W. Bonicki

EGFR, PIK3CA, KRAS and BRAF mutations in meningiomas

Meningiomas are among the most frequent intracranial tumors. Treatment involves surgical resection with optional subsequent radiotherapy for high-grade meningiomas or radiosurgery following incomplete tumor removal. At present, no pharmacological agents are used as treatment. The use of targeted therapies has been considered, and specific therapies, including anti-EGFR treatment, have been clinically tested. The experience from the treatment of various types of cancers shows that patient outcome depends on the mutational status of particular molecules, including epithelial growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA). Therefore, the aim of the present study was to assess the occurrence and potential use of these markers in patients with meningioma. In total, 55 formalin-fixed, paraffin-embedded meningioma samples were subjected to genomic sequencing of EGFR (exons 18–21), KRAS (exon 1), BRAF (exon 15) and PI3K (exons 9, 20). No mutations were identified in EGFR, KRAS or BRAF. Point mutations in PIK3CA were revealed in the samples of two patients with atypical and anaplastic meningiomas. Although these mutations appear to be rare, this result, along with previously reported findings, indicates that the PI3K/protein kinase B pathway may serve as a more reasonable molecular target for meningioma than EGFR.

Subthalamic nucleus deep brain stimulation after bilateral pallidotomy in the treatment of generalized dystonia

Although it is pallidal (globus pallidus pars interna, GPi) deep brain stimulation (DBS) that has been most consistently employed in treating medically refractory dystonia, the effectiveness of the thalamus, zona incerta, or subthalamic nucleus (STN) stimulation has also been demonstrated. However, there is very little data on how DBS in the STN affects dystonia treatment. Therefore, we report a case of a patient after STN DBS and prior pallidotomy. A 27-year-old female patient complaining about disabling movements of the neck, trunk and limbswas admitted to theMovement Disorder division of the Department of Neurology (Jagiellonian University Medical College, Kraków, Poland). The patient was unable to walk, even when assisted, and was bedridden. She required constant help in basic activities of daily living. The patient had no history of birth trauma or serious neonatal illness, her family history was unremarkable. Her past medical history revealed the following: at the age of 12, she experienced clumsiness due to cramps of the right hand while writing; subsequently, over the next years, she developed sustained twisting and repetitivemovements of both upper limbs as well as of the neck, shoulder girdle and the trunk. Postural and rest tremor of both arms was also intermittently present. At the age of 19, the patient was admitted to the Department of Genetics at the Institute of Psychiatry and Neurology inWarszawa, Poland. At that time, dysarthria, torticollis with head rotation to the right and backwards, adduction of the right shoulder, dystonic movements, sometimes with postural and rest tremor of the upper limbs, and abnormal excessive lordosis in the supine position were found on neurological examination. Further clinical evaluation and laboratory testing for primary dystonia, Huntington’s disease, Wilson’s disease, other types of heredodegenerative dystonia and psychogenic dystonia yielded negative results and she was finally diagnosed with DYT1 negative primary generalized dystonia. Within the next two years, the symptoms deteriorated; moreover, progressive gait disturbances and frequent falling appeared. As the pharmacological treatment (levodopa, MAO-B inhibitor, tetrazepam, diazepam,

MRI versus CT in the diagnosis of Nelson's syndrome

Abstract. The purpose of the study was to evaluate the utility of MRI and CT in the diagnosis of Nelsons syndrome, i. e. pituitary tumours in patients bilaterally adrenalectomized for Cushings disease. Thirteen patients, followed up for 5–29 years after adrenalectomy, were studied. In 6 of them CT and MRI revealed no changes in the pituitary gland. In the remaining 7 patients only three CT scans were suggestive of a pituitary adenoma. MRI studies with administration of gadodiamide confirmed the CT diagnosis of Nelson’s tumour in 3 patients and disclosed microadenomas in a further 4 patients. Neurosurgical treatment in 4 patients confirmed the MRI findings. Additionally CT and MRI examinations were performed in 5 patients suspected of a recurrent Nelsons tumour 3–11 years after neurosurgery. MRI visualized recurrent adenomas in 3 patients that were not well seen by CT scans. In our experience MRI was more effective than CT in the diagnosis of Nelsons syndrome.

Ganglion cell tumours in the sella turcica in close morphological connection with pituitary adenomas.

Ganglion cell tumours in the sellar region are uncommon. They are usually associated with pituitary adenomas, while isolated ganglion cell neoplasms are extremely rare. We report the clinicopathological studies of five cases diagnosed as ganglion cell tumours located in the intrasellar region: four mixed/collision tumours composed of gangliocytoma and pituitary adenoma, and one isolated ganglioglioma unrelated to adenoma. Clinically, two patients presented with acromegaly, while three others were initially diagnosed as non-functioning adenomas. In four cases, the histopathological examination of surgical specimens revealed intermixed lesions composed of pituitary adenoma and ganglion cell elements. The adenomas appeared to secrete growth hormone. Electron microscopy enabled identification of the sparsely granulated somatotroph cells. Neoplastic neuronal lesions were composed of mature ganglion cells, including binucleate or multinucleate cells. In all cases, boundaries between adenomatous and gangliocytic components were not clearly demarcated, and numerous gangliocytic cells were closely intermingled with adenomatous tissue. One case lacked endocrine symptoms, and no pituitary adenoma was identified in the surgically excised material; it was finally diagnosed as low-grade ganglioglioma. The etiopathogenesis of ganglion cell neoplasms in the sellar region is not clearly defined. Our study revealed that if ganglion cell neoplasms were combined with adenoma, both neoplastic components were closely related to each other, and numerous neuronal elements were strictly intermingled with adenoma cells. Such a tissue pattern indicates that these neoplastic changes, including their common respective etiopathogeneses, are closely related. The identification of both components in sellar regions may have some nosological implications.

Alternative splicing of iodothyronine deiodinases in pituitary adenomas. Regulation by oncoprotein SF2/ASF.

Pituitary tumors belong to the group of most common neoplasms of the sellar region. Iodothyronine deiodinase types 1 (DIO1) and 2 (DIO2) are enzymes contributing to the levels of locally synthesized T3, a hormone regulating key physiological processes in the pituitary, including its development, cellular proliferation, and hormone secretion. Previous studies revealed that the expression of deiodinases in pituitary tumors is variable and, moreover, there is no correlation between mRNA and protein products of the particular gene, suggesting the potential role of posttranscriptional regulatory mechanisms. In this work we hypothesized that one of such mechanisms could be the alternative splicing. Therefore, we analyzed expression and sequences of DIO1 and DIO2 splicing variants in 30 pituitary adenomas and 9 non-tumorous pituitary samples. DIO2 mRNA was expressed as only two mRNA isoforms. In contrast, nine splice variants of DIO1 were identified. Among them, five were devoid of exon 3. In silico sequence analysis of DIO1 revealed multiple putative binding sites for splicing factor SF2/ASF, of which the top-ranked sites were located in exon 3. Silencing of SF2/ASF in pituitary tumor GH3 cells resulted in change of ratio between DIO1 isoforms with or without exon 3, favoring the expression of variants without exon 3. The expression of SF2/ASF mRNA in pituitary tumors was increased when compared with non-neoplastic control samples. In conclusion, we provide a new mechanism of posttranscriptional regulation of DIO1 and show deregulation of DIO1 expression in pituitary adenoma, possibly resulting from disturbed expression of SF2/ASF.

Pallidal or Subthalamic Deep Brain Stimulation for the Generalized Dystonia Treatment

One of the most effective treatments of medically refractory generalized dystonia (GD) is pallidal deep brain stimulation (GPi DBS). For selected group of GD patients’ subthalamic deep brain stimulation (STN DBS) might be similarly effective. The authors present a group of patients diagnosed with GD, treated with GPi or STN DBS. Materials and methods: Between 2005 and 2009 eleven female and eight male patients with diagnosed GD were treated with GPi DBS or STN DBS. Mean age at implantation was 26 ± 6. Two patients were diagnosed with DYT-1 mutation. Seven patients were diagnosed with PANK-2 mutation. One patient with previous bilateral pallidotomies and six patients with diagnosed PANK-2 mutation were qualified to STN DBS. Rest of the group was qualified to GPi DBS. Clinical status of the patients was evaluated with a package of dystonia scales. The follow-up evaluation was conducted 60 months after implantation. Results: The patients reported subjective improvement following surgery that was confirmed with tailored scales. Mean improvement was evaluated with Global Dystonia Scale to 48%. More significant improvement was reported in the GPi group than in the STN group (51% vs. 38%) The best results were achieved in the DYT-1 group (89%). Conclusion: Although analyzed group is not large, the authors state that deep brain stimulation is effective and safe method of GD treatment. Decision which anatomical target is optimal should be undertaken individually depending on clinical history, phenotype and etiology of GD.

DNA methylation profiling in nonfunctioning pituitary adenomas

Nonfunctioning pituitary adenomas (NFPAs) are among the most frequent intracranial tumors but their molecular background, including changes in epigenetic regulation, remains poorly understood. We performed genome-wide DNA methylation profiling of 34 NFPAs and normal pituitary samples. Methylation status of the selected genomic regions and expression level of corresponding genes were assessed in a group of 75 patients. NFPAs exhibited distinct global methylation profile as compared to normal pituitary. Aberrant DNA methylation appears to contribute to deregulation of the cancer-related pathways as shown by preliminary functional analysis. Promoter hypermethylation and decreased expression level of SFN, STAT5A, DUSP1, PTPRE and FGFR2 was confirmed in the enlarged group of NFPAs. Difference in the methylation profiles between invasive and non-invasive NFPAs is very slight. Nevertheless, invasiveness-related aberrant epigenetic deregulation of the particular genes was found including upregulation of ITPKB and downregulation CNKSR1 in invasive tumors.