Differentially Expressed miRNAs Influence Metabolic Processes in Pituitary Oncocytoma.

Spindle cell oncocytomas (SCO) of the pituitary are rare tumors accounting for 0.1-0.4% of all sellar tumors. Due to their rarity, little information is available regarding their pathogenesis. Our aim was to investigate miRNA expression profile of pituitary oncocytomas. Total RNA was extracted from 9 formalin-fixed paraffin embedded pituitary samples (4 primary, 3 recurrent oncocytomas and 2 normal tissues). Next-generation sequencing was performed for miRNA profiling. Transcriptome data of additional 6 samples' were obtained from NBCI GEO database for gene expression reanalysis and tissue-specific target prediction. Bioinformatical analysis, in vitro miRNA mimics transfection, luciferase reporter system and AlamarBlue assay were applied to characterize miRNA's function. 54 differentially expressed miRNAs and 485 genes in pituitary SCO vs. normal tissue and 8 miRNAs in recurrent vs. primary SCO were determined. Global miRNA downregulation and decreased level of DROSHA were detected in SCO samples vs. normal tissue. Transcriptome analysis revealed cell cycle alterations while miRNAs influenced mainly metabolic processes (tricarboxylic acid cycle-TCA, carbohydrate, lipid metabolism). Through miRNA-target interaction network the overexpressed Aconitase 2 potentially targeted by two downregulated miRNAs (miR-744-5p, miR-127-3p) was revealed. ACO2 and miR-744-5p interaction was validated by luciferase assay. MiR-127-3p and miR-744-5p significantly decreased cell proliferation in vitro. Our study firstly reported miRNA profile of pituitary oncocytoma. Our results suggest that tumor suppressor miRNAs may have an essential role in the pathogenesis of pituitary oncocytoma. Earlier reports showed downregulated TCA cycle in SCO which is extended by our results adding the role of miR-744-5p targeting ACO2.

[Early experience with CyberKnife treatment in case of intra-, suprasellar hypernephroma metastasis]. / Korai tapasztalataink CyberKnife-kezeléssel suprasellarisan is terjedo hypernephroma-áttét esetén.

Among tumours found in the suprasellar region metastases are very rare and the most frequent primary tumours are lung and breast cancer. Data of a patient with clear cell renal carcinoma with intra-suprasellar metastasis will be discussed. As in most of the tumours in the sellar region, the first symptom was visual deterioration with visual field defect. A transsphenoidal debulking of the tumour was performed and the residual tumor was treated by CyberKnife hypofractionated stereotactic radiotherapy. Both our patient's visual acuity and visual field impairment improved after the surgery and CyberKnife treatment. At 6-month after irradiation, MR of the sella showed a complete remission of the tumour. This was the first treatment with CyberKnife in our country in case of a tumour close to the optic chiasm. According to our best knowledge, there are 21 cases in the literature with renal cell carcinoma metastasis in the suprasellar region.

[The role of miRNAs in the pathogenesis of pituitary adenomas]. / A mikro-RNS-ek szerepe az agyalapimirigy-daganatok tumorbiológiájában.

MicroRNAs (miRNAs) are short, single stranded RNA molecules which play regulatory roles through posttranscriptional regulation of their target genes. Based on our current knowledge, more than 30% of the human protein-coding genes are regulated by miRNAs, hence influencing basic cellular mechanisms including cell proliferation, differentiation and cell death. Differential miRNA expression pattern has been detected in many different types of tumors and, recently, several publications have referred to miRNAs as potential therapeutic targets. Through adjustment of miRNA levels by artificial miRNAs administration or miRNA inhibition, we can influence not only one target gene but also complex biological pathways. Pituitary adenoma is the second most frequent intracranial tumor. In spite of this, the molecular mechanism of the pituitary adenoma formation is not yet entirely revealed. Recently, more and more evidences have been found suggesting that miRNAs have an important role in pituitary adenoma pathogenesis. Here, we summarize the recent results related to this role and highlight the therapeutic potentials in pituitary adenomas. Orv Hetil. 2018; 159(7): 252-259.

[Neurovascular compression of the medulla oblongata: a rare cause of secondary hypertension]. / Nyúltveloi neurovascularis kompresszió. A szekunder hypertonia ritka oka.

Compression of the rostral ventrolateral medulla oblongata is one of the rarely identified causes of refractory hypertension. In patients with severe, intractable hypertension caused by neurovascular compression, neurosurgical decompression should be considered. The authors present the history of a 20-year-old man with severe hypertension. After excluding other possible causes of secondary hypertension, the underlying cause of his high blood pressure was identified by the demonstration of neurovascular compression shown by magnetic resonance angiography and an increased sympathetic activity (sinus tachycardia) during the high blood pressure episodes. Due to frequent episodes of hypertensive crises, surgical decompression was recommended, which was performed with the placement of an isograft between the brainstem and the left vertebral artery. In the first six months after the operation, the patient's blood pressure could be kept in the normal range with significantly reduced doses of antihypertensive medication. Repeat magnetic resonance angiography confirmed the cessation of brainstem compression. After six months, increased blood pressure returned periodically, but to a smaller extent and less frequently. Based on the result of magnetic resonance angiography performed 22 months after surgery, re-operation was considered. According to previous literature data long-term success can only be achieved in one third of patients after surgical decompression. In the majority of patients surgery results in a significant decrease of blood pressure, an increased efficiency of antihypertensive therapy as well as a decrease in the frequency of highly increased blood pressure episodes. Thus, a significant improvement of the patient's quality of life can be achieved. The case of this patient is an example of the latter scenario.

ACTH-secreting Crooke cell carcinoma of the pituitary.

PURPOSE: While pituitary adenomas are common, pituitary carcinomas are rare. It is unclear whether pituitary carcinomas arise de novo or evolve from adenomas. METHODS: We studied the clinical characteristics and tissue samples from eight pituitary surgeries and the autopsy from a patient with pituitary carcinoma. A 16-year-old female patient was diagnosed with an aggressive Crooke cell macroadenoma. Following transsphenoidal surgery, clinical signs of Cushing disease quickly reappeared. During the 14-year course of the illness, eight pituitary surgeries, three courses of extracranial irradiation and two (90) Yttrium-DOTATOC treatments were undertaken. A bilateral adrenalectomy was performed. The patient died of metastatic disease and uncontrolled hypercortisolism due to an adrenal remnant. A systematic morphologic study (histologic staining, electron microscopy) of all available surgical and autopsy specimens was undertaken. RESULTS: Brisk mitotic activity, high Ki-67 and p53 immunolabelling were present in the pituitary samples from the onset. High proportion of tumour cells showed irregular nuclei and large nucleoli, and gradual increase in MGMT staining was observed. The tumour remained of Crooke cell type throughout the course. Autopsy disclosed a postirradiation sarcoma in the pituitary area. CONCLUSIONS: The question whether pituitary carcinomas arise de novo or transform from an adenoma cannot be answered at present with certainty.

[Neuroendocrine dysfunctions and their consequences following traumatic brain injury]. / Koponyasérülésekhez társuló neuroendokrinológiai zavarok és következményeik.

Posttraumatic hypopituitarism is of major public health importance because it is more prevalent than previously thought. The prevalence of hypopituitarism in children with traumatic brain injury is unknown. Most cases of posttraumatic hypopituitarism remain undiagnosed and untreated in the clinical practice, and it may contribute to the severe morbidity seen in patients with traumatic brain injury. In the acute phase of brain injury, the diagnosis of adrenal insufficiency should not be missed. Determination of morning serum cortisol concentration is mandatory, because adrenal insufficiency can be life threatening. Morning serum cortisol lower than 200 nmol/L strongly suggests adrenal insufficiency. A complete hormonal investigation should be performed after one year of the trauma. Isolated growth hormone deficiency is the most common deficiency after traumatic brain injury. Sports-related chronic repetitive head trauma (because of boxing, kickboxing, football and ice hockey) may also result in hypopituitarism. Close co-operation between neurosurgeons, endocrinologists, rehabilitation physicians and representatives of other disciplines is important to provide better care for these patients.

[Role of the intraoperative electrical brain stimulation in conserving the speech and language function in neurosurgical procedures on conscious patients]. / Az intraoperatív elektromos agyi stimuláció szerepe a nyelvi és beszédfunkciók megorzése céljából éber betegeken végzett idegsebészeti beavatkozások során.

AIM OF THE STUDY: To summarize the results gained with awake craniotomies, which were performed in either low grade glioma patients or epilepsy surgical patients whose tumor or epileptogenic zone, was in the vicinity of eloquent, mostly language, cortices. PATIENT SELECTION AND METHODS: In our retrospective study we selected 16 patients who were operated awake between 1999-2011 at the Neurosurgical Department of MAV Kórház Budapest, or at the National Institute of Neurosciences in Budapest, or at the Neurosurgical Department of the University of Debrecen in Debrecen. In the presurgical evaluation if it was possible we performed functional magnetic resonance imaging, tractography and detailed neuropsychological testing. At the National Institute of Neurosciences all patients were operated with the aid of MR guided neuronavigation. RESULTS: Anesthesia was carried out without complications in all of the 16 cases. Monitoring of sleep deepness has significantly contributed to the safety of anesthesia during the superficial anesthezied states of the operation. The intraoperative neuropsychological tasks used for testing language were sensitive enough to judge the little disturbances in speech during stimulation. Stimulation evoked seizures could be adequately managed during surgery and did not influence the outcome of the procedures. The use of neuronavigation helped significantly by planning the optimal place for the craniotomy and by intraoperative orientation. CONCLUSIONS: Awake craniotomies require well practiced surgical teams, which requires the cooperation of neuro-anesthesiologits, neurosurgeons, neuropsychologist and electrophysiologists. It has two goals, first to reduce the time of surgery to minimize surgical complications, secondly the detailed intraoperative mapping of cognitive and motor functions to avoid any neurological deficit. The intraoperative anatomical data provided by the neuronavigation and the functional data provided by awake intraoperative stimulation of the patient together serve the safety of the patient which is essential in the neurologically minimal invasive neurosurgical approach of the 21st century.

Aspirin Mediates Its Antitumoral Effect Through Inhibiting PTTG1 in Pituitary Adenoma.

CONTEXT: DNA demethylation and inhibitory effects of aspirin on pituitary cell proliferation have been demonstrated. OBJECTIVE: Our aim was to clarify the molecular mechanisms behind the aspirin-related effects in pituitary cells. METHODS: DNA methylome and whole transcriptome profile were investigated in RC-4B/C and GH3 pituitary cell lines upon aspirin treatment. Effects of aspirin and a demethylation agent, decitabine, were further tested in vitro. PTTG1 expression in 41 human PitNET samples and whole genome gene and protein expression data of 76 PitNET and 34 control samples (available in Gene Expression Omnibus) were evaluated. RESULTS: Aspirin induced global DNA demethylation and consequential transcriptome changes. Overexpression of Tet enzymes and their cofactor Uhrf2 were identified behind the increase of 5-hydroxymethylcytosine (5hmC). Besides cell cycle, proliferation, and migration effects that were validated by functional experiments, aspirin increased Tp53 activity through p53 acetylation and decreased E2f1 activity. Among the p53 controlled genes, Pttg1 and its interacting partners were downregulated upon aspirin treatment by inhibiting Pttg1 promoter activity. 5hmC positively correlated with Tet1-3 and Tp53 expression, and negatively correlated with Pttg1 expression, which was reinforced by the effect of decitabine. Additionally, high overlap (20.15%) was found between aspirin-regulated genes and dysregulated genes in PitNET tissue samples. CONCLUSION: A novel regulatory network has been revealed, in which aspirin regulated global demethylation, Tp53 activity, and Pttg1 expression along with decreased cell proliferation and migration. 5hmC, a novel tissue biomarker in PitNET, indicated aspirin antitumoral effect in vitro as well. Our findings suggest the potential beneficial effect of aspirin in PitNET.

MicroRNA profile indicates downregulation of the TGFß pathway in sporadic non-functioning pituitary adenomas.

MicroRNAs (miRs) are small, 16-29 nucleotide long, non-coding RNA molecules which regulate the stability or translational efficiency of targeted mRNAs via RNA interference. MiRs participate in the control of cell proliferation, cell differentiation, signal transduction, cell death, and they play a role in carcinogenesis. The aims of our study were to analyse the expression profile of miRs in sporadic clinically non-functioning pituitary adenomas (NFPA) and in normal pituitary tissues, and to identify biological pathways altered in these pituitary tumors. MiR expression profiles of 12 pituitary tissue specimens (8 NFPA and 4 normal pituitary tissues) were determined using miR array based on quantitative real-time PCR with 678 different primers. Five overexpressed miRs and mRNA expression of Smads (Smad1-9), MEG and DLK1 genes were evaluated with individual Taqman assays in 10 NFPA and 10 normal pituitary tissues. Pathway analysis was performed by the DIANA-mirPath tool. Complex bioinformatical analysis by multiple algorithms and association studies between miRs, Smad3 and tumor size was performed. Of the 457 miRs expressed in both NFPA and normal tissues, 162 were significantly under- or overexpressed in NFPA compared to normal pituitary tissues Expression of Smad3, Smad6, Smad9, MEG and DLK1 was significantly lower in NFPA than in normal tissues. Pathway analysis together with in silico target prediction analysis indicated possible downregulation of the TGFß signaling pathway in NFPA by a specific subset of miRs. Five miRs predicted to target Smad3 (miR-135a, miR-140-5p, miR-582-3p, miR-582-5p and miR-938) were overexpressed. Correlation was observed between the expression of seven overexpressed miRs and tumor size. Downregulation of the TGFß signaling through Smad3 via miRs may have a possible role in the complex regulation of signaling pathways involved in the tumorigenesis process of NFPA.

[Consensus on the change of criteria for cure of acromegaly during the last decade]. / Konszenzus a kritériumok változásáról az acromegalia gyógyulásának megítélésében - nemzetközi ajánlás, 2010.

The Acromegaly Consensus Group redefined the consensus criteria for cure of acromegaly. 74 neurosurgeons and experienced endocrinologists summarized the latest results on diagnosis and treatment of acromegaly. In this consensus statement the reliable growth hormone and insulin-like growth factor-1 assays were established. Definition of disease control was discussed based on the available publications and evidence. This short communication summarizes the clinical aspects of consensus criteria for diagnosis and cure of acromegaly based on the original article.

[Familial isolated pituitary adenoma syndrome]. / Familiáris izolált hypophysisadenoma.

Familial pituitary adenomas occur in multiple endocrine neoplasia type 1, Carney complex, as well as in familial isolated pituitary adenoma syndrome. Familial isolated pituitary adenoma syndrome is an autosomal dominant disease with incomplete penetrance. Pituitary adenomas occur in familial setting but without any other specific tumors. In 20-40% of families with this syndrome, mutations have been identified in the aryl hydrocarbon receptor interacting protein gene while in the rest of the families the causative gene or genes have not been identified. Families carrying aryl hydrocarbon receptor interacting protein gene mutations have a distinct phenotype with younger age at diagnosis and a predominance of somatotroph and lactotroph adenomas. Germline mutations of the aryl hydrocarbon receptor interacting protein gene can be occasionally identified in usually young-onset seemingly sporadic cases. Genetic and clinical testing of relatives of patients with aryl hydrocarbon receptor interacting protein gene mutations can lead to earlier diagnosis and treatment at an earlier stage of the pituitary tumor.

Dynamic changes of CB1-receptor expression in hippocampi of epileptic mice and humans.

The endocannabinoid system plays a central role in retrograde synaptic communication, and controls both glutamatergic and gamma-aminobutyric acid (GABA)ergic transmission via type 1 cannabinoid (CB1) receptor. Both in sclerotic human hippocampi and in the chronic phase of pilocarpine-induced epilepsy in mice with sclerosis, CB1-receptor-positive interneuron somata were preserved both in the dentate gyrus and in the CA1 area, and the density of CB1-immunostained fibers increased considerably in the dentate molecular layer. This suggests that, although CB1 receptors are known to be reduced in density on glutamatergic axons, the CB1-receptor-expressing GABAergic axons sprout, or there is an increase of CB1-receptor levels on these fibers. The changes of CB1 immunostaining in association with the GABAergic inhibitory system appear to correlate with the severity of pyramidal cell loss in the CA1 subfield. These results confirm the involvement of the endocannabinoid system associated with GABAergic transmission in human temporal lobe epilepsy (TLE), as well as in the chronic phase of the pilocarpine model in mice. Pharmacotherapy aimed at the modulation of endocannabinoid-mediated retrograde synaptic signaling should take into account the opposite change in CB1-receptor expression observed on glutamatergic versus GABAergic axon terminals.

[Macroprolactinemia associated with pituitary macroadenoma: treatment with quinagolide]. / Macroprolactinaemiával társuló hypophysismacroadenoma kezelése quinagoliddal.

According to current concept, macroprolactin is biologically inactive and, therefore, its accumulation in serum has little, if any, pathological significance. Authors present the history of a 80-year-old man who proved to have, among other associated disorders, an intra- and parasellar pituitary tumor measuring 21x12x12 mm in size which was revealed by pituitary MRI. His hormonal evaluation indicated a marked hyperprolactinemia mainly due to macroprolactinemia (total prolactin, 514 ng/ml; reference range, 1.6-10.7 ng/ml; macroprolactin 436 ng/ml, monomer prolactin 78.2 ng/ml). Tests for function of the pituitary-thyroid axis showed a mild subclinical primary hypothyroidism. The function of the pituitary-adrenal axis was normal, and other hormonal tests revealed low-normal serum gonadotropins and decreased testosterone level, whereas serum insulin-like growth factor I was normal. Although the majority of current guidelines state that dopamine-agonist treatment which is successfully used in prolactin-producing pituitary tumors and in other hyperprolactinemic disorders is unnecessary in patients with macroprolactinemia, the authors introduced a dopamine-agonist, quinagolide. During prolonged treatment, plasma prolactin returned close to the upper limit of normal (12.3 ng/ml) and 9 months after the beginning of treatment pituitary MRI showed a remarkable shrinkage of the pituitary tumor. Authors propose that in this patient the pituitary tumor secreted macroprolactin, and they recommend a treatment trial with dopamine-agonist in pituitary macroadenomas associated with macroprolactinemia.

[Intracranial propagation of invasive aspergilloma in an immuncompromised patient]. / Intracranialis terjedést mutató invazív aspergilloma immunszupprimált beteg esetében.

Aspergillus infection of the central nervous system is a rare disease, occasionally seen among immunocompromised patients. The most frequent pathway is hematogenic dissemination. Less known is the direct propagation from the paranasal sinuses, which is usually observed in immunocompetent patients. We report a patient who developed cavernous sinus syndrome due to an invasive intracranial aspergilloma after longlasting chemo- and steroid therapy for chronic lymphoid leukemia and immunhemolytic anemia. The characteristic features seen on radiological images--brain CT and MRI--suggested the possibility of invasive aspergilloma. Postoperative histology defined the diagnosis. Our case review highlights the importance of considering the possibility of an invasive opportunistic infection of the CNS in an immunocompromised patient presenting a new neurological sign.

Demethylation Status of Somatic DNA Extracted From Pituitary Neuroendocrine Tumors Indicates Proliferative Behavior.

BACKGROUND: Cytosine intermediaries 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), epigenetic hallmarks, have never been investigated in pituitary neuroendocrine tumors (PitNET). OBJECTIVE: To examine methylation-demethylation status of global deoxyribonucleic acid (DNA) in PitNET tissues and to assess its correlation with clinical and biological parameters. MATERIALS AND METHODS: Altogether, 57 PitNET and 25 corresponding plasma samples were collected. 5mC and 5hmC were investigated using liquid chromatography-tandem mass spectrometry. Expression of DNA methyltransferase 1 (DNMT1); tet methylcytosine dioxygenase 1 through 3 (TET1-3); and ubiquitin-like, containing PHD and RING finger domains 1 and 2 (UHRF1-2) were measured by reverse transcription-polymerase chain reaction. Levels of 5hmC and UHRF1-2 were explored by immunohistochemistry. Effect of demethylating agent decitabine was tested on pituitary cell lines. RESULTS: 5hmC/5mC ratio was higher in less differentiated PitNET samples. A negative correlation between Ki-67 proliferation index and 5hmC, 5hmC to 5mC ratio were revealed. Higher 5mC was observed in SF-1 + gonadotroph adenomas with a higher Ki-67 index. Expressions of TET2 and TET3 were significantly higher in adenomas with higher proliferation rate. UHRF1 showed gradually increased expression in higher proliferative adenoma samples, and a significant positive correlation was detected between UHRF2 expression and 5hmC level. Decitabine treatment significantly decreased 5mC and increased 5hmC levels in both cell lines, accompanied with decreased cell viability and proliferation. CONCLUSION: The demethylation process negatively correlated with proliferation rate and the ratio of 5hmC to 5mC was higher in less differentiated adenomas. Therefore, epigenetic markers can be potential biomarkers for PitNET behavior. Altering the epigenome in adenoma cells by decitabine decreased proliferation, suggesting that this treatment might be a novel medical treatment for PitNET.

Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus.

Endocannabinoid signaling is a key regulator of synaptic neurotransmission throughout the brain. Compelling evidence shows that its perturbation leads to development of epileptic seizures, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. To elucidate whether long-term reorganization of endocannabinoid signaling occurs in epileptic patients, we performed comparative expression profiling along with quantitative electron microscopic analysis in control (postmortem samples from subjects with no signs of neurological disorders) and epileptic (surgically removed from patients with intractable temporal lobe epilepsy) hippocampal tissue. Quantitative PCR measurements revealed that CB(1) cannabinoid receptor mRNA was downregulated to one-third of its control value in epileptic hippocampus. Likewise, the cannabinoid receptor-interacting protein-1a mRNA was decreased, whereas 1b isoform levels were unaltered. Expression of diacylglycerol lipase-alpha, an enzyme responsible for 2-arachidonoylglycerol synthesis, was also reduced by approximately 60%, whereas its related beta isoform levels were unchanged. Expression level of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D and fatty acid amide hydrolase, metabolic enzymes of anandamide, and 2-arachidonoylglycerol's degrading enzyme monoacylglycerol lipase did not change. The density of CB(1) immunolabeling was also decreased in epileptic hippocampus, predominantly in the dentate gyrus, where quantitative electron microscopic analysis did not reveal changes in the ratio of CB(1)-positive GABAergic boutons, but uncovered robust reduction in the fraction of CB(1)-positive glutamatergic axon terminals. These findings show that a neuroprotective machinery involving endocannabinoids is impaired in epileptic human hippocampus and imply that downregulation of CB(1) receptors and related molecular components of the endocannabinoid system may facilitate the deleterious effects of increased network excitability.

Properties of in vivo interictal spike generation in the human subiculum.

A large proportion of hippocampal afferents and efferents are relayed through the subiculum. It is also thought to be a key structure in the generation and maintenance of epileptic activity; rhythmic interictal-like discharges were recorded in previous studies of subicular slices excised from temporal lobe epilepsy patients. In order to investigate if and how the subiculum is involved in the generation of epileptic discharges in vivo, subicular and lateral temporal lobe electrical activity were recorded under anesthesia in 11 drug-resistant epilepsy patients undergoing temporal lobectomy. Based on laminar field potential gradient, current source density, multiple unit activity (MUA) and spectral analyses, two types of interictal spikes were distinguished in the subiculum. The more frequently occurring spike started with an initial excitatory current (current source density sink) in the pyramidal cell layer associated with increased MUA in the same location, followed by later inhibitory currents (current source density source) and decreased MUA. In the other spike type, the initial excitation was confined to the apical dendritic region and it was associated with a less-prominent increase in MUA. Interictal spikes were highly synchronized at spatially distinct locations of the subiculum. Laminar data showed that the peak of the initial excitation occurred within 0-4 ms at subicular sites separated by 6 mm at the anterior-posterior axis. In addition, initial spike peak amplitudes were highly correlated in most recordings. A subset of subicular and temporal lobe spikes were also highly synchronous, in one case the subicular spikes reliably preceded the temporal lobe discharges. Our results indicate that multiple spike generator mechanisms exist in the human epileptic subiculum suggesting a complex network interplay between medial and lateral temporal structures during interictal epileptic activity. The observed widespread intra-subicular synchrony may reflect both of its intrinsic and extrinsically triggered activity supporting the hypothesis that subiculum may also play an active role in the distribution of epileptiform activity to other brain regions. Limited data suggest that subiculum might even play a pacemaker role in the generation of paroxysmal discharges.

[Outcome of somatostatin analogue treatment in acromegaly]. / A szomatosztatinanalóg kezelés eredményei acromegaliában.

UNLABELLED: During the past decade the importance of medical therapy, especially treatment with somatostatin analogues has increased significantly in patients with active acromegaly. AIMS: Authors analyzed the outcome of somatostatin analogue treatment in acromegalic patients evaluated and followed up at the 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, during the past 10 years. PATIENTS AND METHODS: Changes in serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentration, as well as morphologic changes of pituitary adenomas followed by MRI scans were evaluated and compared in 32 acromegalic patients (26 women, 6 men) during long-term somatostatin analogue treatment (mean+/-SE, 3.1+/-0.3 years, range, 1-7 years). Primary somatostatin analogue treatment was applied in 10 patients (7 women and 3 men), whereas 15 patients (14 women and 1 man) had pituitary surgery and 7 patients (5 women and 2 men) underwent both pituitary surgery and irradiation therapy prior to somatostatin analogue treatment. RESULTS: After a 3-month treatment with somatostatin analogues, both serum GH and IGF-1 levels decreased significantly and they remained around the same decreased levels throughout the treatment period. Serum GH decreased from 15.7+/-4.9 to 5.5+/-1.4 ng/ml, and serum IGF-1, expressed as a percentage of the upper limit of age- and sex-adjusted reference value, decreased from 204+/-14% to 135+/-12% at the end of treatment. The efficacy of somatostatin analogue treatment was not influenced by surgical or surgical and irradiation therapies which were applied prior to medical treatment. At the end of treatment 36.7% of patients had safe serum GH (<2.5 ng/ml), while serum IGF-1 returned below the upper limit of age- and sex-adjusted reference range in 41.4% of patients. Pituitary MRI showed regression of the adenoma in 46% of patients, and none of the patients had progression of the pituitary adenoma. CONCLUSIONS: Somatostatin analogues are effective therapeutic options for acromegalic patients when primary surgical treatment cannot be performed due to complications and associated disorders, or in patients whose acromegaly remains active after pituitary surgery or after pituitary surgery and irradiation.

Comprehensive Analysis of Circulating miRNAs in the Plasma of Patients With Pituitary Adenomas.

BACKGROUND: Circulating miRNAs in pituitary adenomas would improve patient care, especially as minimally invasive biomarkers of tumor recurrence and progression in nonfunctioning adenoma cases. AIM: Our aim was to investigate plasma miRNA profiles in patients with pituitary adenomas. MATERIALS AND METHODS: A total of 149 plasma and extracellular vesicle (preoperative, early postoperative, and late postoperative) samples were collected from 45 patients with pituitary adenomas. Adenomas were characterized on the basis of anterior pituitary hormones and transcription factors by immunostaining. miRNA next-generation sequencing was performed on 36 samples (discovery set). Individual TaqMan assays were used for validation on an extended sample set. Pituitary adenoma tissue miRNAs were evaluated by TaqMan array and data in the literature. RESULTS: Global downregulation of miRNA expression was observed in plasma samples of pituitary adenomas compared with normal samples. Expression of 29 miRNAs and isomiR variants were able to distinguish preoperative plasma samples from normal controls. miRNAs with altered expression in both plasma and different adenoma tissues were identified. Three, seven, and 66 miRNAs expressed differentially between preoperative and postoperative plasma samples in GH-secreting, FSH/LH+, and hormone-immunonegative groups, respectively. miR‒143-3p was downregulated in late postoperative but not in early postoperative plasma samples compared with preoperative ones exclusively in FSH/LH+ adenomas. The plasma level of miR‒143-3p discriminated these samples with 81.8% sensitivity and 72.3% specificity (area under the curve = 0.79; P = 0.02). CONCLUSIONS: Differentially expressed miRNAs in pituitary adenoma tissues have low abundance in plasma, minimizing their role as biomarkers. Plasma miR‒143-3p level decreased in patients with FSH/LH+ adenomas, indicating successful surgery, but its application for evaluating tumor recurrence needs further investigation.

Protein western array analysis in human pituitary tumours: insights and limitations.

The molecular analysis of pituitary tumours has received a great deal of attention, although the majority of studies have concentrated on the genome and the transcriptome. We aimed to study the proteome of human pituitary adenomas. A protein array using 1005 monoclonal antibodies was used to study GH-, corticotrophin- and prolactin-secreting as well as non-functioning pituitary adenomas (NFPAs). Individual protein expression levels in the tumours were compared with the expression profile of normal pituitary tissue. Out of 316 proteins that were detected in the pituitary tissue samples, 116 proteins had not previously been described in human pituitary tissue. Four prominent differentially expressed proteins with potential importance to tumorigenesis were chosen for validation by immunohistochemistry and western blotting. In the protein array analysis heat shock protein 110 (HSP110), a chaperone associated with protein folding, and B2 bradykinin receptor, a potential regulator of prolactin secretion, were significantly overexpressed in all adenoma subtypes, while C-terminal Src kinase (CSK), an inhibitor of proto-oncogenic enzymes, and annexin II, a calcium-dependent binding protein, were significantly underexpressed in all adenoma subtypes. The immunohistochemical analysis confirmed the overexpression of HSP110 and B2 bradykinin receptor and underexpression of CSK and annexin II in pituitary adenoma cells when compared with their corresponding normal pituitary cells. Western blotting only partially confirmed the proteomics data: HSP110 was significantly overexpressed in prolactinomas and NFPAs, the B2 bradykinin receptor was significantly overexpressed in prolactinomas, annexin II was significantly underexpressed in somatotrophinomas, while CSK did not show significant underexpression in any tumour. Protein expression analysis of pituitary samples disclosed both novel proteins and putative protein candidates for pituitary tumorigenesis, though validation using conventional techniques are necessary to confirm the protein array data.