efficiently sensitized all primary glioma samples for TRAIL-induced apoptosis and tremendously reduced their clonogenic survival. Due to the pleiotropic effect of bortezomib-enhanced TRAIL DISC formation upon TRAIL triggering, down-regulation of cFLIP(L) and activation of the intrinsic apoptosis pathway seem to cooperatively contribute to the antitumor effect of bortezomib/TRAIL cotreatment. CONCLUSION: TRAIL sensitivity of tumor cell lines is not a reliable predictor for the behavior of primary tumor cells. The widespread TRAIL resistance in primary glioma cells described here questions the therapeutic clinical benefit of TRAIL as a monotherapeutic agent. Overcoming TRAIL resistance by bortezomib cotreatment might, however, provide a powerful therapeutic option for glioma patients.

Comprehensive cytogenetic characterization of an esthesioneuroblastoma.

Esthesioneuroblastoma is a malignant neuroectodermal tumor originating from olfactory epithelial cells in the nasal vault. Due to the rarity of this tumor entity, cytogenetic data are very limited. Therefore, we performed comprehensive cytogenetic analyses of an esthesioneuroblastoma, Hyam's grade III-IV, using trypsin-Giemsa staining (GTG banding), multicolor fluorescence in situ hybridization (M-FISH), and locus-specific FISH complemented by molecular karyotyping using high-density single nucleotide polymorphism arrays. GTG banding of 25 metaphases revealed 54 structural intrachromosomal aberrations, predominantly located on 2q, 6q, 21q, and 22q, which were confirmed by FISH analysis. Interestingly, we found two novel, so far not described deletions, del(2)(q37) and del(21)(q22). Using GTG banding, locus-specific FISH, and M-FISH, we detected numeric changes of chromosomes 5, 17, 19, and 22, as well as trisomy 8 at low frequency. Applying SNP array karyotyping, we confirmed the chromosomal aberrations del(2)(q37.3), del(3)(q27.2), del(10)(q26.11), chromosomal imbalance on 17q, del(21)(q22), and revealed a number of so far unknown aberrations (gain of 2q14.3, 13q33.3, and 13q34). While the cytogenetically revealed low frequency mosaic del(6)(q22q24) was not visible using SNP array karyotyping, some of the smaller imbalances (SNP array data) could not have been detected by classic cytogenetic analysis. Therefore, our study supports the usefulness of applying complementary methods for cytogenetic analysis.

Cytogenetic and molecular biological characterization of an adult medulloblastoma.

Medulloblastoma is a malignant invasive embryonal tumor, occurring in children mainly. It is rare in adults (<1% of adult brain tumors), and so comprehensive cytogenetic and molecular biological data on adult medulloblastomas are very limited. Conventional therapies provide disappointing long-term disease control, and new therapeutic options are being tested. We performed comprehensive cytogenetic analyses of an adult medulloblastoma, WHO grade IV, using trypsin-Giemsa staining (GTG-banding), multicolor fluorescence in situ hybridization (M-FISH), and locus-specific FISH, complemented by molecular karyotyping using high-density single nucleotide polymorphism (SNP) arrays. GTG-banding of 25 metaphases revealed 31 structural chromosomal aberrations, predominantly located on chromosomes 4q, 9q, 10q, 11p, and 20q, which were confirmed by M-FISH. Two novel, so far not described translocations were found: t(4;11)(q25;p15) and t(9;20)(p23;p12). GTG-banding, locus-specific FISH, and M-FISH detected numerical changes of chromosomes 8, 14, 18, 19, 20, 21, and 22. Molecular karyotyping by SNP array confirmed chromosomal changes -2p, -10q, -16q, and -Xq and revealed de novo partial uniparental disomy 1q and 9q. Applying an upcoming therapeutic approach, we found that primary medulloblastoma cells were resistant to TRAIL, a novel anticancer cytokine, but could be efficiently sensitized by cotreatment with the proteasome inhibitor bortezomib. Bortezomib-TRAIL cotreatment may serve as a powerful therapeutic option for medulloblastoma patients.

WHO grade related expression of TRAIL-receptors and apoptosis regulators in meningioma.

BACKGROUND AND AIMS: The expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and key regulators of the extrinsic apoptosis pathway correlate with clinical features and the WHO grade of malignancy in some tumor entities. Expression of pro-apoptotic TRAIL receptors and executioners of apoptosis are a prerequisite for TRAIL-based therapies as a promising future targeted therapy. METHODS: Human meningioma tissues (n=24 WHO grade I, n=7 WHO grade II, n=6 WHO grade III) were immunohistochemically analyzed for the expression of TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4, caspase-8, cFLIP, Bcl-2, Bcl-XL, Mcl-1, Bax, and Bak. Staining intensities were quantified by an automated software-based algorithm. RESULTS: While TRAIL-R1 and TRAIL-R3 were nearly absent in meningiomas, TRAIL-R2 and TRAIL-R4 were abundantly expressed. However, only TRAIL-R4 expression correlated with the WHO grade of malignancy. Bcl-2 showed a non-significant upregulation in WHO grade III meningiomas. Bcl-XL and Mcl-1 expression was significantly higher in WHO grade II compared to grade I. Bcl-XL and TRAIL-R4 expression correlated with the mitotic activity (Ki67) of the tumor. Furthermore, TRAIL-R2 expression correlated with TRAIL-R4. Bak expression correlated with both, Bcl-XL and Mcl-1 expression. The expression patterns did neither correlate with the progression-free nor with the overall survival of the meningioma patients. CONCLUSIONS: Apoptosis-inducing TRAIL-R2 and all key executioners of the extrinsic apoptosis pathway are abundantly expressed in meningioma. For some regulators of apoptosis with opposite functions, the expression of the pro-apoptotic protein significantly correlated with the expression level of the respective anti-apoptotic binding partner, possibly resulting in a steady-state of apoptosis. TRAIL-R2 might serve as a novel therapeutic target in meningioma.

Cytogenetic and molecular cytogenetic analyses in diffuse astrocytomas.

Diffuse astrocytomas are highly variable tumors and show complex biologic behavior that is based on multi-step oncogenesis. We report cytogenetic and molecular cytogenetic investigations in 23 cases of diffuse astrocytomas. The results of conventional karyotyping, interphase fluorescence in situ hybridization (FISH), comparative genomic hybridization, multicolor FISH, and spectral karyotyping are reported. Various numerical and structural chromosomal aberrations were identified. Clustering of structural alterations in the short arm of chromosome 2 (2p) and the long arm of chromosome 7 (7q) were detected. Using spectral karyotyping, additional chromosome rearrangements not detectable by conventional methods were found. Some of these anomalies have not been previously described in diffuse astrocytomas. An independent validation of these discrepant findings is required.

Comparative genomic hybridization in glioma: a meta-analysis of 509 cases.

Much data about genetic imbalances in tumors have been accumulated by comparative genomic hybridization (CGH). In order to distinguish between significantly and coincidentally involved regions in glioma by means of a meta-analysis, we summarized and analyzed the CGH results of 509 cases published in 26 reports between 1992 and 2001. The expansion of all aberrations to the 850-band level impressively visualized distinct patterns in astrocytoma, oligodendroglioma, and ependymoma as well as loci of frequent aberrations. For example, in astrocytoma the frequency of gains culminated at 7p12, 8q24.1, and 12q13-q15 (the loci of EGF-R, C-MYC and CDK4, respectively) and losses at 9p21 (the locus of p15 and p16) and 10q23.3 where PTEN resides. Most chromosomes were variably prone to copy number changes at different scales of aberrations. At the whole chromosome level the analysis showed +7, -10 in astrocytoma and +9, +18 in ependymoma, but +20q, -9p in astrocytoma and +1q, -22q in ependymoma at the p-q arm level. Furthermore, we could confirm the correlation between the average number of copy alterations per patient (average number of copy alterations [ANCA] index) and malignancy for astrocytoma in a refined graduation as well as for oligodendroglioma. As a new parameter, the average number of affected GTG-bands per patient (average number of affected GTG bands [ANAG] index) showed an even more striking correlation with the World Health Organization grade for gains and losses.

NEUROGATE: a new MR-compatible device for realizing minimally invasive treatment of intracerebral tumors.

The authors report on the handling and the practicability of a newly developed MR-compatible device, the NEUROGATE (Daum GmbH, Germany), which allows precise planning, simulation and control of stereotactic biopsy in patients with suspect intracranial lesions, and which allows minimally invasive maneuvers to be performed in a comfortable way. Twenty-eight patients were examined stereotactically in the Signa SP interventional 0.5 Tesla MRI (General Electric Medical Systems, USA), including 15 patients with malignant intracerebral tumors and poor general medical conditions (8 gliomas, 7 metastases) who were treated by laser-induced interstitial thermotherapy (LITT) after definite intraoperative neuropathological diagnosis. As a special stereotactic holding device, the NEUROGATE was favored as a reliable tool for stereotaxy and minimally invasive procedures.

Cell cycle, oncogenic and tumor suppressor pathways regulate numerous long and macro non-protein-coding RNAs.

BACKGROUND: The genome is pervasively transcribed but most transcripts do not code for proteins, constituting non-protein-coding RNAs. Despite increasing numbers of functional reports of individual long non-coding RNAs (lncRNAs), assessing the extent of functionality among the non-coding transcriptional output of mammalian cells remains intricate. In the protein-coding world, transcripts differentially expressed in the context of processes essential for the survival of multicellular organisms have been instrumental in the discovery of functionally relevant proteins and their deregulation is frequently associated with diseases. We therefore systematically identified lncRNAs expressed differentially in response to oncologically relevant processes and cell-cycle, p53 and STAT3 pathways, using tiling arrays. RESULTS: We found that up to 80% of the pathway-triggered transcriptional responses are non-coding. Among these we identified very large macroRNAs with pathway-specific expression patterns and demonstrated that these are likely continuous transcripts. MacroRNAs contain elements conserved in mammals and sauropsids, which in part exhibit conserved RNA secondary structure. Comparing evolutionary rates of a macroRNA to adjacent protein-coding genes suggests a local action of the transcript. Finally, in different grades of astrocytoma, a tumor disease unrelated to the initially used cell lines, macroRNAs are differentially expressed. CONCLUSIONS: It has been shown previously that the majority of expressed non-ribosomal transcripts are non-coding. We now conclude that differential expression triggered by signaling pathways gives rise to a similar abundance of non-coding content. It is thus unlikely that the prevalence of non-coding transcripts in the cell is a trivial consequence of leaky or random transcription events.

Bortezomib sensitizes primary meningioma cells to TRAIL-induced apoptosis by enhancing formation of the death-inducing signaling complex.

A meningioma is the most common primary intracranial tumor in adults. Here, we investigated the therapeutic potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in 37 meningiomas. Freshly isolated primary meningioma cells were treated with TRAIL with or without different sensitizing protocols, and apoptotic cell death was then quantified. Mechanisms of TRAIL sensitization were determined by a combination of Western blotting, flow cytometry, receptor complex immunoprecipitation, and siRNA-mediated knockdown experiments. Tumor necrosis factor-related apoptosis-inducing ligand receptor expression was analyzed using immunohistochemistry and quantified by an automated software-based algorithm. Primary tumor cells from 11 (29.7%) tumor samples were sensitive to TRAIL-induced apoptosis, 12 (32.4%) were intermediate TRAIL resistant, and 14 (37.8%) were completely TRAIL resistant. We tested synergistic apoptosis-inducing cotreatment strategies and determined that only the proteasome inhibitor bortezomib potently enhanced expression of the TRAIL receptors TRAIL-R1 and/or TRAIL-R2, the formation of the TRAIL death-inducing signaling complex, and activation of caspases; this treatment resulted in sensitization of all TRAIL-resistant meningioma samples to TRAIL-induced apoptosis. Bortezomib pretreatment induced NOXA expression and downregulated c-FLIP, neither of which caused the TRAIL-sensitizing effect. Native TRAIL receptor expression could not predict primary TRAIL sensitivity. This first report on TRAIL sensitivity of primary meningioma cells demonstrates that TRAIL/bortezomib cotreatment may represent a novel therapeutic option for meningiomas.

Comprehensive high-resolution genomic profiling and cytogenetics of two pediatric and one adult medulloblastoma.

Medulloblastoma (WHO grade IV) is a rare, malignant, invasive, embryonal tumor which mainly occurs in children and represents less than 1% of all adult brain tumors. Systematic comprehensive genetic analyses on medulloblastomas are rare but necessary to provide more detailed information. Therefore, we performed comprehensive cytogenetic analyses (blood and tissue) of two pediatric and one adult medulloblastoma, using trypsin-Giemsa staining, spectral karyotyping (tissues only), SNP-arrays, and gene expression analyses. We confirmed frequently detected chromosomal aberrations in medulloblastoma, such as +7q, -8p/q, -9q, -11q, -12q, and +17q and identified novel genetic events. Applying SNP-array, we identified constitutional de novo losses 5q21.1, 15q11.2, 17q21.31, 19p12 (pediatric medulloblastoma), 9p21.1, 19p12, 19q13.3, 21q11.2 (adult medulloblastoma) and gains 16p11.1-16p11.2, 18p11.32, Yq11.223-Yq11.23 (pediatric medulloblastoma), Xp22.31 (adult medulloblastoma) possibly representing inherited causal events for medulloblastoma formation. We show evidence for somatic segmental uniparental disomy in regions 1p36, 6q16.3, 6q24.1, 14q21.2, 17p13.3, and 17q22 not previously described for primary medulloblastoma. Gene expression analysis supported classification of the adult medulloblastoma to the WNT-subgroup and classification of pediatric medulloblastomas to group 3 tumors. Analyses of tumors and matched normal tissues (blood) with a combination of complementary techniques will help to further elucidate potentially causal genetic events for medulloblastomas.

Giant intradiploic epidermoid cyst with large osteolytic lesions of the skull: a case report.

INTRODUCTION: We report a case of tumor growth over a period of four decades, presenting with large multicentric lytic lesions of the skull and a profound mass effect, without neurological deficits. Clinical and radiological features of a patient with a giant intradiploic epidermoid and its impact on the choice of treatments are discussed. CASE PRESENTATION: An 81-year-old Caucasian man, who had first noticed a painless subcutaneous swelling over the left frontal scalp about 40 years ago, presented after a short episode of dizziness, which he experienced after treatment of focal retinal detachment. Computed tomography (CT) and magnetic resonance imaging (MRI) examinations revealed an exceptionally large tumor involving major parts of the skull with extensive destruction of the bone and distinct deformation of the brain. Considering his age and the absence of neurological deficits or pain, the patient refused the option of tumor removal and cranioplasty, yet agreed to a biopsy, which confirmed the suspected diagnosis. CONCLUSIONS: The course of the disease demonstrates that even patients with large tumors, inducing distinct pathomorphological changes, do not necessarily experience significant impairment of their quality of life without surgery. This is an impressive example of the chance to lead a long and satisfying life without specific medical treatment, avoiding the inherent risks of these procedures. Yet, there is a clear indication for surgery of intradiploic epidermoids in most cases described in the literature.

Detection of novel genomic aberrations in anaplastic astrocytomas by GTG-banding, SKY, locus-specific FISH, and high density SNP-array.

Astrocytomas represent the largest and most common subgroup of brain tumors. Anaplastic astrocytoma (WHO grade III) may arise from low-grade diffuse astrocytoma (WHO grade II) or as primary tumors without any precursor lesion. Comprehensive analyses of anaplastic astrocytomas combining both cytogenetic and molecular cytogenetic techniques are rare. Therefore, we analyzed genomic alterations of five anaplastic astrocytomas using high-density single nucleotide polymorphism arrays combined with GTG-banding and FISH-techniques. By cytogenetics, we found 169 structural chromosomal aberrations most frequently involving chromosomes 1, 2, 3, 4, 10, and 12, including two not previously described alterations, a nonreciprocal translocation t(3;11)(p12;q13), and one interstitial chromosomal deletion del(2)(q21q31). Additionally, we detected previously not documented loss of heterozygosity (LOH) without copy number changes in 4/5 anaplastic astrocytomas on chromosome regions 5q11.2, 5q22.1, 6q21, 7q21.11, 7q31.33, 8q11.22, 14q21.1, 17q21.31, and 17q22, suggesting segmental uniparental disomy (UPD), applying high-density single nucleotide polymorphism arrays. UPDs are currently considered to play an important role in the initiation and progression of different malignancies. The significance of previously not described genetic alterations in anaplastic astrocytomas presented here needs to be confirmed in a larger series.

Multiple meningioma with different grades of malignancy: case report with genetic analysis applying single-nucleotide polymorphism array and classical cytogenetics.

Multiple meningiomas with synchronous tumor lesions represent only 1-9% of all meningiomas and usually show a uniform histology. The simultaneous occurrence of different grades of malignancy in these nodules is observed in only one third of multiple meningiomas. We report a case of a sporadic multiple meningioma presenting with different histopathological grades (WHO I and II). The tumor genome of both nodules was analyzed by GTG-banding, spectral karyotyping (SKY), locus-specific FISH, and single nucleotide polymorphism array (SNP-A) karyotyping. GTG-banding and SKY revealed 25 structural and 33 numerical aberrations with a slightly increased aberration frequency in the WHO grade II nodule. We could confirm terminal deletions on chromosomes 1p [ish del(1)(p36)(p58-,pter-) 16.5% WHO grade I and 20.9% WHO grade II], partial deletions on 22q, and/or monosomy 22 (monosomy 22 14% WHO grade I and 34% WHO grade II) as the most frequent aberrations in both meningioma nodules. In the meningioma WHO grade II, in addition, a de novo paracentric inversion within chromosomal band 1p36 was detectable. Furthermore, for meningiomas de novo, dicentric chromosomes 4 could be identified in both tumor nodules. We also detected previously published segmental uniparental disomy regions 1p31.1, 6q14.1, 10q21.1, and 14q23.3 in normal control DNA of the patient and in both tumor nodules. Taken together, we describe a very rare case of multiple meningioma with overlapping but also distinct genetic aberration patterns in two nodules of different WHO grades of malignancy.

Intracranial hemangiopericytoma: Case study with cytogenetics and genome wide SNP-A analysis.

The tumor entity of hemangiopericytoma is not universally recognized as a nosological entity by pathologists, and there is a trend toward reassigning it to other categories gradually. However, hemangiopericytomas occurring in the nervous system are included in the new WHO classification of brain tumors, and are distinguished from both meningioma and fibrous tumors. Since there are few genetic studies, we performed a comprehensive cytogenetic analysis of an infratentorial hemangiopericytoma in a 55-year-old female. It was originally classified as a grade II tumor but recurred as a grade III tumor with a proliferation index of 20%. Using trypsin-Giemsa staining (GTG-banding) and multicolor fluorescence in situ hybridization (M-FISH), we could confirm the loss of chromosomal material 10q, which has been previously described in hemangiopericytoma, and we identified de novo chromosomal aberrations on chromosome 8. Applying genome-wide high-density single nucleotide polymorphism array (SNP-A) analysis, we detected segments with loss or gain, as well as clonal deletions or regions suggestive of segmental uniparental disomy. These findings, together with the results of conventional histological and immunohistochemical characterization, provide additional evidence for the nosological separation of hemangiopericytoma in the central nervous system as a biologically different entity.