Biomedical subjects

Jürgen Kreutzer

Publications and source records attributed to Jürgen Kreutzer.

9 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

Abundant hypermethylation of SOCS-1 in clinically silent pituitary adenomas.

Janus kinase (JAK)/signal transducers and activators of transcription (STAT) cascade are required for cytokines, growth factors, G-proteins and hormones (growth hormone and prolactin). Gatekeepers in this pathway are the suppressor of cytokine signalling (SOCS) family of proteins. Their expression level is epigenetically regulated by DNA methylation. We have investigated the CpG island methylation status of SOCS-1 in a cohort of pituitary adenomas (PA; n=57), craniopharyngiomas (CP; n=30) and normal pituitary tissue (NP; n=11) using methylation sensitive single-strand conformation polymorphism analysis (MS-SSCP) and direct sequencing. SOCS-1 hypermethylation was identified in 51% (29/57) of surgical specimens obtained from PA patients. 83% of these tumours were clinically silent. In contrast, no methylation of SOCS-1 was observed in CPs or NPs. Quantitative real-time PCR and western blot analysis confirmed reduced SOCS-1 expression in the majority of pituitary adenomas. The data is compatible with epigenetic silencing of the SOCS-1 gene and constitutive activation of the JAK-STAT pathway in PA. This appears to contribute particularly to those tumours characterized by a hormone-inactive status.

Adenoma↗

PubMed2006

Nuclear beta-catenin accumulation as reliable marker for the differentiation between cystic craniopharyngiomas and rathke cleft cysts: a clinico-pathologic approach.

Clinical and histopathologic differentiation of cystic lesions from the sellar region, that is, craniopharyngiomas (CPs) and Rathke cleft cysts (RCCs), is challenging and has paramount importance with respect to variable clinical manifestation and adapted surgical treatment strategies in both entities. Here, we retrospectively evaluated clinico-pathologic findings in 81 patients presenting with a cystic tumor located in the sellar region. All patients underwent transsphenoidal or transcranial resections. Microscopic inspection of surgical specimens identified CP in 51 patients, and RCC in 30 patients. Amongst the panel of immunohistochemical marker proteins used for histopathologic analysis, nuclear accumulation of beta-catenin was detectable only in CP. On the basis of the histopathologic and immunohistochemical analysis, clinical presentation (sex, age, ophthalmologic, and endocrinologic deficits), imaging (tumor location, size, and calcification), as well as a description of cyst contents obtained during operation were retrospectively evaluated. In purely cystic CPs, an isointense signal was more frequent in T1-weighted magnetic resonance images and calcification of the tumor capsule in computed tomography scans. In addition, the size of RCC was smaller and this tumor entity was more often located within the sella. Aberrant (nuclear) immunohistochemical staining for beta-catenin appeared, however, as most reliable factor for the differentiation between purely cystic CPs and RCCs, whereas tumor location, tumor size, and calcification of the tumor capsule were less consistent parameters. The data are compatible with distinct pathogenic pathways associated with these related histopathologic entities.

Adolescent↗

PubMed2006

Surgical treatment of recurrent Cushing's disease.

OBJECTIVE: The aim of this study was to evaluate the role of transsphenoidal selective adenomectomy alone or in combination with adjuvant therapy in treatment of recurrent Cushing's disease. METHODS: A total of 16 patients with recurrent Cushing's disease underwent reoperation, 15 via a transsphenoidal approach and one via a combined transsphenoidal/transcranial approach. Selective adenomectomies were performed in 13 patients and hemihypophysectomies were performed in three patients. Endocrinologically, recurrence was diagnosed by an overnight 2-mg dexamethasone suppression test. All patients underwent a 1.5-T magnetic resonance imaging scan, and eight patients underwent inferior petrosal sinus sampling. RESULTS: After selective adenomectomy, six of the 13 patients went into remission. Recurrence always occurred at the localization of the original tumor. In three patients without intraoperative tumor detection, hypophysectomy did not lead to remission. In 10 patients with persistent disease, adjuvant therapy (radiotherapy, adrenalectomy) led to normalization of basal cortisol levels in eight patients and clinical remission in one patient. One patient was lost to follow-up. In 10 patients, no evidence of an adenoma was visible on the preoperative magnetic resonance imaging scan. Inferior petrosal sinus sampling allowed correct prediction of the tumor localization in two of eight patients. CONCLUSION: By performing repeated selective adenomectomy, patients with recurrent Cushing's disease can be cured without the risk of endocrine deficits or major complications. Dynamic endocrine tests are of paramount importance for surgical decision making. Imaging and inferior petrosal sinus sampling are not helpful in locating the recurrent tumor. If normalization can not be achieved, adjuvant therapy is mandatory.

Adenoma↗

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

Common mutations of beta-catenin in adamantinomatous craniopharyngiomas but not in other tumours originating from the sellar region.

Dysregulation of the Wnt signalling pathway contributes to developmental abnormalities and carcinogenesis of solid tumours. Here, we examined beta-catenin and adenomatous polyposis coli (APC) by mutational analysis in pituitary adenomas (n=60) and a large series of craniopharyngiomas (n=41). Furthermore, the expression pattern of beta-catenin was immunohistochemically analysed in a cohort of tumours and cysts of the sellar region including pituitary adenomas (n=58), craniopharyngiomas (n=57), arachnoidal cysts (n=8), Rathke's cleft cysts (n=10) and xanthogranulomas (n=6). Whereas APC mutations were not detectable in any tumour entity, beta-catenin mutations were present in 77% of craniopharyngiomas, exclusively of the adamantinomatous subtype. All mutations affected exon 3, which encodes the degradation targeting box of beta-catenin compatible with an accumulation of nuclear beta-catenin protein. In addition, a novel 81-bp deletion of this exonic region was detected in one case. Immunohistochemical analysis confirmed a shift from membrane-bound to nuclear accumulation of beta-catenin in 94% of the adamantinomatous tumours. Aberrant distribution patterns of beta-catenin were never observed in the other tumour entities under study. We conclude that beta-catenin mutations and/or nuclear accumulation serve as diagnostic hallmarks of the adamantinomatous variant, setting it apart from the papillary variant of craniopharyngioma.

Adolescent↗

PubMed2005

Transsphenoidal surgery in acromegaly investigated by intraoperative high-field magnetic resonance imaging.

OBJECTIVE: The aim of the study was to evaluate the effect of intraoperative high-field (1.5 Tesla) magnetic resonance imaging (MRI) on the results of transsphenoidal surgery of GH-secreting pituitary macroadenomas. METHODS: Twenty-three acromegalic patients (mean tumor size, 25 +/- 12 mm; untreated preoperative GH, 4.2-159 microg/l; IGF-I, 349-1111 microg/l) were investigated by intraoperative high-field MRI. If intraoperative imaging depicted an accessible tumor remnant, resection was continued. RESULTS: In five patients intraoperative MRI led to further tumor removal, two of these met the consensus criteria for endocrine remission after 3 months. In two patients basal GH and oral glucose tolerance test (OGTT) were <2 microg/l, only IGF-I was slightly elevated, and in one patient GH was <5 microg/l and OGTT was 2 microg/l, with elevated IGF-I. Final intraoperative MRI showed no tumor remnants in 14 patients; eight of them met the consensus criteria for remission of acromegaly. In the patients with MRI showing incomplete removal (four suspect findings and five patients with intended partial removal) none was normalized. CONCLUSION: With regard to the patients with a tumor configuration in whom complete tumor removal was considered (n = 18), intraoperative MRI increased the rate of endocrine normalization from 33 to 44% applying the consensus criteria, and improved endocrine outcome to 'nearly normalization' in another 17%. With regard to preoperative GH levels and tumor size, intraoperative MRI can help to achieve endocrine remission in patients who are normally considered not to be curable. However, taking GH as the tumor marker, even intraoperative high-field MRI was not able to detect tumor remnants in every case.

Acromegaly↗

PubMed2004

Diagnosis and treatment of pituitary tumors.

PURPOSE OF REVIEW: Treatment of pituitary adenomas remains an interdisciplinary challenge involving neurosurgeons, endocrinologists and radiation oncologists. The different disciplines inaugurated advanced techniques to improve the already relatively high standard of outcome for the benefit of patients, covering molecular pathogenesis, novel therapeutic strategies for the different adenoma subtypes, developments in perioperative magnetic resonance imaging and radiosurgical management of pituitary adenomas. RECENT FINDINGS: Despite the progress achieved in medical treatment of hormone-secreting pituitary adenomas throughout recent years, surgery remains the primary therapy of choice except for prolactinomas. Recent studies in molecular pathogenesis aiming to find novel therapy targets and reports on new pharmacological drugs effecting GH-secreting pituitary adenomas are reviewed (for example, lanreotide 60, SOM320 and pegvisomant). Advances in surgical treatment of pituitary macroadenomas are obtained by pre- and especially by intraoperative (high-field) MRI offering a higher rate of safe and complete tumor removal. Therapy pitfalls mentioned in the literature throughout the last year as well as key points in the management of pituitary adenomas with focus on acromegaly and Cushing's disease are reported. Adjuvant irradiation for recurrent or residual adenomas is often a necessity. In comparison to standard conventional radiation strategies an increasing number of radiation oncologists and neurosurgeons report their experience with radiosurgery especially for smaller tumor remnants in pituitary adenomas. SUMMARY: Recent molecular studies suggest a new level of complexity in the tumorigenisis of pituitary adenomas in terms of possible cell-type-specific molecular changes. Except for prolactinomas surgery remains the primary treatment for pituitary adenomas. New pharmacological drugs achieve very encouraging endocrine results although no long-term follow-up is available so far. The results of trans-sphenoidal surgery will further improve by modern imaging techniques, especially by applying intraoperative high-field magnetic resonance imaging and neuronavigation. The results of radiosurgical techniques with regard to tumor control are mostly convincing, but definitive conclusions on long-term recurrence and/or late complications are not reliable so far.

Adenoma↗

PubMed2003

Robotic bone preparation does not increase cement penetration into the proximal femur: a matched-pair cadaver study comparing hand-broaching versus robotic bone preparation.

In a cadaver study, we prepared 20 matched pairs of human femora using chipped-tooth broaches and robotic milling with the same geometry. For robotic bone preparation the CASPAR robotic system with a rotating milling head was used. Cancellous bone was irrigated with 1 liter of pulsed lavage and the specimens were embedded in specially-designed pots. After vacuum mixing, bone cement was introduced in a retrograde manner and subjected to a standard pressure protocol with a constant force of 3,000 N. Radiographs were taken and horizontal sections were obtained at predefined levels, using a diamond saw. Microradiographs of the bone slices were taken, digitized and analyzed to assess cement penetration into cancellous bone. No femoral fractures or fissures occurred with either preparation technique. The microradiographic evaluation showed no morphometric differences between chipped-tooth broaches and robotic milling as regards cement penetration into cancellous bone. Therefore, in the presence of pulsed lavage, we conclude that robotic bone preparation does not increase cement penetration into cancellous bone of the proximal end of the femur.

Analysis of Variance↗