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Christian Hagel

Publications and source records attributed to Christian Hagel.

17 recordsLinked to original sources
PubMed2006

Histopathology and clinical outcome of NF1-associated vs. sporadic malignant peripheral nerve sheath tumors.

The differences in the clinical course and histopathology of sporadic and neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNST) were investigated retrospectively. The collective comprised 38 NF1 patients and 14 sporadic patients. NF1 patients were significantly younger at diagnosis (p<0.001) and had a significantly shorter survival time than sporadic patients (median survival 17 months vs. 42 months, Breslow p<0.05). The time interval to local recurrence and metastatic spread was also significantly shorter in NF1 patients (9.4 months vs. 30.0 months, p<0.01; 9.1 months vs. 33.2 months, p<0.001, respectively). In patients with the original histopathological data available (22 NF1 patients, 14 sporadic cases), NF1-associated MPNST showed a significantly higher cellularity compared to sporadic tumors (p<0.001) whereas sporadic MPNST featured a significantly higher pleomorphism (p<0.01). Most importantly, while histopathological variables correlated with French Fédération Nationale des Centres de Lutte Contre le Cancer grading in sporadic MPNST, this was not the case for NF1-associated tumors. The differences between NF1-associated and sporadic MPNST in regard to the clinical course and histopathology may reflect some fundamental differences in biology and pathomechanism of the two tumor groups. Our findings indicate the necessity for a separate grading scheme which takes into account the genetic background in NF1 patients.

Adolescent↗
PubMed2006

Expression of doublecortin in tumours of the central and peripheral nervous system and in human non-neuronal tissues.

Doublecortin is a microtubule-associated phosphoprotein involved in neuronal migration and differentiation expressed in migrating neuroblasts in the central nervous system. We systematically analysed doublecortin expression in 179 tumours of the central and 65 tumours of peripheral nervous system as well as in 74 different non-neuronal tissues to evaluate the specificity of doublecortin as a marker for neuronal differentiation in glioneuronal tumours. Glioneuronal tumours and oligodendrogliomas grade II and III uniformly showed a high intensity and frequency of doublecortin staining, whereas intermediate doublecortin expression was observed in astrocytic tumours of grade II-IV. In pilocytic astrocytomas and ependymomas only scattered doublecortin positive cells were detected. In the peripheral nervous system, doublecortin expression was found in neurofibroma but was absent in schwannoma. Double staining of tumour tissue revealed co-expression of doublecortin and neurofilament in cells of gangliocytomas and gangliogliomas and co-expression of doublecortin with S100 protein or GFAP in glial tumours, respectively. In a tissue array comprised of 74 different normal non-neuronal human tissues, doublecortin expression was demonstrated in epithelia of the kidney, liver, salivary glands and duodenum among others. Interestingly, doublecortin expression could not be shown in brain metastases of tumours originating from these tissues. Immunohistochemical data was further corroborated by Western blot analysis and reverse transcription polymerase chain reaction. In conclusion, doublecortin can be regarded as specific neuronal marker only in normal developing brain, but lacks specificity in glioneuronal and glial tumours and other non-neuronal human tissues where it is expressed in a wide variety of tumours and tissues.

Biomarkers, Tumor↗
PubMed2006

Low-grade and anaplastic gliomas: differences in architecture evaluated with diffusion-tensor MR imaging.

PURPOSE: To prospectively evaluate whether diffusion-tensor magnetic resonance (MR) imaging depicts differences in World Health Organization (WHO) grade II and III glial brain tumors on the basis of tumor architecture and peritumoral tract invasion. MATERIALS AND METHODS: The study protocol was approved by the local ethics committee, and written informed consent was obtained. Diffusion-tensor MR imaging was performed in 23 patients (15 men, eight women; mean age, 47 years) with histologically confirmed brain gliomas. Eleven of the 23 tumors were low-grade gliomas (WHO grade II) and 12 were anaplastic gliomas (WHO grade III). Regions of interest were placed in the tumor center, tumor border, normal-appearing white matter (NAWM) adjacent to the tumor, and NAWM of the contralateral hemisphere. fractional anisotropy (FA) ratios were calculated for regions of interest in relation to the NAWM of the contralateral hemisphere. Pairwise comparisons were performed by using the Mann-Whitney U test. RESULTS: Median FA ratios for grade II versus grade III gliomas were 0.406 versus 0.405, respectively, for tumor center, 0.733 versus 0.449, respectively, for tumor border, and 0.962 versus 0.943, respectively, for NAWM adjacent to the tumor. Differences in FA ratio between low-grade and high-grade tumors were significant in the tumor border only (P = .01). Differences in FA ratio were not significant between low-grade and high-grade gliomas in the tumor center or in the NAWM adjacent to the tumor. CONCLUSION: The periphery of low-grade gliomas contains a considerable amount of preserved fiber tracts. In high-grade gliomas, however, most of these tracts are disarranged. Low FA ratios in the tumor center are consistent with a high degree of disorganization of myelinated fiber tracts in the center of both low-grade and high-grade gliomas.

Adult↗
PubMed2006

Embryonic stem cell-derived neuronally committed precursor cells with reduced teratoma formation after transplantation into the lesioned adult mouse brain.

The therapeutic potential of embryonic stem (ES) cells in neurodegenerative disorders has been widely recognized, and methods are being developed to optimize culture conditions for enriching the cells of interest and to improve graft stability and safety after transplantation. Whereas teratoma formation rarely occurs in xenogeneic transplantation paradigms of ES cell-derived neural progeny, more than 70% of mice that received murine ES cell-derived neural precursor cells develop teratomas, thus posing a major safety problem for allogeneic and syngeneic transplantation paradigms. Here we introduce a new differentiation protocol based on the generation of substrate-adherent ES cell-derived neural aggregates (SENAs) that consist predominantly of neuronally committed precursor cells. Purified SENAs that were differentiated into immature but postmitotic neurons did not form tumors up to four months after syngeneic transplantation into the acutely degenerated striatum and showed robust survival.

Animals↗
PubMed2006

Prognostic relevance of FDG PET in patients with neurofibromatosis type-1 and malignant peripheral nerve sheath tumours.

PURPOSE: In patients with neurofibromatosis type-1 (NF1) and malignant peripheral nerve sheath tumours (MPNSTs), survival rates are low and time to death is often less than 2 years. However, there are patients with a more favourable prognosis who develop metastases rather late or not at all. Since histopathology and tumour grading are not well correlated with prognosis, we aimed to evaluate the potential of (18)F-fluorodeoxyglucose positron emission tomography (FDG PET) for prediction of patient outcome in MPNST. METHODS: FDG PET was performed in 16 patients with NF1 and MPNSTs. Standardised uptake values (SUVs) were calculated for each tumour and correlated to tumour grade and patient outcome in terms of survival or death. RESULTS: Three patients with tumour grade II had an SUV <3. None of these patients developed metastases or died during a follow-up of 41-62 months. Thirteen patients with tumour grades II and III had an SUV >3. Only one of these patients is still alive after 20 months; the remaining 12 died within 4-33 months. SUV predicted long-term survival with an accuracy of 94%, compared with 69% for tumour grade. In Kaplan-Meier survival analysis, patients with an SUV >3 had a significantly shorter mean survival time, 13 months, than patients with an SUV <3, in whom the mean survival time was 52 months. Tumour grading did not reveal differences in survival time (15 vs 12 months). CONCLUSION: Tumour SUV obtained by FDG PET was a significant parameter for prediction of survival in NF1 patients with MPNSTs while histopathological tumour grading did not predict outcome.

Adolescent↗
PubMed2005

August 2004: 64-year-old man with intermittent paresthesia of the abdomen and of the legs.

A 64-year-old-man had a 2-year history beginning with a sense of abdominal "constriction." Additional slowly rising symptoms, such as tingling of the legs, mild gait ataxia and painful micturition, led to MRI investigation of the spinal cord. A fusiform enlargement of the cord extending from T5 to T8 was shown. The space occupying lesion infiltrated diffusely the spinal cord. A contrast medium enhancing exophytic tumor pellet was approached via a 2-level laminoplasty and resected. Biopsies were taken from different exophytic tumor areas whereas the intramedullary part was spared. The histologic examination confirmed the typical pattern of a pilocytic astrocytoma in all specimens. In our surgical experience with 226 intramedullary tumors and with 117 patients affected by intracranial pilocytic astrocytoma this case is unique because of its combination of tumor location, growth pattern and age of the patient.

Abdomen↗
PubMed2005

Well-differentiated neurocytoma: what is the best available treatment?

Most neurocytomas are well differentiated, being associated with better long-term survival than the more aggressive atypical lesions. Atypical neurocytomas are characterized by an MIB-1 labeling index >3% or atypical histologic features. This analysis focuses on well differentiated neurocytomas in order to define the optimal treatment. A case with a follow-up of 132 months is presented. The patient developed two recurrences two and four years after first surgery, each showing an increasing proliferation activity. Furthermore, all published well-differentiated neurocytoma cases were reviewed for surgery, radiotherapy, and prognosis. Additional relevant data were obtained from the authors. Complete resection (CTR), complete resection plus radiotherapy (CTR + RT), incomplete resection (ITR), and incomplete resection plus radiotherapy (ITR + RT) were compared for outcome by using the Kaplan-Meier method and the log-rank test. Data were complete in 301 patients (CTR, 108; CTR + RT, 27; ITR, 81; ITR + RT, 85). Local control and survival were better after CTR than after ITR (P < 0.0001 and P = 0.0085, respectively). Radiotherapy improved local control after ITR (P < 0.0001) and after CTR (P = 0.0474), but not survival (P = 0.17 and P = 1.0, respectively). In the ITR + RT group, doses < or =54 Gy (n = 33) and >54 Gy (n = 32) were not significantly different for local control (P = 0.88) and survival (P = 0.95). The data demonstrated CTR to be superior to ITR for local control and survival. After CTR and ITR, radiotherapy improved local control, but not survival. A radiation dose of 54 Gy appeared sufficient. Application of postoperative radiotherapy should be decided individually, taking into account the risk of local failure, the need for another craniotomy, and potential radiation toxicity.

Adolescent↗
PubMed2004

Impaired cell adhesion and apoptosis in a novel CLN9 Batten disease variant.

We describe the ninth variant of neuronal ceroid lipofuscinosis (NCL) or Batten disease, due to defects in a putative new gene, CLN9. We therefore refer to the new variant as CLN9-deficient. Two Serbian sisters and two German brothers are described. Their clinical history is characteristic for juvenile NCL. They show similar gene expression patterns. The existence of this variant is supported by the presence of curvilinear inclusions, fingerprint profiles, and granular osmiophilic deposits in neurons, lymphocytes, and conjunctival cells. Enzyme screening and sequencing of the coding regions of other NCL genes was negative. CLN9-deficient cells have a distinctive phenotype. They have rounded cell bodies, have prominent nucleoli, attach poorly to the culture dish, and are sensitive to apoptosis but have increased growth rates. Gene expression of proteins involved in cell adhesion and apoptosis is altered in these cells. Sphingolipid metabolism is also perturbed. They have decreased levels of ceramide, sphingomyelin, lactosylceramide, ceramide trihexoside, and globoside and increased activity of serine palmitoyl transferase.

Adolescent↗
PubMed2004

CD44 expression and tumour cell density correlate with response to tamoxifen/carboplatin chemotherapy in glioblastomas.

In order to identify response predictors for a post-operative glioblastoma therapy consisting of tamoxifen, carboplatin and radiotherapy, expression of 12 antigens was evaluated in 36 newly diagnosed tumours and 13 recurrences. Results were correlated with the clinical course of the disease. Antigen expression was assessed immunohistochemically for CD44s, TGF-beta2, TGF-alpha, progesterone receptor, estrogen receptor, EGFR, urokinase, urokinase inhibitor 1, CD87, p53 protein and Ki-67. Vessel density was determined by labelling of endothelia with von Willebrand factor. Response to chemotherapy correlated positively with cell density (p < 0.05) and negatively with CD44 over-expression (p < 0.02). Further, a positive correlation between age and CD44 expression (p < 0.05) and a negative correlation between age and p53 accumulation (p < 0.01) was found. In tumour recurrences expression of CD44 was significantly higher in local recurrences than in distant multifocal recurrences (p < 0.02), suggesting that CD44 may predominantly be associated with cell adhesion in glioblastomas.

Adult↗
PubMed2004

Histomorphologic examination of skeletal muscle preparations does not differentiate between malignant hyperthermia-susceptible and -normal patients.

BACKGROUND: It has been suggested that malignant hyperthermia (MH) can be diagnosed by specific myopathologic alterations. The purpose of this study was to investigate whether there are characteristic myopathologic changes in skeletal muscles of MH-susceptible (MHS) compared with MH-normal (MHN) patients. METHODS: Four hundred forty patients with clinical suspicion of MH were classified as MHN, MH equivocal (MHE), or MHS by the in vitro contracture test with halothane and caffeine. In addition, a small muscle sample excised from each patient was analyzed by histologic, histochemical, immunohistochemical, and computer-aided morphometric methods. RESULTS: MHN was diagnosed in 243 patients, MHE was diagnosed in 65, and MHS was diagnosed in 132. No myopathologic abnormalities were found in 53.5% of the MHN, 53.9% of the MHE, and 56.1% of the MHS patients. Thirty-five percent of all patients showed one, 9.8% showed two, and only 0.9% showed three different pathologic findings within skeletal muscle preparations. The frequency of pathologic findings did not differ between the MHN and the MHS patients; only fiber type I predominance was observed more often in MHN. MHE patients could not be assigned to a diagnostic group by detection of myopathologic alterations. In six clinically unaffected patients, a former unrecognized myopathy, such as central core disease, was diagnosed. This disease is characterized by a specific alteration (cores). CONCLUSIONS: Histologic differences between MHS and MHN statuses could not be demonstrated in this study. Histopathologic examinations can neither improve the diagnosis of MH nor contribute to a better definition of the MH status. However, histopathologic examinations might be useful to detect formerly unrecognized specific myopathies.

Adolescent↗
PubMed2003

Expression of serine proteases and metalloproteinases in human pituitary adenomas and anterior pituitary lobe tissue.

Data on the dural invasiveness of pituitary adenomas have been correlated to the expression of matrix metalloproteinases (e.g. MMP-9). Serine proteases have not yet been investigated in human pituitary adenomas. In this study, paraffin-embedded material from 84 human pituitary adenomas (acromegaly n=18, Cushing's disease n=21, prolactinoma n=18, thyroid-stimulating hormone-secreting adenoma n=1, nonsecreting adenoma n=26) and 9 nontumourous anterior pituitary lobes (obtained from patients with prostate cancer) was immunohistochemically analysed for expression of MMP-2, MMP-9, tissue inhibitor of metalloproteinases-2 (TIMP-2), urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and interleukin-6 (IL-6). Cavernous sinus invasion was determined by assessment of preoperative magnetic resonance imaging and intraoperative inspection (invasive n=50, noninvasive n=34). In pituitary adenomas, reactions were positive (diffuse expression) to MMP-2 (74% of cases), MMP-9 (49%), TIMP-2 (88%), uPA (89%), uPAR (90%), tPA (69%), and PAI-1 (87%). A weak expression of IL-6 was found in 12% of the adenomas. All reactions were positive (focal expression) in every sample of anterior lobe tissue, except for uPA (negative in 3 out of 9 cases), and IL-6 (faintly positive in 5 out of 8 cases). Adenomas showed remarkably greater expression of uPA than anterior lobe tissue (Chi-square P<0.05). Nonsecreting adenomas exhibited a stronger tendency towards overexpression of uPA in invasive tumours when compared to noninvasive adenomas (Chi-square P=0.053). We found no correlation of MMP-9 expression and tumour invasion. TIMP-2 was overexpressed in noninvasive as compared to invasive adenomas (Chi-square P<0.05). The interrelationship between MMPs and serine proteinases in pituitary adenomas remains to be elucidated. From our data, a correlation between IL-6 and an activation of MMP-9 cannot be proven. The uPA-system may, however, play a role in dural invasion of pituitary adenomas.

Adenoma↗
PubMed2003

Atypical focal MRI lesions in a case of juvenile Alexander's disease.

We present a juvenile case of Alexander's disease with atypical focal magnetic resonance imaging-detected lesions and elevated levels of lactate in cerebrospinal fluid. The diagnosis was based on the neuropathological finding of a diffuse accumulation of Rosenthal fibers within the brain and the spinal cord. The diagnosis was confirmed by detection of a mutation in exon 1 at nucleotide position 249 of glial fibrillary acidic protein cDNA, a finding previously reported in cases of infantile Alexander's disease.

Alexander Disease↗
PubMed2003

Recurrent deep-vein thrombosis based on homozygous factor V Leiden mutation acquired after liver transplantation.

Several genetic liver diseases can be treated by liver transplantation (LT). However, some genetic defects also may be acquired by this procedure. We describe a patient who developed recurrent deep-vein thromboses after LT for hepatitis C virus-associated hepatocellular carcinoma on the basis of a homozygous Leiden mutation of the factor V gene in the donor liver. Liver donors with a history of venous thrombosis should be screened for the presence of activated protein C (APC) resistance. In addition, we recommend looking for APC resistance in liver recipients who develop venous thromboembolic disease in the post-LT course. Molecular analysis of donor tissue may be necessary to make a definite diagnosis of factor V Leiden mutation in these patients. As a consequence, intensified postoperative thromboprophylaxis or lifelong anticoagulant therapy may be necessary if this thrombophilic gene defect is detected.

Activated Protein C Resistance↗
PubMed2003

Histological findings in ruptured aneurysms treated with GDCs: six examples at varying times after treatment.

BACKGROUND AND PURPOSE: A novel plastic embedding approach was used to histologically evaluate inflammatory changes and scar formation over time and to better visualize the mesh attenuation within the aneurysm lumen of acutely ruptured aneurysms after treatment with GDCs. METHODS: Autopsies were performed on six patients with acute subarachnoid hemorrhage who had died between 5 and 272 days after GDC treatment. The aneurysms containing the platinum coils were embedded in plastic along with the intact parent vessels, were sliced, and were ground to a thickness of 5 to 10 micro m. In addition, 250- micro m-thick sections were prepared. Histologic examinations were performed. Three exemplary cases representing the time lapse from treatment to death are discussed in detail. RESULTS: At the three exemplary time periods (5, 13, and 272 days) after coiling, a continuing healing process could be observed. At 5 days after placement of GDCs, a blood clot consisting of erythrocytes and fibrin was found throughout the cavity. Thirteen days after the procedure, large foamy macrophages were observed near the coils in the aneurysm cavity. Two hundred seventy-two days after the intervention, scar formation within the aneurysm appeared to be completed, with vascularized connective tissue filling the cavity and embedding the coils. Large foreign body giant cells were found adjacent to the coils. A layer of long slender cells, resembling endothelium, sealed the aneurysm neck. CONCLUSION: We postulate that within days after GDC treatment, blood clotting and thrombus formation prevent rebleeding and that solid scar formation covered by a layer of long slender cells, resembling endothelium, seals the aneurysm over time.

Adult↗
PubMed2002

Polyneuropathy in neurofibromatosis 2: clinical findings, molecular genetics and neuropathological alterations in sural nerve biopsy specimens.

Neurofibromatosis 2 (NF2) is an autosomal dominant disease characterised by development of tumours in the central and peripheral nervous system. Some NF2 patients develop acro-distal sensory motor polyneuropathy that can hardly be explained by the tumour burden alone. In the present study eight sural nerve biopsy specimens from seven NF2 patients suffering from polyneuropathy were investigated, data including clinical course of the disease, electrophysiological findings, teased fibre preparations, histopathological, morphometric, immunohistochemical, electron microscopic and molecular genetic findings. All patients suffered from distal symmetric reflex loss, symmetrical stocking-like hypalgesia and hypesthesia and loss of vibration sense later followed by a slowly progressive distal muscle atrophy and paresis. Sural nerve biopsy specimens revealed a pathological reduction of nerve fibre density correlating with age. In addition, diffuse proliferation of Schwann cells was observed in five of eight biopsies, and small endoneurial tumourlets of schwannomas and perineuriomas were found in two of eight and one of eight samples, respectively. Ki-67 labelling revealed a slight endoneurial proliferative activity in three cases. Schwann cell onion bulbs with or without central myelinated axon were seen in two cases. The findings suggest an axonopathy of multifactorial origin resulting not only from gross tumour growth but, in addition, from small endoneurial tumourlets, diffuse proliferation of Schwann cells and proliferation of perineurial cells.

Adolescent↗
PubMed2002

Cytoplasmic localization of wild-type p53 in glioblastomas correlates with expression of vimentin and glial fibrillary acidic protein.

Cytoplasmic accumulation of wild-type p53 in tumor cells indicates that the tumor suppressor is inactive with regard to growth suppressive functions. Whether this occurs randomly during tumor development or characterizes a certain tumor cell subset is not known. Here we assayed primary glioblastomas for expression and subcellular localization of p53 and determined a correlation with expression of intermediate filament proteins characterizing glial cell development. Sixty-nine percent of the tumors were p53 positive in immunohistochemistry. A significant number of tumors (23%) accumulated wild-type p53 in the cytoplasm, which correlated with the presence of vimentin and glial fibrillary acidic protein, except for 1 case. Tumors with exclusive nuclear p53 contained none or only one of these intermediate filament proteins. In an alternative approach, tumors positive for glial fibrillary acidic protein were screened for expression of p53 and vimentin. Thirty-eight percent of these tumors showed cytoplasmic p53, and all of those also expressed vimentin. Tumors with only nuclear p53 were vimentin negative, except for 1 case. No mutation was detected in p53 exons 5 to 8 in tumors with cytoplasmic p53, suggesting that they express wild-type p53. The data indicate that a cytoplasmic accumulation of wild-type p53 in human primary glioblastomas correlates with a certain intermediate filament protein expression, suggesting that it identifies a certain subset of tumors.

Active Transport, Cell Nucleus↗