Biomedical subjects

Volkmar Hans

Publications and source records attributed to Volkmar Hans.

11 recordsLinked to original sources

PubMed2007

Nuclear beta-catenin accumulation associates with epithelial morphogenesis in craniopharyngiomas.

Activation of the Wnt/wingless signalling cascade is a key mechanism in developmental morphogenesis, whereas aberrant nuclear accumulation of beta-catenin in adult tissues seems to be associated with neoplastic transformation and tumour progression. Adamantinomatous craniopharyngiomas carry activating mutations in exon 3 of the beta-catenin gene, which results in a distinct pattern of nuclear beta-catenin accumulation in up to 95% of respective tumour specimens. To better characterise the impact of nuclear beta-catenin aggregation in these neoplasms, we systematically examined epithelial differentiation and cell cycle-associated molecules in accumulating compared to non-accumulating tumour cell clusters using a cohort of 65 adamantinomatous craniopharyngiomas. Monoclonal antibodies directed against cytokeratins 5/6 (CK5/6) were utilised to differentiate squamous from simple epithelium, the latter being identified by immunoreactivity for cytokeratins 8 and 18 (CK8/CK18). Intriguingly, nuclear beta-catenin accumulation in whorl-like tumour cell clusters was always associated with a distinct CK8 and CK18 immunoreactivity, whereas surrounding non-accumulating tumour cells showed exclusively squamous differentiation indicated by CK5/6 expression. In addition, a low proliferation activity combined with an increased expression of p21(WAF1/CIP1), a key control protein of the cell cycle, was observed in beta-catenin accumulating cells. Our data support an impact of nuclear beta-catenin on different cytoarchitectural and epithelial differentiation patterns in adamantinomatous craniopharyngiomas.

Adolescent↗

PubMed2006

Molecular neuropathology of epilepsy-associated glioneuronal malformations.

Glioneuronal malformations (malformations of cortical development [MCD]) include focal cortical dysplasias (FCD) as well as highly differentiated glioneuronal tumors (i.e. gangliogliomas) and constitute frequent findings in patients with pharmacoresistent focal epilepsies. Tailored resection strategies evolved as promising treatment options and allow a systematic neuropathologic and molecular biologic examination of the epileptogenic area in these patients. The histopathologic appearance and immunophenotype of glioneuronal lesions are, however, characterized by numerous similarities and suggest impaired proliferation, migration, and differentiation of neural precursor cells to play a pathogenetic role. Recent studies point toward molecular alterations within a variety of genes and pathways involved in development of the central nervous system, neuronal growth, and maturation. Compromised signaling within insulin- or reelin-transduction cascades are common findings and were associated with specific MCD entities. Unraveling pathogenic mechanisms may advance refined classification systems for epilepsy-associated malformations and open new avenues for the development of targeted treatment strategies in pharmacoresistent focal epilepsies associated with cortical malformations.

Brain Neoplasms↗

PubMed2006

Chromosomal translocations fusing the BCL6 gene to different partner loci are recurrent in primary central nervous system lymphoma and may be associated with aberrant somatic hypermutation or defective class switch recombination.

Primary central nervous system lymphomas (PCNSLs) are diffuse large B cell lymphomas confined to the brain. Only minimal data exist on chromosomal aberrations underlying PCNSLs. We studied 41 PCNSLs by fluorescence in situ hybridization for breakpoints affecting the BCL6 locus in chromosomal band 3q27. Of 37 cases evaluable, 14 (38%) carried a breakpoint in the BCL6 locus. Two of these showed juxtaposition of BCL6 to the IGH locus. In 4 cases, the BCL6 breakpoints were cloned using long-distance inverse polymerase chain reaction. All breakpoints were located within the BCL6 major translocation cluster. The translocation partners were the IGH gene in 14q32.33, the IGL gene in 22q11.22, and the histone 1 H4I gene in 6p22.1. In the fourth case, a deletion in 3q leads to loss of an 837-kb fragment extending from the first intron of BCL6 to the third intron of the lipoma-preferred partner (LPP) gene. This deletion may bring the BCL6 gene under the control of regulatory elements of the LPP gene or the miRNA-28 gene located in intron 4 of LPP. DNA sequence analysis of the junctional sequences provided evidence that aberrant class switch recombination or somatic hypermutation may be involved in the generation of BCL6 translocations.

Base Sequence↗

PubMed2006

Primary hypophysitis: clinical-pathological correlations.

OBJECTIVE: Primary hypophysitis comprises of three distinct histomorphological entities: lymphocytic, granulomatous and xanthomatous. Clinical features of the three subtypes for diagnostic and treatment strategies have yet not been well characterized. METHODS: Endocrine function, visual fields and acuity as well as magnetic resonance imaging characteristics were assessed before and after transphenoidal surgery in the largest series of 31 patients with primary hypophysitis (21 lymphocytic, 6 granulomatous, and 4 xanthomatous cases). RESULTS: Only lymphocytic hypophysitis occurred during pregnancy (30%) and was associated with other autoimmune diseases (24%). Visual fields and acuity abnormalities were not seen in xanthomatous hypophysitis. Lymphocytic and granulomatous hypophysitis most often resulted in severe dysfunction of the adrenal, gonadal and thyroidal axes as well as diabetes insipidus. For patients presenting with xanthomatous hypophysitis most often, mild anterior pituitary axis failure was documented and posterior pituitary involvement was hardly found. The outcome after transphenoidal biopsy was generally favorable. Pre- or postsurgical glucocorticoid treatment was very effective in 75% of the lymphocytic form in reducing the pituitary size. In contrast, glucocorticoid therapy was less effective in granulomatous or xanthomatous hypophysitis. CONCLUSION: Diffuse destruction of the complete pituitary gland including the infundibulum has to be considered in lymphocytic and granulomatous hypophysitis, whereas in xanthomatous, a circumscribed anterior pituitary lesion leading to compression of the pituitary gland without alteration of the pituitary stalk and optic chiasm can be assumed.

Adult↗

PubMed2005

Distinct allelic variants of TSC1 and TSC2 in epilepsy-associated cortical malformations without balloon cells.

Epilepsy-associated malformations of cortical development (MCDs) comprise a variety of dysplastic and neoplastic lesions of yet undetermined molecular pathology. Histopathologic similarities between MCDs and dysplastic brain lesions in the autosomal inherited neurocutaneous phacomatosis tuberous sclerosis (TSC), which affects the TSC1 and/or TSC2 genes, suggest common pathogenetic mechanisms. Previous studies revealed different alterations of TSC1 and TSC2 in epilepsy-associated malformations and glio-neuronal tumors despite histopathologic similarities. In order to examine current clinico-pathologic classification systems of cortical malformations on the molecular level, we carried out a mutational analysis of TSC1 and TSC2 in a series of surgical specimens obtained from patients with FCD without Taylor type balloon cells (FCDIIa; n = 20), architectural dysplasias (FCDI; n = 15), nodular cortical heterotopias (NCH; n = 4), and heterotopic white matter neurons (WMNH; n = 19). In FCDIIa, abundant genomic polymorphisms were detected in TSC2 (intron 4) but no allelic variants observed in exon 17 of TSC1. This allelic distribution pattern is in contrast to findings in FCDI and WMNH but also to those previously reported in FCDIIb (Taylor's balloon cell type). The latter revealed increased frequencies of specific alleles only in TSC1. The determination of characteristic molecular genetic alterations in specific epilepsy-associated malformations will support a comprehensive clinico-pathologic classification system and help to identify molecular pathways with potential pathogenetic relevance. Our work is supported by DFG (SFB TR3 [AJB], DFG Bl 421/1-1 [IB]), BONFOR, and Deutsche Krebshilfe.

Alleles↗

PubMed2004

Selective transduction of malignant glioma by lentiviral vectors pseudotyped with lymphocytic choriomeningitis virus glycoproteins.

Malignant gliomas are the most frequent primary brain tumors and have a dismal prognosis due to their infiltrative growth. Gene therapy using viral vectors represents an attractive alternative to conventional cancer therapies. In a previous study, we established lentiviral vectors pseudotyped with lymphocytic choriomeningitis virus (LCMV) glycoproteins (GPs) and demonstrated transduction of human malignant glioma cells in culture. In the current approach, we compared the transduction efficacy of LCMV-GP- and vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped lentiviral vectors for malignant glioma cells and normal brain cells in vitro and in vivo. LCMV-GP pseudotypes transduced almost exclusively astrocytes, whereas VSV-G pseudotypes infected neurons as well as astrocytes. LCMV-GP pseudotypes showed an efficient transduction of solid glioma parts and specific transduction of infiltrating tumor cells. In contrast, VSV-G-pseudotyped lentiviral vectors transduced only a few tumor cells in solid tumor parts and infected mostly normal brain cells in infiltrating tumor areas. In conclusion, lentiviral vectors pseudotyped with LCMV glycoproteins represent an attractive option for gene therapy of malignant glioma.

Animals↗

PubMed2004

Transition from meningeal melanocytoma to primary cerebral melanoma. Case report.

The authors describe the first case of an intracranial transition of a melanocytoma into a primary malignant melanoma within a short time. A 37-year-old woman presented with progressive brainstem syndrome due to a tumor, originally diagnosed and treated 12 years earlier, that extended from the petroclival area to the anterior craniocervical junction. The histological workup following subtotal tumor resection of the initial tumor had revealed the typical features of a fibrous melanocytic meningioma without increased proliferation. Ten years after the patient had completed treatment for the melanocytic meningioma, control neuroimaging demonstrated growth of the residual tumor with compression of the brainstem. Another neurosurgical intervention revealed a dark tumor of hard consistency. At this time immunohistochemical examinations demonstrated melanocytic features (expression of vimentin, S100 protein, and melan A) of the lesion with focally increased proliferation (5% of Ki-67-positive cells) but no higher mitotic activity. Clinical signs of deterioration along with imaging-confirmed tumor progression precipitated another operation within 7 months. A neuropathological examination revealed epithelial and anaplastic changes and indicated that the MIB-1 indices were greater than 25%. Pleomorphic changes and a focal high mitotic activity led to the diagnosis of a primary cerebral malignant melanoma. The patient's later clinical course consisted of a rapid diffuse meningeal spread of the lesion throughout the entire brain and spine. Despite whole-brain and stereotactic radiation therapy as well as chemotherapy, the patient died 4 months after the last neuropathological diagnosis. Although grossly resembling a meningioma, melanocytomas lack the former's histological and immunohistochemical features. The biological behavior of a melanocytoma is variable and recurrence may happen after subtotal resection, but intracranial transition into a malignant melanoma has not been observed previously.

Adult↗

PubMed2004

Associations between polymorphisms in the thymidylate synthase gene, the expression of thymidylate synthase mRNA and the microsatellite instability phenotype of colorectal cancer.

Microsatellite instability (MSI) is a characteristic feature of up to 15% of colorectal cancers (CRC) and is associated with better response to adjuvant chemotherapy with 5-fluorouracil (5-FU). In this study we have investigated the association between the MSI status and the mRNA expression as well as the polymorphisms of the cellular target of 5-FU therapy, thymidylate synthase. Polymorphisms in the 3'- and the 5'-UTR of the TS gene were determined by a PCR assay in 53 colorectal cancer tissues. TS mRNA was quantified by real-time RT-PCR. Data were correlated with the MSI phenotype. There was neither a significant correlation between the polymorphisms in the TS gene and the MSI phenotype nor between the mRNA expression and MSI status. CRC with a 3R/3R or 2R/3R genotype showed a significantly higher TS mRNA expression than those with 2R/2R genotype (p=0.001 and p=0.026, respectively). No association was seen between the polymorphism of the 3'-UTR and mRNA expression. From our results, we conclude that there is no association between MSI status and TS expression. Samples containing the 3R/3R or 2R/3R genotype of TS seem to have higher mRNA levels perhaps due to a higher mRNA stability. Polymorphic variants of the 3'-UTR do not influence the TS mRNA level. Genotyping of the 5'-UTR and quantitation of TS mRNA levels might serve as predictors for the response to 5-FU based chemotherapy.

5' Untranslated Regions↗

PubMed2003

Deletion of Trp-557 and Lys-558 in the juxtamembrane domain of the c-kit protooncogene is associated with metastatic behavior of gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) typically express high levels of the Kit-receptor. The majority of GISTs carry mutations in the c-kit protooncogene clustering in exon 11. The significance of c-kit mutations for the biological behavior of GISTs is still under discussion. We evaluated 55 sporadic GISTs with available follow-up data for c-kit mutations in the juxtamembrane domain and detected mutations in 35 cases (63.6%). We found a mutational hotspot in codons 557 (tryptophan) and 558 (lysine) preferentially in histomorphologically malignant tumors. In the group of GISTs carrying c-kit mutations, 16 of 21 malignant, but only 3 of 8 benign GISTs and 3 of 6 lesions with uncertain malignant potential, carried mutations of Trp-557 and/or Lys-558. We investigated whether mutations in these 2 amino acids had an impact on biological behavior. Trp-557 and/or Lys-558 were mutated in all 15 metastatic GISTs carrying c-kit mutations but only in a minority of nonmetastatic tumors. A combined deletion of Trp-557 and Lys-558 occurred exclusively in 8 metastatic GISTs. We conclude that in addition to histomorphological evaluation determination of mutations in exon 11 may be an additional parameter for predicting the metastatic risk of GISTs and may be important for the decision that patients will need close clinical follow-up or further adjuvant treatment with kit antagonists.

Adult↗

PubMed2003

The regional oxygen saturation of pituitary adenomas is lower than that of the pituitary gland: microspectrophotometric study with potential clinical implications.

OBJECTIVE: To study the regional oxygen saturation (rSO(2)) of pituitary adenomas, in comparison with that of the pituitary gland. METHODS: Microspectrophotometric (MSP) measurements of rSO(2) in adenomas and pituitary tissue were performed for a series of patients undergoing first-time transsphenoidal pituitary adenoma surgery, in a standardized anesthesia setting. The areas of measured tissue were sampled for histopathological and immunohistochemical (CD34 and CD45) assessments. The results of MSP measurements were compared with the results of the histopathological and immunohistochemical assessments. RESULTS: Thirty-six MSP measurements and tissue samples were obtained among 22 patients with pituitary macroadenomas, including 14 from adenoma tissue, 17 from the anterior pituitary lobe, and 5 from the posterior pituitary lobe. The rSO(2) of adenoma tissue (mean +/- standard deviation, 43.3 +/- 23.2%) was statistically significantly (P = 0.001) lower than the values for the anterior pituitary lobe (mean +/- standard deviation, 71.8 +/- 18.3%) and posterior pituitary lobe (mean +/- standard deviation, 74.9 +/- 4.8%). The difference between the rSO(2) values for the anterior pituitary lobe and posterior pituitary lobe was not significant. There were no statistically significant differences in microvessel density (as assessed with CD34 staining) or lymphocyte density (as assessed with CD45 staining) among the three tissue types. CONCLUSION: As assessed with MSP measurements, the rSO(2) of adenoma tissue was significantly lower than that of the pituitary gland, indicating differences in their blood supply and/or metabolism in pituitary macroadenomas. Further studies are needed to determine whether MSP measurements can reliably facilitate intraoperative delineation of adenoma and pituitary tissue, in the effort to achieve complete tumor removal with minimal injury to pituitary tissue.

Adenoma↗

PubMed2002

Combined surgery, radiation, and PCV chemotherapy for astrocytomas compared to oligodendrogliomas and oligoastrocytomas WHO grade III.

The time to tumor progression (TTP), time to death (TTD) and complications were studied prospectively in a cohort of patients treated by surgery and adjuvant radio- and intensified PCV chemotherapy for astrocytomas (AIII), oligodendrogliomas (OIII) and oligoastrocytomas (OAIII) WHO grade III. The treatment was carried out in 48 patients: 24 AIII, 20 OAIII and four OIII, at the same medical institution. OIII and OAIII were grouped together (OIIIOAIII). With the exception of age (mean age 48.5 years for AIII and 38.5 years for OIIIOAIII, respectively) and number of PCV cycles completed (median of three cycles for AIII and 4.75 for OIIIOAIII respectively), the patients' characteristics at study entry (gender, Karnofsky Performance Score (KPS), tumor localization) and at completion of therapy (extent of tumor resection, dose of adjuvant radiotherapy) were not statistically different between the two patient groups. The median TTP and TTD for AIII were 26.8 and 27.9 months, respectively. The median TTP and TTD for OIIIOAIII were not reached yet. The 75th percentile of TTP and TTD for OIIIOAIII was reached at 49.4 and 51.5 months, respectively. The Kaplan-Meier analysis showed significantly longer TTP (p = 0.009) and TTD (p = 0.002) for OIIIOAIII as compared to AIII. A new neurological deficit, following surgery, occurred in 14.5% of the patients. Brain radiation necrosis occurred in one patient. The most significant toxicity of PCV-chemotherapy was hematologic and reached WHO grade III and IV in 30% of the patients. This study compared for the first time the outcome of AIII with OIIIOAIII when treated with combined surgery, radiotherapy, and intensified PCV chemotherapy: longer TTP and TTD were observed in anaplastic glioma with oligodendroglial components WHO grade III as compared to pure astrocytoma WHO grade III. This is in accordance with results in patients treated by surgery with adjuvant radiation alone. The efficacy of additional adjuvant PCV chemotherapy in prolonging TTP and TTD has to be verified in prospective controlled studies.

Adult↗