[Accreditation in pathology and neuropathology : Paths and pitfalls]. / Akkreditierung in der Pathologie und Neuropathologie : Wege und Pitfalls.

There are many good reasons for accreditation in pathology or neuropathology as per DIN EN ISO/IEC 17020, regardless of the size and range of services of the facility. Only accreditation - in contrast to certification - also confirms professional competence. This article describes how to establish a quality management system that conforms to standards as effectively as possible and how to maintain it, involve staff, and avoid common pitfalls. Adequate resources and active management support are essential. In this way, not only can accreditation succeed, but the facility itself and its employees can benefit from quality management in their daily work.

Bevacizumab treatment for symptomatic spinal ependymomas in neurofibromatosis type 2.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome associated with vestibular schwannomas, meningiomas, and spinal ependymomas. There have been anecdotal reports of radiographic response of spinal ependymomas in NF2 patients being treated for progressive vestibular schwannomas with bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF). AIMS: The aim of this study was to review the clinical effects of bevacizumab treatment for symptomatic, NF2-associated ependymomas METHODS: We conducted a retrospective review of all patients with NF2 treated with bevacizumab for symptomatic ependymoma at three NF2 specialty centers. Tumor size was evaluated by linear measurements; radiographic response was defined as >20% reduction in tumor size. We also performed immunohistochemical evaluation of NF2-associated symptomatic ependymomas from five patients, including two from this clinical series. RESULTS: Eight patients with NF2 and symptomatic ependymoma were treated with bevacizumab. All patients had subjective clinical improvement with bevacizumab, although only five of eight patients evaluated had radiographic response. All tumors expressed VEGF-R2. Four of five evaluated ependymomas expressed VEGF-R1; one without VEGF-R1 expression was from a patient who showed clinical but not radiographic response. CONCLUSIONS: Treatment using bevacizumab improved symptoms related to NF2-associated ependymomas, often without concurrent radiographic response. This treatment effect may be related to VEGF-R1 expression in NF2-associated ependymoma.

Impact of protein content on proton diffusibility in intracranial cysts.

PURPOSE: The physical background of diffusion phenomena in intracranial cysts is unclear in some cases. To evaluate a potential dependency of proton diffusion on the concentration of proteins in cystic lesions we investigated the correlation of diffusion weighted imaging (DWI) and magnetization transfer ratio imaging (MTR) in intracranial cystic pathologies in vivo and in vitro with protein solutions. MATERIALS AND METHODS: 21 patients (14 male/7 female) with intracranial cystic lesions underwent preoperative MRI (1.5T) including MTR and DWI sequences. For comparison a series of samples with declining concentration of albumin was investigated in vitro with a 7T animal scanner. RESULTS: In the patients examination mean ADC values were 1.93×10-3mm2/sec and mean MTR values were 0.2. Mean ADC value of the albumin solutions was 0.22× 0-3mm2/sec and mean MTR was 0.12. ADC and MTR values showed a strong negative correlation in the patients (Spearman's rank correlation rs=-0.80, p<0.01) and a very strong negative correlation in the in vitro examinations (rs=-1.0, p<0.01). CONCLUSION: The strong negative correlation of ADC and MTR values suggest a strong influence of proteins on proton diffusion in intracranial cysts. The phenomena can be explained by macromolecules that bind nearby protons in their vicinity.

Mismatch repair deficiency: a temozolomide resistance factor in medulloblastoma cell lines that is uncommon in primary medulloblastoma tumours.

BACKGROUND: Tumours are responsive to temozolomide (TMZ) if they are deficient in O(6)-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient. METHODS: The effect of TMZ on medulloblastoma (MB) cell killing was analysed with clonogenic survival assays. Expression of DNA repair genes and enzymes was investigated using microarrays, western blot, and immunohistochemistry. DNA sequencing and promoter methylation analysis were employed to investigate the cause of loss of the expression of MMR gene MLH1. RESULTS: Temozolomide exhibited potent cytotoxic activity in D425Med (MGMT deficient, MLH1 proficient; IC(50)=1.7 µM), moderate activity against D341Med (MGMT proficient, MLH1 deficient), and DAOY MB cells (MGMT proficient, MLH1 proficient). MGMT inhibitor O(6)-benzylguanine sensitised DAOY, but not D341Med cells to TMZ. Of 12 MB cell lines, D341Med, D283Med, and 1580WÜ cells exhibited MMR deficiency due to MLH1 promoter hypermethylation. DNA sequencing of these cells provided no evidence for somatic genetic alterations in MLH1. Expression analyses of MMR and MGMT in MB revealed that all patient specimens (n=74; expression array, n=61; immunostaining, n=13) are most likely MMR proficient, whereas some tumours had low MGMT expression levels (according to expression array) or were totally MGMT deficient (3 out of 13 according to immunohistochemistry). CONCLUSION: A subset of MB may respond to TMZ as some patient specimens are MGMT deficient, and tumours appear to be MMR proficient.

Use of Erythropoietin as adjuvant therapy in nerve reconstruction.

BACKGROUND AND AIMS: Adjuvant therapies may improve the outcome after nerve reconstruction. We analyzed the influence of recombinant human Erythropoietin (rHuEpo), which has proven angiogenic and neuroprotective effects, on the quality of peripheral nerve regeneration. METHODS: Thirty two female Lewis rats underwent nerve reconstruction by means of tubulization (groups I and II) or autologous sciatic nerve grafting (groups III and IV). Groups I and III received daily subcutaneous rHuEpo injections over 2 weeks (1,000 U/kg bw) with normal saline injections as controls (groups II and IV). Data on histology and muscle weight were collected after 7 weeks. Axon count and diameter were assessed by a new method based on digital segmentation. RESULTS: Atrophy of the tibial muscle was less severe in the rHuEpo-treated group compared to controls resulting in significant higher muscle weight quotients (p = 0.006). The same trend was found in the gastrocnemius muscle, but without being statistically significant. No significant differences in axon count or axon diameter were detected in the presence of rHuEpo treatments. CONCLUSION: Our findings give evidence for a positive effect of Erythropoietin on functional recovery after nerve grafting. Muscle recovery benefited from rHuEpo administration despite absence of improved neural morphology. Semi-automated axon detection facilitated accurate morphometrical assessment.

Clinical relevance of positron emission tomography and magnetic resonance imaging in the progression of internal plexiform neurofibroma in NF1.

Neurofibromatosis type 1 (NF1) is a frequent and inherited disease with a predisposition for malignant peripheral nerve sheath tumor (MPNST) development. MPNST are soft tissue sarcomas that arise from peripheral nerves, being one of the most aggressive malignancies in humans with extremely poor prognosis. MPNST frequently arise from a previously undetected plexiform neurofibroma (PNF). The malignant transformation of an internal PNF to an MPNST is difficult to assess and requires advanced imaging techniques like magnetic resonance imaging or positron emission tomography. Despite the high quality of current diagnostics, the changing tumor biology inside a plexiform neurofibroma cannot currently be visualized accurately. We report 4 cases of NF1 patients with PNF who showed imaging findings suspicious for malignant degeneration, but proved to have MPNST in only one case. Three tumors might represent an intermediate type between PNF and MPNST. Ablative surgery and complete histological work-up of specimens is the only way to clarify tumor status, thereby enabling provision of adequate local treatment.

Expression of insulin-like growth-factor-1 receptor (IGF-1R) in peripheral nerve sheath tumors in neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal-dominant inherited disease, characterised by the development of nerve sheath tumors. NF1 is the most frequently inherited disease associated with a predisposition for cancer (in particular malignant peripheral nerve sheath tumors: MPNST). NF1 is a progressive disease with phase-like growth spurts of dermal or plexiform neurofibroma (PNF). These tumors can cause severe disfigurement of patients. Growth control of these tumors is poorly understood. The aim of this study was to identify the expression of insulin-like growth factor 1-receptor (IGF-1R) in peripheral nerve sheath tumors. Factor and receptor are involved in the growth control of numerous physiological and pathological processes, including Schwann cell development. MATERIALS AND METHODS: The investigation included tumors of NF1-patients only (neurofibroma, MPNST). Sections of the specimens were immunohistochemically typed for several antigens (target antigens: IGF-1R, S-100, EMA, CD34, MIB-1), using both single and double-staining methods. Double-staining allowed the sub-typing of the IGF-1R-expressing cells in the mixed nerve sheath tumors. The expression was also investigated in Schwann cell cultures and co-cultures with fibroblasts. RESULTS: Staining of S-100 and IGF-1R, PNF were more intensely marked than MPNST (r = -0.439, p < 0.002, N = 49). The proliferation index was tumor-type dependent: MPNST > neurofibroma. The IGF-1R-expression correlated positively with the MIB-1 index in neurofibroma (r = 0.372, p = 0.021, N = 38). The receptor expression was higher in PNF than in dermal neurofibroma (r = 0.335, p = 0.040, N = 38). IGF-1R was detected in Schwann cells (S-100 positive) and in perineurial cells (EMA-positive) of all nerve sheath tumors. However, the receptor was also identified in CD34-marked endothelia of neurofibromas but not in endothelia of MPNST. In Schwann cell cultures, a strong receptor-expression became evident. This expression was independent of co-cultivation of tumor cells with fibroblasts. The statistical calculations excluded the impact of gender on the receptor expression. CONCLUSION: This investigation provides evidence for the expression of IGF-1R in nerve sheath tumors in NF1. The expression pattern varied between the tumor types, the cell types, and between tumors of the same type. IGF and IGF-1R are a prerequisite to maintain Schwann cell stability in the postnatal period and to prevent Schwann cell apoptosis. The first evidence for IGF-1R expression in mutated Schwann cells may indicate a tumor-type associated receptor expression in NF1.

[Congenital hemiplegia. A disease with manifold problems]. / Kongenitale Hemiplegie. Eine Krankheit mit vielen Problemen.

Congenital hemiplegia, defined as unilateral motor disability, is the hemiplegic type of cerebral palsy. The prevalence of congenital hemiplegia is estimated to be about 0.41-0.79/1000 live births. We examined 223 children (122 boys and 101 girls) suffering from congenital hemiplegia at the age of 3 months to 12 years. Mild hemiplegia was found in 31%, a moderate form in 48%, and a severe form in 21%. The upper limb was affected in more than half of the patients, only the lower extremity in one third, and both upper and lower limbs in 20%. Electroencephalographic abnormalities were found in 75.8% of the patients. The most frequent type of epilepsy was complex partial seizures (33%). Severity of the motor handicap, grade of EEG abnormalities, and the prevalence of epilepsy showed a significant correlation. The magnitude of the lesions in neuroimaging directly correlated with these three clinical variables, particularly in children with cortical and subcortical defects (84.2%). Strabismus was the most common visual impairment (17%), while hearing impairment was found in 8% of the patients. Of them, 38.3% showed no cognitive deficits, while those with severe congenital hemiplegia were found to have a lower intelligence quotient.

Fatal recurrent subarachnoid hemorrhage after complete endovascular aneurysm occlusion.

Endovascular treatment of aneurysms has become an alternative to the neurosurgical approach. Here, we describe a patient presenting with a subarachnoid hemorrhage (SAH) due to a basilar tip aneurysm, which was completely occluded with coils. Fourteen days later the patient died due to massive recurrent SAH. Histologic evaluation showed aneurysm rerupture with coil dislocation in the subarachnoid space. This is a rare histologically documented case of fatal recurrent hemorrhage early after coil embolization of cerebral aneurysms.

Disarrangement of fiber tracts and decline of neuronal density correlate in glioma patients--a combined diffusion tensor imaging and 1H-MR spectroscopy study.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) and MR spectroscopy are noninvasive, quantitative tools for the preoperative assessment of gliomas with which the quantitative parameter fractional anisotropy (FA) and the concentration of neurometabolites N-acetylaspartate (NAA), choline (Cho), creatine (Cr) of the brain can be determined. Measurements of FA and NAA reflect the integrity of fiber tracts and the presence of neurons, respectively. This investigation examines changes of FA and NAA and compares these different aspects in architecture of gliomas after spatial coregistration. METHODS: DTI and chemical shift (1)H-MR spectroscopy was performed in 34 healthy volunteers and 69 patients with histologically confirmed (n = 48) or morphologically suspected (n = 21) non-necrotic brain glioma. Volumes of interest (VOIs) were placed in the tumor center (TC), the tumor border (TB), the normal-appearing white matter adjacent to the tumors (TNWM), and in the white matter of the contralateral hemisphere (NWMC). Median FA values and NAA/Cr and NAA/Cho ratios were calculated in the patients' VOIs and the gray and white matter of the volunteers. Correlations of FA values and NAA ratios were calculated. RESULTS: Continuous changes of FA and NAA from the tumor center to the periphery (the adjacent white matter and the contra-lateral hemisphere, respectively) were observed, where median values were: TC: 0.73 +/- 0.45, 0.47 +/- 0.58, 0.17 +/- 0.15 (NAA/Cr, NAA/Cho, FA); TB: 1.06 +/- 0.53, 1.00 +/- 0.15, 0.23 +/- 0.08; TNWM: 1.42 +/- 2.48, 1.21 +/- 0.95, 0.34 +/- 0.09; and NWMC: 1.63 +/- 0.72, 1.56 +/- 1.34, 0.38 +/- 0.08. Correlation of median FA values and NAA ratios in the cumulative group of patients was high (r = 0.99 [NAA/Cr], 0.95 [NAA/ Cho] at P < .01). Correlation between the individual NAA ratios and the FA values was moderate (r = 0.53 [NAA/Cr], 0.51 [NAA/Cho] at P < .01). CONCLUSION: In gliomas, the degree of tissue organization decreases continuously from the surrounding tissue toward the center of the tumor accompanied by a concordant decrease of NAA. This uniform behavior of FA and NAA reflects a decreasing integrity of both neuronal structures and fibers.

Expression of SOX9 and SOX10 in central neuroepithelial tumor.

The SOX group E transcription factors play an integral role in the specification and differentiation of astrocytes and oligodendrocytes. We have examined the pattern of expression for SOX9 and SOX10 in primary brain tumors by immunohistochemistry. Pediatric and adult high grade tumors display strong nuclear staining for both SOX9 and SOX10 (astrocytic, oligodendroglial and primitive neuroectodermal tumors). In comparison pediatric pilocytic astrocytoma express much less SOX9 and SOX10. Reactive astrogliosis is characterized by an increase of SOX9 only.

[Abdominal approaches and drainages of the abdominal cavity]. / Zugangswege zur Bauchhöhle und Möglichkeiten der Drainage.

Appropriate access to the abdominal cavity is the first and crucial step for successful abdominal surgical intervention. In planning the incision, several variables have to be considered, such as anatomy of the abdominal wall, localization of the target organ, and individual conditions (previous incisions, minimal access surgery, etc). Medial laparotomy is the preferred incision for emergency cases and ill-defined pathologies, allowing access and hence exploration to all quadrants. Transverse laparotomies give superior access to the dorsal and right aspects of the liver and cause less pain in patients unfit for regional anesthetic procedures. Draining of the abdominal cavity is used after various resective and reconstructive procedures, but there is little evidence for its use in a number of operations such as gastric, hepatic, and colorectal resections. Advantages and disadvantages of different abdominal wall incisions and drainages are discussed.

Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL.

A cerebral arteriopathy with subcortical infarcts and leukoencephalopathy is described with a pedigree suggestive for an autosomal dominant condition. In contrast to the vasculopathy designated with the acronym CADASIL, no deposits of granular osmiophilic material were detected in the vasculature and no point mutations in the NOTCH 3 gene were found. The disease occurred in a family living near Hamburg, Germany, and affected 11 women and 11 men over the last six generations. Onset of the disease was between the age of 12 and 50. Clinical symptoms included gait disturbances, dysarthria, sensomotoric deficits and a progressive dementia. Migraine-like complaints and epileptic seizures were observed in one case each. Cranial computer tomography and magnetic resonance imaging scans showed large confluent areas with decreased density in the white matter and small necroses in the brain stem, the basal ganglia and the white matter. A correlation with factors predisposing for vascular diseases could not be demonstrated. In five cases an autopsy was performed which disclosed an angiopathy affecting predominantly the penetrating arteries with consecutive lacunar infarcts, diffuse demyelination and rarefication of the subcortical white matter and degeneration of the pyramidal tracts. Histologically, the vessels showed concentric and excentric intimal proliferation, an elastosis and hyalinosis, splitting of the lamina elastica interna and a degeneration of the tunica muscularis. Electron microscopy revealed fragmentation and thickening of the basal lamina but electron-dense granules characteristic for CADASIL were not detected.