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Jürgen Honegger, Michael Buchfelder and Rudolf Fahlbusch

Object. This study aimed to elucidate the endocrinological outcome of craniopharyngioma surgery. In particular, endocrinological results were analyzed in relation to the surgical approach. The study includes 143 patients who underwent pre- and postoperative endocrinological assessment and who had not previously undergone surgery.

Methods. Diabetes insipidus was the most common postoperative deficiency in both the transcranial and transsphenoidal groups. The overall percentage of patients with diabetes insipidus increased from 16.1% preoperatively to 59.4% postoperatively. After transcranial surgery, the rate of anterior pituitary deficiency also increased. However, normal preoperative anterior pituitary function was maintained in more than 50% of patients for each endocrine axis. Similar results were attained in the group of patients undergoing complete tumor removal. The best result was achieved for gonadal function: the incidence of hypogonadism increased only slightly from 77.4 to 79.8%. The rate of anterior pituitary failure at presentation was much higher in the transsphenoidal than in the transcranial group. During transsphenoidal surgery, intact anterior pituitary functions were generally preserved. The rate of panhypopituitarism increased only slightly, from 40% before surgery to 42.9% after surgery. Endocrinological results were not inferior in patients with a ventrally displaced pituitary. This variant required midline incision of the gland for exposure of the craniopharyngioma. In the entire series of 143 patients the pituitary stalk was generally preserved. Postoperative panhypopituitarism was encountered in only one of eight patients in whom the pituitary stalk was partially resected because of tumor infiltration. None of the 88 patients who remained recurrence-free demonstrated endocrinological deterioration during follow-up review, compared with the early postoperative assessment 3 months postsurgery. On the other hand, complete recovery of one endocrine axis was observed in nine of these patients during later follow-up evaluations. In five of them, diabetes insipidus had regressed.

Conclusions. It is worth preserving the pituitary stalk and gland at surgery because of the definite chance that intact anterior pituitary functions can be maintained. Postoperative diabetes insipidus must be accepted as a common sequela following attempts at complete removal of the craniopharyngioma.

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Rudolf Fahlbusch, Michael Buchfelder and Uwe Schrell

✓ During a period of 3 years, 25 patients with intra- and extrasellar macroprolactinomas were pretreated with dopamine agonists for a period of 2 to 6½ weeks prior to transsphenoidal microsurgical tumor resection. Dopamine agonists were administered orally to 17 patients, intramuscularly to three patients, and both orally and intramuscularly to five patients. Repeated computerized tomography (CT) examinations revealed that all neoplasms except one cystic tumor were reduced in size during the course of dopamine-agonist administration. No complications attributable to medical pretreatment were observed. Tumor shrinkage increased the efficacy of surgery, especially in cases with considerable extrasellar extension of the adenomas. Within 3 months following adenomectomy, prolactin levels were adjusted to normal levels in 19 patients by additional low-dose treatment with dopamine agonists. Thin-collimation CT assessments performed at least 3 months after surgery showed no evidence of residual tumor tissue in 23 patients. It is concluded that administration of dopamine agonists for some weeks prior to surgery is a useful adjunct to transsphenoidal microsurgery for macroprolactinomas. The new injectable form of bromocriptine is particularly valuable for this purpose.

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Jürgen Honegger, Michael Buchfelder and Rudolf Fahlbusch

This study aimed to elucidate the endocrine outcome of craniopharyngioma surgery. In particular, endocrine results were analyzed in relation to the surgical approach. The study includes 161 patients who underwent pre- and postoperative endocrine assessment, 143 of whom had not previously undergone surgery.

Diabetes insipidus was the most common postoperative deficiency in both the transcranial and transsphenoidal groups. In the case of primary surgery (surgery as initial therapy), the overall percentage of patients with diabetes insipidus increased from 16.1% preoperatively to 59.4% postoperatively. After transcranial surgery, the rate of anterior pituitary deficiency also increased. However, normal preoperative anterior pituitary function was maintained in more than 50% of patients for each endocrine axis. Similar results were attained in the group of patients undergoing complete tumor removal. The best result was achieved for gonadal function: the incidence of hypogonadism increased only slightly from 77.4 to 79.8%. During transsphenoidal surgery, anterior pituitary function was generally preserved. An additional deficient axis was encountered postoperatively in only four (11.4%) of 35 primary surgery cases. Endocrine results were not inferior in patients with a ventrally displaced pituitary. This variant required midline incision of the gland for exposure of the craniopharyngioma. Panhypopituitarism was encountered in only one of eight patients in whom the pituitary stalk was partially resected because of tumor infiltration. None of the 88 patients who remained recurrence-free demonstrated endocrine deterioration during follow-up review, compared with the early postoperative assessment 3 months postsurgery. On the other hand, complete recovery of one endocrine axis was observed in nine of these patients during later follow-up evaluations. In five of them, diabetes insipidus had regressed.

The authors conclude that it is worth preserving the pituitary stalk and gland at surgery because anterior pituitary function is more often maintained than is generally believed. Postoperative diabetes insipidus must be accepted as a consequence of complete removal of the pituitary. However, pituitary function may recover and diabetes insipidus in particular may abate with time.

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Rudolf Fahlbusch, Oliver Ganslandt, Michael Buchfelder, Werner Schott and Christopher Nimsky

Object. The aim of this study was to evaluate whether intraoperative magnetic resonance (MR) imaging can increase the efficacy of transsphenoidal microsurgery, primarily in non—hormone-secreting intra- and suprasellar pituitary macroadenomas.

Methods. Intraoperative imaging was performed using a 0.2-tesla MR imager, which was located in a specially designed operating room. The patient was placed supine on the sliding table of the MR imager, with the head placed near the 5-gauss line. A standard flexible coil was placed around the patient's forehead. Microsurgery was performed using MR-compatible instruments. Image acquisition was started after the sliding table had been moved into the center of the magnet. Coronal and sagittal T1-weighted images each required over 8 minutes to acquire, and T2-weighted images were obtained optionally. To assess the reliability of intraoperative evaluation of tumor resection, the intraoperative findings were compared with those on conventional postoperative 1.5-tesla MR images, which were obtained 2 to 3 months after surgery.

Among 44 patients with large intra- and suprasellar pituitary adenomas that were mainly hormonally inactive, intraoperative MR imaging allowed an ultra-early evaluation of tumor resection in 73% of cases; such an evaluation is normally only possible 2 to 3 months after surgery. A second intraoperative examination of 24 patients for suspected tumor remnants led to additional resection in 15 patients (34%).

Conclusions. Intraoperative MR imaging undoubtedly offers the option of a second look within the same surgical procedure, if incomplete tumor resection is suspected. Thus, the rate of procedures during which complete tumor removal is achieved can be improved. Furthermore, additional treatments for those patients in whom tumor removal was incomplete can be planned at an early stage, namely just after surgery.

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Rudolf Fahlbusch, Jürgen Honegger, Werner Paulus, Walter Huk and Michael Buchfelder

Object. The goal of this study was to assess the outcome of surgical management in 168 consecutive patients harboring craniopharyngiomas treated between January 1983 and April 1997.

Methods. In 148 patients undergoing initial (primary) surgery, the pterional approach was most frequently used (39.2%), followed by the transsphenoidal approach (23.6%). For large retrochiasmatic craniopharyngiomas, the bifrontal interhemispheric approach was used increasingly over the pterional approach and led to improved surgical results. Total tumor removal was accomplished in 45.7% of transcranial and 85.7% of transsphenoidal procedures. The main reasons for incomplete removal were attachment to and/or infiltration of the hypothalamus, major calcifications, and attachment to vascular structures. The success rate in total tumor removal was inferior in the cases of tumor recurrence. The operative mortality rate in transcranial surgery was 1.1% in primary cases and 10.5% in cases of tumor recurrence. No patient died in the group that underwent transsphenoidal surgery. The rate of recurrence-free survival after total removal was 86.9% at 5 years and 81.3% at 10 years. In contrast, the 5-year recurrence-free survival rate was only 48.8% after subtotal removal and 41.5% after partial removal. Following primary surgery, the actuarial survival rate was 92.7% at 10 years, with the best results after complete tumor removal. At last follow up, 117 (79%) of 148 patients who underwent primary surgery were independent and without impairment.

Conclusions. Total tumor removal while avoiding hazardous intraoperative manipulation provides favorable early results and a high rate of long-term control in craniopharyngiomas.

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Rudolf Fahlbusch, Jürgen Honegger, Werner Paulus, Walter Huk and Michael Buchfelder

The surgical management of 168 consecutive patients harboring craniopharyngiomas treated between January 1983 and April 1997 is described. In 148 patients undergoing initial (primary) surgery, the pterional approach was most frequently used (39.2%) followed by the transsphenoidal approach (23.6%). For large retrochiasmatic craniopharyngiomas, the bifrontal interhemispheric approach was used increasingly over the pterional approach and led to improved surgical results. Total tumor removal was accomplished in 45.7% of transcranial and 85.7% of transsphenoidal procedures. The main reasons for incomplete removal were attachment and/or infiltration of the hypothalamus, major calcifications, and attachment to vascular structures. The success rate in total tumor removal was inferior in the cases of tumor recurrence. The operative mortality rate in transcranial surgery was 1.1% in primary cases and 10.5% in cases of tumor recurrence. No patient died in the group undergoing transsphenoidal surgery. The rate of recurrence-free survival after total removal was 86.9% at 5 years and 81.3% at 10 years. In contrast, the 5-year recurrence-free survival rate was only 48.8% after subtotal removal and 41.5% after partial removal. Following primary surgery, the actuarial survival rate was 92.7% at 10 years, with the best results after complete tumor removal. At last follow up, 117 (79%) of 148 patients who underwent primary surgery were independent and without impairment.

Total tumor removal while avoiding hazardous intraoperative manipulation provides favorable early results and a high rate of long-term control in craniopharyngiomas.

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Sven Berkmann, Sven Schlaffer, Christopher Nimsky, Rudolf Fahlbusch and Michael Buchfelder

Object

The loss of anatomical landmarks, frequently invasive tumor growth, and tissue changes make transsphenoidal reoperation of nonfunctioning pituitary adenomas (NFAs) challenging. The use of intraoperative MRI (iMRI) may lead to improved results. The goal of this retrospective study was to evaluate the impact of iMRI on transsphenoidal reoperations for NFA.

Methods

Between September 2002 and July 2012, 109 patients underwent reoperations in which 111 transsphenoidal procedures were performed and are represented in this study. A 1.5-T Magnetom Sonata Maestro Class scanner (Siemens) was used for iMRI. Follow-up iMRI scans were acquired if gross-total resection (GTR) was suspected or if no further removal seemed possible.

Results

Surgery was performed for tumor persistence and regrowth in 26 (23%) and 85 (77%) patients, respectively. On the initial iMRI scans, GTR was confirmed in 19 (17%) patients. Remnants were located as follows: 65 in the cavernous sinus (71%), 35 in the suprasellar space (38%), 9 in the retrosellar space (10%). Additional resection was possible in 62 (67%) patients, resulting in a significant volume reduction and increased GTR rate (49%). The GTR rates of invasive tumors on initial iMRI and postoperative MRI (poMRI) were 7% and 25%, respectively. Additional remnant resection was possible in 64% of the patients. Noninvasive tumors were shown to be totally resected on the initial iMRI in 31% of cases. After additional resection for 69% of the procedures, the GTR rate on poMRI was 75%. Transcranial surgery to resect tumor remnants was indicated in 5 (5%), and radiotherapy was performed in 29 (27%) patients. After GTR, no recurrence was detected during a mean follow-up of 2.2 ± 2.1 years.

Conclusions

The use of iMRI in transsphenoidal reoperations for NFA leads to significantly higher GTR rates. It thus prevents additional operations and reduces the number of tumor remnants. The complication rates do not exceed the incidences reported in the literature for primary transsphenoidal surgery. If complete tumor resection is not possible, iMRI guidance can facilitate tumor volume reduction.

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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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Bernd Markus Hofmann, Michal Hlavac, Ramon Martinez, Michael Buchfelder, Otto Albrecht Müller and Rudolf Fahlbusch

Object

The aim of this paper was to demonstrate the long-term results following microsurgery in a single surgeon's continuous series of patients with Cushing disease (CD), to assess the influence of changes in surgical procedures, and to compare the results with those of other treatment modalities. In particular, preoperative diagnosis, tumor size, results of histological examination, and complications were considered.

Methods

Between 1971 and 2004, 426 patients suffering from newly diagnosed CD underwent primary surgery. Pre-operative measures included clinical examination, endocrinological workup (testing of the hypothalamic-pituitary-adrenal axis, and 2- and 8-mg dexamethasone overnight suppression tests), sellar imaging (polytomography, computed tomography, and magnetic resonance [MR] imaging), and in patients with negative results on imaging studies, inferior petrosal sinus sampling. Follow-up examinations consisting of endocrinological workup, and imaging took place 1 week and 3 months after surgery and then at yearly intervals.

Results

During microsurgery as first treatment, the adenoma finding rate was 86.6%. After selective adenomectomy, the remission rate was 75.9%, and this rate showed no improvement over the years. The best results were achieved in microadenomas confirmed on MR imaging or histopathological investigation. The recurrence rate (15%) and the complication rate (5.9%) declined over the years. If no adenoma was found, exploration of the sella turcica was performed in 45.6%, hypophysectomy in 3.5%, and hemihypophysectomy in 50.9% of these patients, leading to an early remission in 37.9%. In case of persistence or recurrence, further treatment (repeated operation, adrenalectomy, radio-therapy, or medical treatment) was used to control the disease.

Conclusions

Microsurgery remains the treatment of first choice in CD, even though no improvement in remission rates was observed over the years, because complication or remission rates for other treatment options are comparable or worse.

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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.