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Till Burkhardt, Daniel Lüdecke, Lothar Spies, Linus Wittmann, Manfred Westphal, and Jörg Flitsch

OBJECT

Cushing’s disease (CD) may cause atrophy of different regions of the human brain, mostly affecting the hippocampus and the cerebellum. This study evaluates the use of 3-T MRI of newly diagnosed patients with CD to detect atrophic degeneration with voxel-based volumetry.

METHODS

Subjects with newly diagnosed, untreated CD were included and underwent 3-T MRI. Images were analyzed using a voxelwise statistical test to detect reduction of brain parenchyma. In addition, an atlas-based volumetric study for regions likely to be affected by CD was performed.

RESULTS

Nineteen patients with a mean disease duration of 24 months were included. Tumor markers included adre-nocorticotropic hormone (median 17.5 pmol/L), cortisol (949.4 nmol/L), and dehydroepiandrosterone sulfate (5.4 μmol/L). The following values are expressed as the mean ± SD. The voxelwise statistical test revealed clusters of significantly reduced gray matter in the hippocampus and cerebellum, with volumes of 2.90 ± 0.26 ml (right hippocampus), 2.89 ± 0.28 ml (left hippocampus), 41.95 ± 4.67 ml (right cerebellar hemisphere), and 42.11 ± 4.59 ml (left cerebellar hemisphere). Healthy control volunteers showed volumes of 3.22 ± 0.25 ml for the right hippocampus, 3.23 ± 0.25 ml for the left hippocampus, 50.87 ± 4.23 ml for the right cerebellar hemisphere, and 50.42 ± 3.97 ml for the left cerebellar hemisphere.

CONCLUSIONS

Patients with untreated CD show significant reduction of gray matter in the cerebellum and hippocampus. These changes can be analyzed and objectified with the quantitative voxel-based method described in this study.

Restricted access

Jörg Flitsch, Christian Bernreuther, Christian Hagel, and Dieter K. Lüdecke

The growth of prostate cancer is controlled by several hormones and growth factors. In cases of metastasized prostate cancer, antigonadotropic therapy is currently considered state-of-the-art treatment. Surgical therapies such as adrenalectomy and hypophysectomy are no longer in use. Nevertheless, hypophysectomy has proven efficacy for palliative pain treatment as well as increasing duration of survival.

The authors present the case of a 63-year-old man with metastatic prostate cancer who presented with high serum prostate-specific antigen levels (1216 μg/L) and cavernous sinus syndrome. His disease was progressing despite leuprorelin and docetaxel therapy, and he had severe bone pain despite high-dose pain therapy. He was also anemic. Contrast-enhanced MR imaging showed a pituitary lesion as well as metastatic infiltration of the skull base including the cavernous sinus. The patient's serum level of prolactin was mildly elevated, testosterone was below the detection limit, and insulin-like growth factor–I (IGF-I) was in the upper range for a patient of his age (233 μg/L). Because of the elevated prolactin and high-normal IGF-I levels he was offered a hypophysectomy in addition to pituitary tumor removal. Histological examination of the resected lesion confirmed a nonsecreting pituitary adenoma with infiltration of prostate cancer cells. Postoperatively the patient's prostate-specific antigen levels dropped to 876 μg/L, his bone pain resolved, and the cavernous sinus syndrome improved. Nevertheless, he died of septicemia 4 months after surgery.

Older publications as well as this case have shown the benefit of hypophysectomy for pain treatment. A reduction of IGF-I levels even in the final stage metastasized prostate cancer may play a major role. Respectively, clinical studies with somatostatin analogs are currently in progress, which may lead to a “new” way of treatment in these otherwise hopeless patients. On the basis of the pain relief seen after hypophysectomy in this case and similar benefits reported in older publications, the authors raise the question whether this treatment should be offered more frequently, and whether additional medical options of hormone treatment may be beneficial in similar cases.

Free access

Roman Rotermund, Marius M. Mader, Till Burkhardt, Jakob Matschke, Jens Aberle, Kara Krajewski, Jörg Flitsch, and Amir-Hossein Rahvar

OBJECTIVE

The purpose of this study was to analyze the clinical and biochemical outcome of consecutive patients with acromegaly after microscopic transsphenoidal surgery (MTS) at a single center over an 8-year period.

METHODS

A retrospective analysis of patients with acromegaly treated via MTS between 2008 and 2015 at the authors’ center was performed. The mean follow-up was 29 months (range 1–120 months). Parameters investigated included tumor size, pre- and postoperative insulin-like growth factor–I, growth hormone levels, pretreatment, perioperative complications, and clinical outcome.

RESULTS

A total of 280 patients with acromegaly were treated surgically at the authors’ center over the abovementioned time frame and were included in analyses. For 231 of these patients, complete follow-up data were available for evaluation. One hundred eighty-eight patients (81%) showed remission initially according to current criteria. So far, 23 of these patients relapsed in the further course, so that on follow-up 165 patients (71%) demonstrated full remission by surgery alone. Most patients in whom remission after surgery failed were treated with somatostatin receptor ligands and/or dopamine agonists as second-line treatment. The main postoperative complications included transient hyponatremia and diabetes insipidus (13/280; 4.6%). CSF leakage only occurred in 2 cases (2/280; 0.7%). No surgery-related death occurred.

CONCLUSIONS

The data underline the effectiveness of MTS in acromegaly. Many patients with recurrent disease or incomplete tumor resection can be successfully managed pharmacologically.

Free access

Till Burkhardt, Jörg Flitsch, Philine van Leyen, Nina Sauer, Jens Aberle, Ulrich Grzyska, and Dieter K. Lüdecke

OBJECT

Correct diagnosis and precise localization of adenomas in patients with Cushing's disease are essential for avoiding unsuccessful transsphenoidal pituitary exploration. In addition to the well-established inferior petrosal sinus sampling, preoperative cavernous sinus sampling (CSS) was introduced as a potentially improved way to predict adenoma lateralization. The authors present their results with CSS in a consecutive series of patients with Cushing's disease.

METHODS

During 1999–2014, transsphenoidal surgeries were consecutively performed in 510 patients with Cushing's disease. For most patients, suppression of cortisol in high-dose dexamethasone tests and stimulation of adrenocorticotropic hormone and cortisol after administration of corticotropin-releasing hormone were sufficient to prove the diagnosis of adrenocorticotropic hormone–dependent hypercortisolism. Of the 510 patients, 67 (13%) were referred to the department of neuroradiology for CSS according to the technique of Teramoto. The indications for CSS were unclear endocrine test results or negative MRI results. Data for all patients were retrospectively analyzed.

RESULTS

A central/peripheral gradient was found in 59 patients; lateralization to the left or right side was found in 51. For 8 patients with a central/peripheral gradient, no left/right gradient could be determined. For another 8 patients with equivocal test results, no central/peripheral gradient was found. No severe CSS-associated complications were encountered. Of the 51 patients who underwent transsphenoidal surgery, the predicted lateralization was proven correct for 42 (82%).

CONCLUSIONS

As MRI techniques have improved, the number of potential candidates for this invasive method has decreased in the past decade. However, because detecting minute adenomas remains problematic, CSS remains a useful diagnostic tool for patients with Cushing's disease.

Free access

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.