Non degradation of chitosan and initial degradation of collagen nerve conduits used for protection of nerve coaptations.

BACKGROUND: Nerve conduits are either used to bridge nerve gaps of up to 3 cm or to protect nerve coaptations. Biodegradable nerve conduits, which are currently commercially available, include Chitosan or collagen-based ones. As histological aspects of their degradation are highly relevant for the progress of neuronal regeneration, the aim of this study was to report the histopathological signs of such nerve conduits, which were removed during revision surgery. MATERIALS AND METHODS: Either Chitosan (n = 2) or collagen (n = 2) nerve conduits were implanted after neuroma resection and nerve grafting (n = 2) or traumatic nerve lesion after cut (n = 1) or crush injury (n = 1) in two females and two men, aged between 17 and 57 years. Revision surgery with removal of the nerve conduits was indicated due to persisting neuropathic pain and sensorimotor deficits, limited joint motion, or neurolysis with hardware removal at a median time of 17 months (range: 5.5-48 months). Histopathological analyses of all removed nerve conduits were performed. RESULTS: A scar neuroma was diagnosed in one out of four patients. Mechanical complication occurred in one patient after nerve conduit implantation bridged over finger joints. Intraoperatively no or only initial signs of degradation of the nerve conduits were observed. Chitosan conduits revealed largely unchanged shape and structure of chitosan, and coating of the conduit by a vascularized fibrous membrane. The latter contained deposits taken up by macrophages, most likely representing dissolved chitosan. Characteristic histopathologic features of the degradation of collagen conduits were a disintegration of the compact collagen into separate fine circular strands, No foreign body reaction was observed in all removed nerve conduits. CONCLUSIONS: Both Chitosan nerve conduits have not been degraded. The collagen nerve conduits showed a beginning degradation process. Furthermore, wrapping the repaired nerve with a nerve conduit did neither prevent adhesions nor improved nerve gliding. Therefore, biodegradation in time should be particularly addressed in further developments of nerve conduits.

Senile plaque calcification of the lamina circumvoluta medullaris in Alzheimer's disease.

Vascular calcification is a common phenomenon in the elderly, predominantly appearing in the basal ganglia and in the lamina circumvoluta medullaris of the hippocampus. Calcifications are not an inherent feature of Alzheimer's disease. On the other hand, a rare presenile type of dementia with symmetrical Fahr-type calcifications and numerous neurofibrillary tangles without senile plaques has been described by Kosaka in 1994 and was termed "diffuse neurofibrillary tangles with calcification" (DNTC). We here report a case of Alzheimer's disease with calcifications both in the basal ganglia and in the lamina circumvoluta medullaris of the hippocampus, differing from DNTC by the presence of senile plaques. The calcifications in the hippocampus were not only vascular in nature but also covered amyloid-ß- and phosphorylated tau-positive plaque-like structures that were linearly arranged along the dentate fascia in the CA1 sector, an unusual finding of pathogenetic interest.

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.

Induction of gliosarcoma and atypical meningioma 13 years after radiotherapy of residual pilocytic astrocytoma in childhood.

BACKGROUND: Malignant transformation of pilocytic astrocytomas in children is rare and often linked to previous radiotherapy. METHODS AND RESULTS: We report a patient who underwent subtotal resection of a right temporal and insular pilocytic astrocytoma at age 8 in 1988 followed by high-dose radiation therapy. A local recurrence, grade WHO III, with signs of focal sarcomatous transformation, was subtotally resected 13 years later in 2001. A new and fast growing right frontal meningioma, grade WHO II, was removed in 2003. In 2004 a second glioma recurrence was partially resected, this time graded gliosarcoma WHO IV. The patient was treated thereafter with repeated courses of temozolomide. Another tumor mass reduction in 2005 was followed by stereotactic radiotherapy. Nevertheless, he deceased 3 months later. CONCLUSION: Most of the reported cases of malignant transformation of pilocytic astrocytomas received radiation therapy beforehand. Irradiation-induced meningiomas in children are known to occur, however not following radiotherapy of low-grade hemispheric gliomas. The presented case illustrates why adjuvant radiotherapy of residual pilocytic astrocytoma in children is not recommended anymore. For children who underwent radiotherapy in the past, we recommend MRI surveillance on a yearly basis far beyond 10 years, even in those who seem to have achieved total remission.

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.

Transplantation of human neural precursor cells in the 6-OHDA lesioned rats: effect of immunosuppression with cyclosporine A.

Neural precursor cells (NPC) may provide a source for restaurative therapy. We wanted to study the immunogenic potential of human NPC. We transplanted human NPCs with or without cyclosporine A (10 mg/kg) expanded in serum-free conditions into the striatum of rats unilaterally lesioned with 6-hydroxydopamine. Four months after transplantation, there was significant improvement of amphetamine-induced rotational behavior 9 non-immunosuppressed (13.1+/-4.9 pre vs 8.5+/-4.0 after grafting) but nor for 11 animals immunosuppressed with CyA (12.3+/-1.7 vs 11.3+/-2.8). The number of TH-IR cells was comparable in both groups (1,580+/-700 vs 1,274+/-295). All grafted animals only showed mild activation of astrocytes and macrophages within the graft. There was no evidence for tumor formation. Immunosuppression of rats, xenotransplanted with human NPC did not improve graft survival or function.

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.

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.

[Cryotherapy of the brain--a new methodologic approach]. / Kryotherapie am Hirn--ein neuer methodischer Ansatz.

Cryodestruction of tissue is influenced by cooling and thawing rates, absolute tissue temperature, number of freeze-thaw cycles, and type of tissue. However, under clinical conditions a MRT visualization of the temperature distribution during cryo-procedures is not possible. Thus, the extent of necrotic areas within the cryo-influenced regions are not precisely predictable. This limitation is particularly relevant for the application of cryoablation in the brain. The present paper proposes the concept of a local, cryo-induced ischemic necrosis. The basic concept is that the MRT-observable and surgically well-manageable frozen region is ischemic. This cryo-induced ischemia causes a necrosis. The extent of the necrotic region is exclusively determined by the ischemia tolerance of the tissue. The effectiveness of this method is demonstrated on sheep brain in vivo. Compared to the freeze-thaw method, histological examinations show a sharper demarcation between regions of necrosis and healthy tissue. In conclusion, the method of MR-controlled local, cryo-induced ischemia enables an exact definition of the region of necrosis in the brain.

Predictive chromosomal clusters of synchronous and metachronous brain metastases in clear cell renal cell carcinoma.

Synchronous (early) and metachronous (late) brain metastasis (BM) events of sporadic clear cell renal cell carcinoma (ccRCC) (n = 148) were retrospectively analyzed using comparative genomic hybridization (CGH). Using oncogenetic tree models and cluster analyses, chromosomal imbalances related to recurrence-free survival until BM (RFS-BM) were analyzed. Losses at 9p and 9q appeared to be hallmarks of metachronous BM events, whereas an absence of detectable chromosomal changes at 3p was often associated with synchronous BM events. Correspondingly, k-means clustering showed that cluster 1 cases generally exhibited low copy number chromosomal changes that did not involve 3p. Cluster 2 cases had a high occurrence of -9p/-9q (94-98%) deletions, whereas cluster 3 cases had a higher frequency of copy number changes, including loss at chromosome 14 (80%). The higher number of synchronous cases in cluster 1 was also associated with a significantly shorter RFS-BM compared with clusters 2 and 3 (P = 0.02). Conversely, a significantly longer RFS-BM was observed for cluster 2 versus clusters 1 and 3 (P = 0.02). Taken together, these data suggest that metachronous BM events of ccRCC are characterized by loss of chromosome 9, whereas synchronous BM events may form independently of detectable genetic changes at chromosomes 9 and 3p.

Does histology predict the clinical outcome after lumbar intervertebral disc herniation: no.

BACKGROUND AND OBJECTIVES: The histological analysis of extirpated intervertebral disc material from patients undergoing discectomy due to lumbar disc herniation remains an established procedure. In looking at whether the high costs that histological examination entails can be justified, it is worthwhile to ascertain the actual diagnostic benefit of this procedure. The aim of this study was to address the following hypothesis: Do histological characteristics such as the presence of inflammatory cells (macrophages) predict the clinical outcome of patients undergoing discectomy? MATERIALS AND METHODS: A total of 343 patients (221 males, 122 females, mean age 44.7 years) were treated microsurgically by root decompression subsequent to interlaminar fenestration. The patient history, the operated disc segment, the radicular and vegetative symptoms as well as the early and long-term outcome were evaluated. The excised disc material was classified histologically. CD68 staining was performed in 11 randomly chosen patients with good and in 11 patients with poor subjective long-term outcome for quantitative evaluation of macrophage count. RESULTS: The follow up rate was 69.7%. Three hundred and five patients underwent disc surgery for the first time and 38 patients underwent relapse disc surgery. Moderate, pronounced and severe degeneration was found in 16, 231 and 92 patients, respectively. Positive subjective assessment of early outcome was 91% and 92% for the primary and relapse group, whereas long-term outcome was positive in 69% and 50% for the primary and the relapse group respectively. No histological features including CD68 (macrophage) count showed statistically significant correlations with the success of clinical treatment. DISCUSSION AND CONCLUSIONS: A reliable prediction of the success of treatment, including patient outcome, cannot be made on the basis of the present histological criteria. The hypothesis must therefore be rejected.

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.

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.

High resolution genomic profiling and classical cytogenetics in a group of benign and atypical meningiomas.

Meningiomas are classified as benign, atypical, or anaplastic. The majority are sporadic, solitary, and benign tumors with favorable prognoses. However, the prognosis for patients with anaplastic meningiomas remains less favorable. High resolution genomic profiling has the capacity to provide more detailed information. Therefore, we analyzed genomic aberrations of benign and atypical meningiomas using single nucleotide polymorphism (SNP) array, combined with G-banding by trypsin using Giemsa stain (GTG banding), spectral karyotyping, and locus-specific fluorescence in situ hybridization (FISH). We confirmed frequently detected chromosomal aberrations in meningiomas and identified novel genetic events. Applying SNP array, we identified constitutional de novo loss or gain within chromosome 22 in three patients, possibly representing inherited causal events for meningioma formation. We show evidence for somatic segmental uniparental disomy in regions 4p16.1, 7q31.2, 8p23.2, and 9p22.1 not previously described for primary meningioma. GTG-banding and spectral karyotyping detected a novel balanced reciprocal translocation t(4;10)(q12;q26) in one benign meningioma. A paracentric inversion within 1p36, previously described as novel, was detected as a recurrent chromosomal aberration in benign and atypical meningiomas. Analyses of tumors and matched normal tissues with a combination of SNP arrays and complementary techniques will help to further elucidate potentially causal genetic events for tumorigenesis of meningioma.

Spheno-orbital meningiomas: outcome after microsurgical treatment: a clinical review of 30 cases.

OBJECTIVE: Spheno-orbital meningiomas represent a delicate subtype of intracranial meningiomas involving the sphenoid wing, orbit and important neurovascular structures such as cavernous sinus, carotid artery or optic nerve. Insidious and aggressive dural, bone and orbital involvement contains several defiances to adequate resection, which provides high rates of recurrence. METHODS: This retrospective case analysis consisted of 30 patients, who were surgically treated for spheno-orbital meningiomas performing a fronto-pterional approach by or under the supervision of the senior author (J. Meixensberger) between May 2001 and February 2006. There were 22 woman and eight men with a mean age of 54.4 years. The follow-up period ranged from 3 to 75 months (mean: 33.7 months). RESULTS: The majority of patients presented with a clinical triad of visual impairment (74%), progressive proptosis (55%) and visual field defects (40%). Total microscopic tumor resection was achieved in ten patients (33%). Visual acuity improved in 65% of the patients, and 40% of these returned to normal vision. Pre-existing cranial nerve deficits remained unchanged in the majority of patients (88%) and improved in 12%. Temporary new cranial nerve deficits occurred in three patients. The rate of permanent non-visual morbidity was 10% (three of 30 patients). Eight patients (27%) received post-operative radiotherapy with an overall tumor growth control rate of 63%. The overall recurrence rate was 27% (eight of 30 patients). CONCLUSION: Sufficient tumor control can be achieved with minimal morbidity and satisfying functional results.