Male sex as a risk factor for the clinical course of skull base chordomas.

OBJECT: Chordomas of the skull base are rare and locally invasive and have a poor prognosis. The aim of this retrospective multicenter study was to evaluate the current pattern of care and clinical course and to identify prognostic factors. METHODS: A total of 47 patients (26 men; mean age 48.5 years) treated in 5 centers were included. Histology was centrally reviewed; additionally, semiquantitative N- and E-cadherin expression analysis was performed. Prognostic factors were obtained from multivariate regression models. For survival analysis the Kaplan-Meier method was used. RESULTS: The median follow-up period was 5.2 years. Complete resection, incomplete resection, and extended biopsy were performed in 14.9%, 80.9%, and 4.3% of patients, respectively. Surgical morbidity was not associated with extent of resection. Adjuvant radiation therapy was performed in 30 (63.8%) of 47 patients. The median progression-free survival (PFS) was 7.3 years. Complete resection prolonged median overall survival (OS) (p = 0.04). Male patients presented with worse PFS (4.8 years vs 9.8 years; p = 0.04) and OS (8.3 years vs not reached; p = 0.03) even though complete resection was exclusively achieved in the male subpopulation. Multivariate analysis confirmed male sex as the most important risk factor for tumor progression (p = 0.04) and death (p = 0.02). Age, duration of symptoms, initial Karnofsky Performance Scale score, brainstem compression, involvement of the petrous bone, infiltration of the dura mater, modality and dose of radiation therapy, and the E- and N-cadherin expression patterns did not gain prognostic relevance. CONCLUSIONS: In skull base chordomas, male patients bear a higher risk of progressive disease and death. Male patients might benefit from more aggressive adjuvant therapy and/or from a closer follow-up schedule.

Infection surveillance in transsphenoidal pituitary surgery - comparison of lipopolysaccharide-binding-protein, interleukin 6, C-reactive protein, white blood cell count, erythrocyte sedimentation rate and body temperature.

BACKGROUND: One of the major concerns in transsphenoidal surgery are infections because the approach to the pituitary includes a route of microbial colonization. To minimize the associated morbidity and mortality, a surveillance program is crucial to monitor for perioperative infections. METHODS: For 1 year, we analysed body temperature (BT), erythrocyte sedimentation rate (ESR), white blood cell count (WBC), C-reactive protein (CRP), interleukin 6 (IL-6) and lipopolysaccharide-binding-protein (LBP) following elective transsphenoidal pituitary surgery. Samples were collected on admission, day 1, 3 and 7 as well as 3 months postoperatively. RESULTS: In 116 patients, all data were available. No postoperative infections occurred within the first postoperative week. BT (37.6 ± 0.6, baseline 37.0 ± 0.5 °C), WBC (11,366 ± 2,541, baseline 6,861 ± 2,123/µl), CRP (25.3 ± 22.6, baseline 3.1 ± 6 mg/l), IL-6 (12 ± 13, baseline 2.7 ± 2.6 pg/ml), and LBP (11.3 ± 4.9, baseline 5.7 ± 2.7 µg/ml) peaked on day 1 postoperatively (each p = 0.001), while ESR peaked on day 3 (25 ± 16, baseline 13 ± 11 mm/h, p = 0.001). BT and IL-6 normalized by day 3 and CRP by day 7, while ESR (23 ± 16 mm/h, p = 0.001), WBC (7,807 ± 2,750/µl, p = 0.001) and LBP (7.3 ± 2.6 µg/ml, p = 0.028) were still increased by day 7. CONCLUSION: The present study establishes normative values for an infection surveillance following transsphenoidal pituitary surgery. CRP, a convenient and reasonable priced parameter, is affected by the procedure for the first postoperative week. IL-6 is more robust and allows a close monitoring on the expense of additional pricing. ESR, WBC and LBP are sustained affected by surgery, and do not offer any advantage. Since no infections were observed, we were unable to calculate the respective sensitivity and specificity.

CRH and SRIF have opposite effects on the Wnt/ß-catenin signalling pathway through PKA/GSK-3ß in corticotroph pituitary cells.

The Wnt/ß-catenin signalling pathway is involved in tumorigenesis including endocrine tumors. We investigated the Wnt/ß-catenin pathway's modulation by corticotropin-releasing hormone (CRH) and somatostatin or somatotropin release-inhibiting factor (SRIF) in mouse pituitary AtT-20 corticotroph cells. The Wnt/ß-catenin signalling pathway was activated by CRH and inhibited by SRIF. We provide evidence that cAMP/PKA signalling is involved affecting the GSK-3ß phosphorylation status at phospho-GSK-3ß (Ser9), thereby altering ß-catenin degradation downstream. Furthermore, CRH and SRIF showed concordant effects on cell proliferation. Our data demonstrate an important role of the Wnt/ß-catenin pathway in the proliferative control of pituitary corticotroph cells and describe a mechanism for its regulation by CRH and SRIF.

Wnt/beta-catenin signaling mediates antineoplastic effects of imatinib mesylate (gleevec) in anaplastic thyroid cancer.

CONTEXT: Dysregulation of Wnt signaling is a key step in neoplastic thyrocyte proliferation. However, it is unclear whether the selective tyrosine kinase (TK) inhibitor, imatinib mesylate, is linked to the Wnt/beta-catenin cascade and is able to modulate the pathway. OBJECTIVE: Conflicting data are reported on the therapeutic effects of imatinib in anaplastic thyroid carcinomas (ATCs), but the molecular mechanism of action is unclear. Here, we further delineated the antitumor effects and the potential efficacy of imatinib in dedifferentiated thyroid carcinomas. RESULTS: Tissue microarray of histologically proven ATCs (n = 12) demonstrated that six of 12 tumors expressed at least one of the imatinib-sensitive TKs. Similarily, imatinib-sensitive TKs were detected in seven of 10 thyroid cancer cell lines derived from metastatic papillary, follicular, and ATCs. Coimmunoprecipitation in ARO cells demonstrated a direct link between c-abl and beta-catenin. Imatinib (10 microM for 48 h) drastically reduced beta-catenin expression and redistributed it from the nucleus to the cell membrane. It stabilized adherens junctions by increasing beta-catenin/E-cadherin binding and reduced the invasive potential of thyroid cancer. Furthermore, imatinib (10 microM for 48 h) attenuated T cell factor/lymphoid enhancer factor activity, reduced cyclin D1 levels and dose-dependently suppressed thyrocyte proliferation by half without affecting apoptosis. CONCLUSION: Our data provide a molecular mechanism for the antitumor activity of imatinib that may help to develop it as a therapeutic option in a subset of ATC patients.