DNA Methylation Pattern in Somatotroph Pituitary Neuroendocrine Tumors.

INTRODUCTION: Growth hormone secretion by sporadic somatotroph neuroendocrine pituitary tumors (PitNETs) is a major cause of acromegaly. These tumors are relatively heterogenous in terms of histopathological and molecular features. Our previous transcriptomic profiling of somatotroph tumors revealed three distinct molecular subtypes. This study aimed to investigate the difference in DNA methylation patterns in subtypes of somatotroph PitNETs and its role in distinctive gene expression. METHODS: Genome-wide DNA methylation was investigated in 48 somatotroph PitNETs with EPIC microarrays. Gene expression was assessed with RNAseq. Bisulfite pyrosequencing and qRT-PCR were used for verifying the results of DNA methylation and gene expression. RESULTS: Clustering tumor samples based on methylation data reflected the transcriptome-related classification. Subtype 1 tumors are densely granulated without GNAS mutation, characterized by high expression of NR5A1 (SF-1) and GIPR. The expression of both genes is correlated with specific methylation of the gene body and promoter. This subtype has a lower methylation level of 5' gene regions and CpG islands than the remaining tumors. Subtype 2 PitNETs are densely granulated and frequently GNAS-mutated, while those in subtype 3 are mainly sparsely granulated. Methylation/expression analysis indicates that ∼50% genes located in differentially methylated regions are those differentially expressed between tumor subtypes. Correlation analysis revealed DNA methylation-controlled genes, including CDKN1B, CCND2, EBF3, CDH4, CDH12, MGMT, STAT5A, PLXND1, PTPRE, and MMP16, and genes encoding ion channels and semaphorins. CONCLUSION: DNA methylation profiling confirmed the existence of three molecular subtypes of somatotroph PitNETs. High expression of NR5A1 and GIPR in subtype 1 tumors is correlated with specific methylation of both genes.

Targeted sequencing of cancer-related genes reveals a recurrent TOP2A variant which affects DNA binding and coincides with global transcriptional changes in glioblastoma.

High-grade gliomas are aggressive, deadly primary brain tumors. Median survival of patients with glioblastoma (GBM, WHO grade 4) is 14 months and <10% of patients survive 2 years. Despite improved surgical strategies and forceful radiotherapy and chemotherapy, the prognosis of GBM patients is poor and did not improve over decades. We performed targeted next-generation sequencing with a custom panel of 664 cancer- and epigenetics-related genes, and searched for somatic and germline variants in 180 gliomas of different WHO grades. Herein, we focus on 135 GBM IDH-wild type samples. In parallel, mRNA sequencing was accomplished to detect transcriptomic abnormalities. We present the genomic alterations in high-grade gliomas and the associated transcriptomic patterns. Computational analyses and biochemical assays showed the influence of TOP2A variants on enzyme activities. In 4/135 IDH-wild type GBMs we found a novel, recurrent mutation in the TOP2A gene encoding topoisomerase 2A (allele frequency [AF] = 0.03, 4/135 samples). Biochemical assays with recombinant, wild type (WT) and variant proteins demonstrated stronger DNA binding and relaxation activity of the variant protein. GBM patients carrying the altered TOP2A had shorter overall survival (median OS 150 vs 500 days, P = .0018). In the GBMs with the TOP2A variant we found transcriptomic alterations consistent with splicing dysregulation. luA novel, recurrent TOP2A mutation, which was found exclusively in four GBMs, results in the TOP2A E948Q variant with altered DNA binding and relaxation activities. The deleterious TOP2A mutation resulting in transcription deregulation in GBMs may contribute to disease pathology.

A rare combination of tumor-induced osteomalacia caused by sinonasal glomangiopericytoma and coexisting parathyroid adenoma: case report and literature review.

BACKGROUND: Tumor-induced osteomalacia (TIO) is a rare, acquired disease of renal phosphate wasting and disturbed vitamin D homeostasis as a result of the action of a phosphaturic protein - FGF-23, produced by a neoplasm. Although the clinical and biochemical profile of the syndrome is characteristic, it remains underreported and unrecognized by clinicians. Hyperparathyroidism is rarely associated with oncogenic osteomalacia, but it should be considered because of potentially life-threatening hypophosphatemia caused by both conditions. CASE PRESENTATION: We report a case of a 42-year-old woman admitted to the Department of Otolaryngology of the Military Institute of Medicine in Warsaw for the endoscopic resection of hormonally active glomangiopericytoma extending into the anterior skull base. She presented with a 5-year history of musculoskeletal pain and progressive weakness of the extremities which finally led her to become bedridden. After the excision of the tumor her symptoms and laboratory results gradually improved except increasing PTH serum levels. Further examination revealed a parathyroid proliferative tumor, which was surgically removed. The patient walked without aids at follow-up 16 months after the surgery. CONCLUSIONS: This case is unusual because of tumor-induced osteomalacia and parathyroid adenoma occurring concomitantly. Further investigations of FGF-23 and PTH interplay should be conducted to elucidate the pathogenesis of hyperparathyroidism and tumorigenesis in some cases of TIO. By presenting this case, we wanted to remind clinicians of a rare and misdiagnosed paraneoplastic syndrome and highlight the importance of monitoring PTH concentrations during the follow-up of patients with TIO.

Difference in miRNA Expression in Functioning and Silent Corticotroph Pituitary Adenomas Indicates the Role of miRNA in the Regulation of Corticosteroid Receptors.

Corticotroph pituitary adenomas commonly cause Cushing's disease (CD), but some of them are clinically silent. The reason why they do not cause endocrinological symptoms remains unclear. We used data from small RNA sequencing in adenomas causing CD (n = 28) and silent ones (n = 20) to explore the role of miRNA in hormone secretion and clinical status of the tumors. By comparing miRNA profiles, we identified 19 miRNAs differentially expressed in clinically functioning and silent corticotroph adenomas. The analysis of their putative target genes indicates a role of miRNAs in regulation of the corticosteroid receptors expression. Adenomas causing CD have higher expression of hsa-miR-124-3p and hsa-miR-135-5p and lower expression of their target genes NR3C1 and NR3C2. The role of hsa-miR-124-3p in the regulation of NR3C1 was further validated in vitro using AtT-20/D16v-F2 cells. The cells transfected with miR-124-3p mimics showed lower levels of glucocorticoid receptor expression than control cells while the interaction between miR-124-3p and NR3C1 3' UTR was confirmed using luciferase reporter assay. The results indicate a relatively small difference in miRNA expression between clinically functioning and silent corticotroph pituitary adenomas. High expression of hsa-miR-124-3p in adenomas causing CD plays a role in the regulation of glucocorticoid receptor level and probably in reducing the effect of negative feedback mediated by corticosteroids.

Double pituitary adenomas in a large surgical series.

PURPOSE: To explore the incidence of double pituitary adenomas in a tertiary center for pituitary surgery and asses their clinical, imaging and histopathological features. METHODS: The medical records of the patients operated on for pituitary tumors at the Department of Neurosurgery of Military Institute of Medicine in Warsaw, Poland between the years 2003 and 2018 were retrospectively analyzed. Among the 3270 treated patients, the diagnosis of double pituitary adenoma was established in 22 patients. Clinical, laboratory, detailed histopathological and diagnostics imaging data were collected and analyzed. RESULTS: There were 21 cases of synchronous and one case of asynchronous double pituitary adenoma. The main clinical finding was acromegaly (12/22) followed by Cushing's disease (3/22). The diagnosis of synchronous double pituitary adenoma was suspected in the preoperative MRI in 11 patients. In the remaining patients the diagnosis of contiguous double pituitary adenoma was confirmed in the histopathological examination. There was no predilection for gender and the mean observation time was 74.2 months. In one case of Cushing's disease the occurrence of double pituitary adenoma led to the initial failure of achieving hormonal remission. One patient presented with double pituitary adenomas as a manifestation of Carney complex. CONCLUSIONS: Double pituitary adenoma is a rare entity that can pose a significant challenge especially in the setting of Cushing's disease. Careful inspection of preoperative MRI and diagnostic work-up before transsphenoidal surgery and thorough histopathological microscopic examinations with immunohistochemical staining for all pituitary hormones is essential for establishing the diagnosis of double pituitary adenoma.

Surgical treatment of pineal cysts in non-hydrocephalic and neurologically intact patients: selection of surgical candidates and clinical outcome.

PURPOSE: Management of patients presenting for various nonspecific complaints without clear neurological abnormalities and with normal ventricular size remains highly controversial. We intended to share our rationale for surgical treatment of patients who show symptoms of transient increase of intracranial pressure owing to the presence of the cyst. MATERIALS AND METHODS: We have retrospectively analyzed 28 cases of patients who presented without Parinaud syndrome nor ventricular enlargement and underwent pineal cyst removal in our centre between 2007 and 2015. We analyzed patients' age, sex, symptoms, preoperative cyst size, perioperative course, treatment outcome and neurologic status at discharge and at follow-up visits 4 and 12 months afterwards. RESULTS: Main complaints included paroxysmal headaches, nausea, vomiting, visual disturbances, syncope and transient depression of consciousness. Mean age of patients was 31 years (17-55); there were 24 females and 4 males. Mean cyst diameter was 17 mm (10-26). Decision about surgical treament was based on signs of transient increases of intracranial pressure. All patients underwent complete cyst excision via midline suboccipital craniotomy and infratentorial supracerebellar route. Short-lasting perioperative neurological signs (notably upgaze palsy) were noted in 22 cases and uniformly resolved within the observation period of 12 months. CONCLUSION: Abnormal neurological findings and ventricular enlargement are not indispensable to justify surgical treatment of pineal cysts. Judicious selection of surgical candidates based predominantly on clinical grounds can lead to excellent operative results.

A Selective and Functional Group-Tolerant Ruthenium-Catalyzed Olefin Metathesis/Transfer Hydrogenation Tandem Sequence Using Formic Acid as Hydrogen Source.

A ruthenium-catalyzed transfer hydrogenation of olefins utilizing formic acid as a hydrogen donor is described. The application of commercially available alkylidene ruthenium complexes opens access to attractive C(sp3)-C(sp3) bond formation in an olefin metathesis/transfer hydrogenation sequence under tandem catalysis conditions. High chemoselectivity of the developed methodology provides a remarkable synthetic tool for the reduction of various functionalized alkenes under mild reaction conditions. The developed methodology is applied for the formal synthesis of the drugs pentoxyverine and bencyclane.

Increased expression of the microRNA 106b~25 cluster and its host gene MCM7 in corticotroph pituitary adenomas is associated with tumor invasion and Crooke's cell morphology.

PURPOSE: MCM7 (minichromosome maintenance complex component 7), a DNA replication licensing factor, is a host gene for the oncogenic miR-106b~25 cluster. It has been recently revealed as a relevant prognostic biomarker in a variety of cancers, including pituitary adenomas. The purpose of this study was to assess whether miR-106b~25 and MCM7 levels correlate with tumor invasiveness in a cohort of ACTH-immunopositive adenomas. METHODS: Tissue samples were obtained intraoperatively from 25 patients with pituitary adenoma. Tumor invasiveness was assessed according to the Knosp grading scale. MCM7, Ki-67 and TP53 levels were assessed by immunohistochemical staining, while the expression of miR-106b-5p, miR-93-5p, miR-93-3p and miR-25-3p were measured using quantitative real-time PCR performed on RNA isolated from FFPE tissues. RESULTS: We have found a significant increase in MCM7 and Ki-67 labeling indices in invasive ACTHomas. Moreover, MCM7 was ubiquitously overexpressed in Crooke's cell adenomas. The expression of miR-93-5p was significantly elevated in invasive compared to noninvasive tumors. In addition, all four microRNAs from the miR-106b~25 cluster displayed marked upregulation in Crooke's cell adenomas. Remarkably, MCM7 and miR-106b-5p both strongly correlated with Knosp grade. A combination of MCM7 LI and miR-106b~25 cluster expression was able to accurately differentiate invasive from noninvasive tumors and had a significant discriminatory ability to predict postoperative tumor recurrence/progression. CONCLUSIONS: miR-106b~25 and its host gene MCM7 are potential novel biomarkers for invasive ACTH-immunopositive pituitary adenomas. Additionally, they are both significantly upregulated in rare Crooke's cell adenomas and might therefore contribute to their aggressive phenotype.

Tandem Catalysis Utilizing Olefin Metathesis Reactions.

Since olefin metathesis transformation has become a favored synthetic tool in organic synthesis, more and more distinct non-metathetical reactions of alkylidene ruthenium complexes have been developed. Depending on the conditions applied, the same olefin metathesis catalysts can efficiently promote isomerization reactions, hydrogenation of C=C double bonds, oxidation reactions, and many others. Importantly, these transformations can be carried out in tandem with olefin metathesis reactions. Through addition of one portion of a catalyst, a tandem process provides structurally advanced products from relatively simple substrates without the need for isolation of the intermediates. These aspects not only make tandem catalysis very attractive from a practical point of view, but also open new avenues in (retro)synthetic planning. However, in the literature, the term "tandem process" is sometimes used improperly to describe other types of multi-reaction sequences. In this Concept, a number of examples of tandem catalysis involving olefin metathesis are discussed with an emphasis on their synthetic value.

[Treatment methods of atypical gunshot wounds to the head--case reports]. / Sposoby leczenia nietypowych obrazen postrzalowych glowy--opisy przypadków.

Due to a high mortality rate, headshot injuries pose serious diagnostic and clinical problems. In this work, we wanted to describe four atypical headshot injuries. The first patient with a headshot injury using a nail gun mishap; the second one after a headshot injury, as a result of attempted murder (the bullet came to a parasagittal halt in the left parietal area); the third victim, after a suicide attempt (the bullet was removed from clivus area, below the pituitary gland); in the case of the fourth patient, after shooting himself with a self-constructed weapon in the chin, the metal body was surgically removed - a bearing pellet from the corpus callosum. Males dominate among victims of headshot injuries. Alcohol is one of the elements that facilitate suicidal behaviour. Anti-spasm, antibacterial, anti-tetanus prophylaxes are incredibly important. In some cases, the metallic body does not have to be removed from the brain. Pulmonary embolism can be a cause of death after 7 days from injury.

In tandem or alone: a remarkably selective transfer hydrogenation of alkenes catalyzed by ruthenium olefin metathesis catalysts.

A system for transfer hydrogenation of alkenes, composed of a ruthenium metathesis catalyst and HCOOH, is presented. This operationally simple system can be formed directly after a metathesis reaction to effect hydrogenation of the metathesis product in a single-pot. These hydrogenation conditions are applicable to a wide range of alkenes and offer remarkable selectivity.

Ectopic Cushing's syndrome in light of modern diagnostic techniques and treatment options.

Ectopic adrenocorticotropic hormone secretion (EAS) is responsible for approximately 10-15% cases of Cushing's syndrome. EAS is associated with various tumors such as small cell lung cancer and well-differentiated bronchial or gastrointestinal neuroendocrine tumors. Hormonal diagnostics include assessments in basic conditions as well as dynamic tests, such as the high-dose dexamethasone suppression test and corticotrophin releasing hormone (CRH) stimulation test. Treatment selection depends on the type of tumor and its extent. In the case of neuroendocrine tumors, the main treatments are surgery and administration of somatostatin analogs that may be additionally radiolabeled for targeted radiotherapy. The tumor histology and the presence and control of hypercortisolemia and metastases are of major importance in prognosis. In this article we presented the principles of modern hormonal and imaging diagnostics techniques as well as the key issues associated with treatment of ACTH-dependent Cushing's syndrome due to EAS.

[Pituitary apoplexy - not always correctly recognized life-threatening entity]. / Udar przysadki mózgowej - nie zawsze rozpoznawany stan zagrozenia zycia.

Pituitary apoplexy is a life-threatening circumstance developing as a result of ischemia or hemorrhage into pre-existing pituitary tumor. Frequency of this condition is hard to be precisely estimated. Clinical course is characteristic and commonly consists of severe headache accompanied by nausea, vomiting, impaired consciousness, visual field impairment as well as eyeballs movement restriction. Symptoms are typically accompanied by secondary adrenal insufficiency. Severe course of pituitary apoplexy requires hospitalization and immediate medical treatment. Corticosteroids are drugs of choice regarding coexisting adrenal insufficiency. In case of a lack of expected both general and neurological improvement during conservative treatment, a surgery might be necessary. Prognosis in case of a proper treatment is good. Every patient after pituitary apople.

Gonadotroph adenoma causing ovarian hyperstimulation syndrome in a premenopausal woman.

INTRODUCTION: Gonadotroph adenomas occur commonly in middle-aged adults without any specific endocrinological symptoms. To date, only 30 cases of gonadotropinoma causing ovarian hyperstimulation syndrome in pre-menopausal women have been reported. CASE REPORT: A 37-year old woman with pituitary macroadenoma and hyperprolactinaemia was admitted to the Department of Endocrinology, Diabetology and Isotope Therapy. She presented with recurrent ovarian cysts, menstrual disturbances, headaches, visual impairment and galactorrhea. Her endocrine profile showed normal values of FSH, elevated concentrations of estradiol and suppressed LH levels. Transsphenoidal resection of the tumor tissue resulted in normalization of the hormone values and improvement in the clinical picture. CONCLUSIONS: Gonadotroph adenomas should be considered in the differential diagnosis in premenopausal women with OHSS.

The role of polymorphisms of genes encoding collagen IX and XI in lumbar disc disease.

The intervertebral disc disease (IDD) is one of the most common musculoskeletal disorders. A number of environment and anthropometric risk factors may contribute to it. The recent reports have suggested the importance of genetic factors, especially these which encode collagen types IX and XI. The allelic variants in the collagen IX genes - COL9A2 (Trp2) and COL9A3 (Trp3) have been identified as genetic risk factors for IDD, because they interfere the cross-linking between collagen types II, IX and XI and result in decreased stability of intervertebral discs. Type XI collagen is a minor component of cartilage collagen fibrils, but it is present in the annulus fibrosus and nucleus pulposus of intervertebral discs. Some studies have shown the association between gene COL11A1 polymorphism c.4603C>T and IDD. The frequency of 4603T allele was significantly higher in the patients with IDD than in the healthy controls.

[Intraneural ganglion of the peroneal nerve--two case reports]. / Torbiel galaretowata nerwu strzalkowego--opis dwóch przypadków.

This paper describes two cases of gelatinous cyst of rare location within the peroneal nerve. Clinical picture was different in described patients. The gelatinous cyst was completely resected in both cases. The final diagnosis was established based on the histo-patological examination.

Analysis of the Use of Sample Size and Effect Size Calculations in a Temporomandibular Disorders Randomised Controlled Trial-Short Narrative Review.

BACKGROUND/OBJECTIVES: Temporomandibular disorder (TMD) is the term used to describe a pathology (dysfunction and pain) in the masticatory muscles and temporomandibular joint (TMJ). There is an apparent upward trend in the publication of dental research and a need to continually improve the quality of research. Therefore, this study was conducted to analyse the use of sample size and effect size calculations in a TMD randomised controlled trial. METHODS: The period was restricted to the full 5 years, i.e., papers published in 2019, 2020, 2021, 2022, and 2023. The filter article type-"Randomized Controlled Trial" was used. The studies were graded on a two-level scale: 0-1. In the case of 1, sample size (SS) and effect size (ES) were calculated. RESULTS: In the entire study sample, SS was used in 58% of studies, while ES was used in 15% of studies. CONCLUSIONS: Quality should improve as research increases. One factor that influences quality is the level of statistics. SS and ES calculations provide a basis for understanding the results obtained by the authors. Access to formulas, online calculators and software facilitates these analyses. High-quality trials provide a solid foundation for medical progress, fostering the development of personalized therapies that provide more precise and effective treatment and increase patients' chances of recovery. Improving the quality of TMD research, and medical research in general, helps to increase public confidence in medical advances and raises the standard of patient care.

Surface Electromyography in Dentistry-Past, Present and Future.

Surface electromyography (sEMG) is a technique for measuring and analyzing the electrical signals of muscle activity using electrodes placed on the skin's surface. The aim of this paper was to outline the history of the development and use of surface electromyography in dentistry, to show where research and technical solutions relating to surface electromyography currently lie, and to make recommendations for further research. sEMG is a diagnostic technique that has found significant application in dentistry. The historical section discusses the evolution of sEMG methods and equipment, highlighting how technological advances have influenced the accuracy and applicability of this method in dentistry. The need for standardization of musculoskeletal testing methodology is highlighted and the needed increased technical capabilities of sEMG equipment and the ability to specify parameters (e.g., sampling rates, bandwidth). A higher sampling rate (the recommended may be 2000 Hz or higher in masticatory muscles) allows more accurate recording of changes in the signal, which is essential for accurate analysis of muscle function. Bandwidth is one of the key parameters in sEMG research. Bandwidth determines the range of frequencies effectively recorded by the sEMG system (the recommended frequency limits are usually between 20 Hz and 500 Hz in masticatory muscles). In addition, the increased technical capabilities of sEMG equipment and the ability to specify electromyographic parameters demonstrate the need for a detailed description of selected parameters in the methodological section. This is necessary to maintain the reproducibility of sEMG testing. More high-quality clinical trials are needed in the future.

A Meta-Analysis of the Global Prevalence of Temporomandibular Disorders.

Background: This meta-analysis aims to evaluate the proportion of people with TMDs in different studies, considering factors such as geographical region, patient age, and sample size. Methods: The search yielded 6984 articles on the incidence of TMDs. Finally, 74 studies with 172,239 subjects and 35,259 with TMDs were selected for final analysis. Analyses were performed using the R statistical language. Results: The incidence of TMDs in the world population was 34%. The age group 18-60 years is the most exposed to TMDs. From the data presented, we observed that for each continent, the female group was 9% to 56% larger than the male group. The highest female-to-male ratio (F:M) was reported in South America (1.56), whereas the lowest F:M ratio was reported in Europe (1.09), suggesting an almost equal distribution of males and females. Conclusions: This suggests that geographical location may play a role in the results of the studies. The prevalence of TMDs was significantly higher in South America (47%) compared to Asia (33%) and Europe (29%). Larger epidemiological studies of TMDs in African and Australian populations are recommended. In conclusion, both visual and statistical assessments suggest that the results of our meta-analysis are robust and unlikely to be significantly affected by publication bias. This suggests that geographical location may play a role in the prevalence of TMDs.

Cushing's disease presenting with recurrent abscesses followed by post-remission hyperthyroidism.

Summary: We report a case of a 59-year-old woman with Cushing's disease who developed hyperthyroidism following treatment of hypercortisolaemia. The patient with a history of recurrent hospitalisations caused by multi-sited soft tissue abscesses was admitted with sepsis. Both her medical history and physical examination suggested Cushing's syndrome. The initial hormonal diagnostic process, conducted after sepsis treatment, brought forth conflicting results. However, hormonal assessment repeated 3 months later indicated pituitary hypercortisolaemia, which was confirmed through bilateral inferior petrosal sinus sampling and was successfully treated with transsphenoidal pituitary surgery. Three months after the surgery, the patient was readmitted to our epartment with symptoms of hyperthyroidism, which was confirmed by laboratory tests. Thyroid scintiscans indicated Graves' disease. However, the absence of anti-thyroid stimulating hormone antibodies suggested other etiologies of hyperthyroidism. Eventually, the patient underwent radioiodine therapy. Currently, her condition is improving and she has had no recurrence of abscesses, severe infections, or hyperthyroidism. In conclusion, while clinical manifestation of hypercortisolaemia might be non-specific, its treatment may trigger the development of autoimmune diseases. Learning points: The presence of recurrent severe infections should prompt physicians to consider the possibility of hypercortisolaemia. Chronic hypercortisolism is debilitating and can lead to significant disability. Dexamethasone suppression testing in patients with active or recent severe inflammatory or infectious illnesses may produce misleading or confusing results. Clinicians should be aware of the potential development of autoimmune diseases following successful treatment of hypercortisolaemia.