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  • Author or Editor: Michael Buchfelder x
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Bernd M. Hofmann, Anke Höllig, Christian Strauss, Rolf Buslei, Michael Buchfelder and Rudolf Fahlbusch

Object

The authors report surgical and endocrinological results of a series of 73 cases of craniopharyngioma that they treated surgically since 1997 to demonstrate their change in treatment strategy and its effect on outcome compared with a previous series and results reported in the literature.

Methods

A total of 73 patients underwent surgery for craniopharyngiomas between May 1997 and January 2005. In patients with poor clinical or neuropsychological condition, even following pretreatment, only stereotactic cyst aspiration took place (8 cases). In the remaining patients, gross-total resection (GTR) was intended and appeared to be possible. The most frequent approaches were subfrontal (27 cases) and transsphenoidal (26 cases); in some cases, a multistep approach was used. The rate of GTR, complications, and functional outcome (comparing pre- and postoperative endocrine and neuropsychological testing) were evaluated. The mean duration of follow-up was 25.2 months.

Results

Gross-total resection was achieved in 88.5% of cases in which a transsphenoidal approach was used and 79.5% of those in which a transcranial approach was used (85.2% of those in which a subfrontal approach was used and 72.7% of those in which a frontolateral approach was used). In the total series, GTR was achieved in 83.1% of cases (vs 49.3% in the authors' former series). The complication rate was 13.8% without any mortality. New endocrine deficits were observed more frequently in patients treated with transcranial approaches over the years (16.3%–66.7% vs 2.6%–50.0%) but were less frequent after transsphenoidal approaches (5.2%–19.2% vs 2.9%–45.7%).

Conclusions

Open surgery with intended total resection remains the treatment of choice in most patients. Initial stereotactic cyst aspiration or medical pretreatment to improve the patients' condition and adequate choice of surgical approach(es) are essential to achieve that goal. Nevertheless, a moderate increase in endocrinological deficits has to be accepted. The authors recommend using radiotherapy only in cases in which there are tumor remnants or disease progression after surgery.

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Christina Stache, Christiane Bils, Rudolf Fahlbusch, Jörg Flitsch, Michael Buchfelder, Harald Stefanits, Thomas Czech, Udo Gaipl, Benjamin Frey, Rolf Buslei and Annett Hölsken

OBJECTIVE

In this study, the authors investigated the underlying mechanisms responsible for high tumor recurrence rates of adamantinomatous craniopharyngioma (ACP) after radiotherapy and developed new targeted treatment protocols to minimize recurrence. ACPs are characterized by the activation of the receptor tyrosine kinase epidermal growth factor receptor (EGFR), known to mediate radioresistance in various tumor entities. The impact of tyrosine kinase inhibitors (TKIs) gefitinib or CUDC-101 on radiation-induced cell death and associated regulation of survivin gene expression was evaluated.

METHODS

The hypothesis that activated EGFR promotes radioresistance in ACP was investigated in vitro using human primary cell cultures of ACP (n = 10). The effects of radiation (12 Gy) and combined radiochemotherapy on radiosensitivity were assessed via cell death analysis using flow cytometry. Changes in target gene expression were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Survivin, identified in qRT-PCR to be involved in radioresistance of ACP, was manipulated by small interfering RNA (siRNA), followed by proliferation and vitality assays to further clarify its role in ACP biology. Immunohistochemically, survivin expression was assessed in patient tumors used for primary cell cultures.

RESULTS

In primary human ACP cultures, activation of EGFR resulted in significantly reduced cell death levels after radiotherapy. Treatment with TKIs alone and in combination with radiotherapy increased cell death response remarkably, assessed by flow cytometry. CUDC-101 was significantly more effective than gefitinib. The authors identified regulation of survivin expression after therapeutic intervention as the underlying molecular mechanism of radioresistance in ACP. EGFR activation promoting ACP cell survival and proliferation in vitro is consistent with enhanced survivin gene expression shown by qRT-PCR. TKI treatment, as well as the combination with radiotherapy, reduced survivin levels in vitro. Accordingly, ACP showed reduced cell viability and proliferation after survivin downregulation by siRNA.

CONCLUSIONS

These results indicate an impact of EGFR signaling on radioresistance in ACP. Inhibition of EGFR activity by means of TKI treatment acts as a radiosensitizer on ACP tumor cells, leading to increased cell death. Additionally, the results emphasize the antiapoptotic and pro-proliferative role of survivin in ACP biology and its regulation by EGFR signaling. The suppression of survivin by treatment with TKI and combined radiotherapy represents a new promising treatment strategy that will be further assessed in in vivo models of ACP.