Mutation analysis of metastatic melanomas in the central nervous system: results of a panel of 5 genes in 48 cases.

Melanocytic lesions in the central nervous system (CNS) may be primary to the site but are more commonly metastases from cutaneous primaries. In fact, melanomas are one of the most common malignancies that can metastasize to the brain, and some patients may not have a diagnosis of melanoma prior to the discovery of the CNS lesion. In such cases, identifying the primary site may be challenging. We reviewed the archives of a large referral center for melanocytic tumors involving the CNS and selected 48 patients for this study based on our inclusion criteria. We used sequencing to identify mutation status of these tumors and compared these with clinicopathological features. Mutations in exon 9, 11, 13, 17, and 18 of KIT gene, exon 15 of BRAF gene, exon 2 and 3 of NRAS gene, exon 4 and 5 of GNAQ and GNA11 genes were analyzed. Mutations in BRAF-exon 15 were the most common among tumors (58.3%). NRAS-exon 2 and NRAS-exon 3 mutations were detected in 3 and 7 cases, respectively. GNAQ-exon 4, GNAQ-exon 5 and GNA11-exon 5 mutation were present in 1 tumor each. Eight tumors were wild type for all 5 genes, and 6 of these were not known primary despite a work-up and clinical follow-up. Only 1 of these tumors showed a mutation in exon 11 of KIT gene. When compared to primary melanocytic lesions of the CNS, metastatic melanomas were characterized by BRAF gene mutations and wild-type GNAQ and GNA11 genes.

Distinctive immunostaining of claudin-4 in spiradenomas.

The intercellular bridges are essential structures in maintaining the histologic organization of the epithelium, while providing a very efficient way to exchange molecules between cells and transduction of the cell-to-cell and matrix-to-cell signals. Derangement in those important structures' physical integrity and/or function, which can be assessed by the presence or absence of several intercellular bridge proteins including claudin-4, E-cadherin, and ß-catenin, was found to be related to several phenomena in the path to the neoplastic transformation. However, these proteins have not been studied in the wide variety of the skin neoplasms, in detail. Herein, we immunohistochemically assessed the expression patterns of these 3 intercellular bridge proteins on a total of 86 epidermal and eccrine adnexal tumors including basal cell carcinoma, squamous cell carcinoma, poroma, spiradenoma, syringoma, and hidradenoma. We observed a selective and distinct claudin-4 expression in the ductal-type cells of all cases of spiradenomas. Similarly, in the poromas, syringomas, and hidradenomas, claudin-4 was only positive in the luminal cells of microcystic structures, although not as conspicuous as in the spiradenomas. On the other hand, E-cadherin and ß-catenin were positive in almost all types of the tumors, in a way which was not contributory to differentiate from each other. In conclusion, we think that claudin-4 can be helpful at least in making a reliable differential diagnosis of spiradenoma when overlapping morphologic features do not allow to further subclassification in the overwhelming variety of the adnexal tumors.

Evaluation of Etanercept Treatment in Newborn Rat Model with Hyperoxic Lung Injury.

BACKGROUND: Many factors contribute to the development of BPD basically by increasing inflammation in preterm lungs. However, premature neonates have insufficient anti-inflammatory capacity. We aimed to evaluate the effect of etanercept, an anti-TNF agent, on BPD development in newborn rat model with hyperoxia-induced lung injury. METHODS: Thirty-two newborn rats were divided into 3 groups as control group (Group 1, n = 11), hyperoxia + placebo group (Group 2, n = 10), and hyperoxia + etanercept group (Group 3, n = 11). Histopathological and biochemical analysis were performed in order to assess inflammation and oxidative stress. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities, and malondialdehyde (MDA) levels were studied, histopathological scoring and radial alveolar count were applied in lung tissue. Lamellar body membrane protein, vascular endothelial growth factor (VEGF), nuclear factor-kappaB (NF-κB) gene expressions were studied in immunohistochemical evaluation of tissue samples. All three groups were compared with each other in terms of all parameters. RESULTS: SOD and GSH-Px activities were significantly higher, whereas MDA levels were lower in group 3, compared to group 2 (p < 0.001). Histopathological scores were lower, lamellar body membrane protein expression and radial alveolar count were higher in group 3 (p < 0.05). NF-κB expression was higher in group 2, but lower in group 3 in comparison with group 1. Expression of VEGF was decreased in group 2 but came close to group 1 with etanercept treatment in group 3. CONCLUSIONS: We found etanercept treatment to be protective in newborn rats with hyperoxia-induced lung damage.

Pituitary macroadenomas (>3 cm) in young adulthood: Pathologic and proliferative characteristics.

BACKGROUND: There are scarce data regarding the significance of the tumor size, hormonal activity and size of the pituitary tumor of the young; therefore, the study was designed to define the relation of the hormonal status of the large pituitary adenomas. OBJECTIVE: We compared those features with tumors of the elderly (>40) with the young patients, and analyzed the clinicopathologic and proliferative features of pituitary macroadenomas in young adulthood (≤40). METHODS: 20-year archives of pituitary tumors in our clinics were reviewed and macroadenomas with diameter≥3 cm were included in the study. We identified 46 pituitary adenomas and immunohistochemically stained them with pituitary hormones, p53 and Ki-67. Twenty-four cases were ≤40-year with an age range of 11-40 years (mean 28.0). Twenty-two cases were >40 with an age range of 44-78 years (mean 58.8). RESULTS: In the young patient group, 15 (62.5%) were functional adenomas (6 prolactinomas, six growth hormone [GH], one adrenocorticotrophic hormone [ACTH] adenoma, two multihormonal [GH+ACTH]) and nine (37.5%) were either gonadotrophic or null cell adenomas. In the elderly group, five (22.7%) were functional adenomas (two adrenocorticotrophic hormone [ACTH] adenoma, one prolactinoma, one growth hormone [GH], one multihormonal [GH+ACTH]) and 17 (77.3%) were either gonadotrophic or null cell adenomas. Ki-67 proliferation index in adenomas of the young was approximately two-folds higher than the elderly (2.7% vs. 1.2%). CONCLUSION: In both groups, rare p53 positivity was identified. In conclusion, pituitary macroadenomas of the young show hormonal expression frequently with relatively high Ki-67 proliferation indices.

Are we counting mitoses correctly?

The number of mitotic figures in a predefined area is essential in pathologic evaluation for most tumors. This information sometimes provides clues in differentiating neoplastic lesions from nonneoplastic ones and sometimes in defining and grading of the tumors as well as prognosticating expected lifetime of the patient. As a generally accepted concept, scanning a certain number of consecutive nonoverlapping areas that are rich in viable tumor cells is required. Invasion fronts or the periphery of the tumors is preferred for counting mitosis. The target area to be counted for mitotic activity for various tumors is standardized as the number of mitosis in an established number of high-power fields. However, suggested mitotic counts, which constitute the basis of these studies, were obtained via the old microscopes, which usually had narrower visual fields than the state-of-the-art microscopes. Because the visual fields of the present microscopes provide larger areas compared with the older ones, corrections in mitosis counting are needed to make them compatible with the criteria, which had been put forward in the original reference studies.

Role of cyclooxygenase 2 and endothelial nitric oxide synthetase in preclinical atherosclerosis.

Cyclooxygenase-2 and endothelial nitric oxide (NO) synthase enzymes may have a role in developing preclinical atherosclerosis. Designed groups were as follows: smoke exposed rats before and during pregnancy, only before pregnancy, and controls. Cross-sectional samples of abdominal aorta were examined immunohistochemically. Cyclooxygenase-2 and eNOS expression was evaluated semi-quantitatively through staining extent (focal, diffuse) and staining intensity. Diffuse COX-2 expression was detected in study groups. Endothelial NO synthase expression was diffuse in study groups. COX-2 and eNOS may contribute to the formation of preatherosclerotic lesions in offspring of rats exposed to cigarette smoke through inflammatory response.

Passive smoke exposure of female rats caused aortic atherosclerotic precursor lesions in their offspring.

The aim of this study was to evaluate the presence and degree of preclinical atherosclerosis in pups of pregnant rats exposed to cigarette smoke. Abdominal aorta examined for atherosclerotic lesions and intimal medial thickness of the abdominal aorta was measured by image analysis. The study groups showed endothelial cellular losses, marked intimal injuries, elastic fiber damages, mononuclear cellular infiltration, and irregularities in internal elastic membrane, with pronounced damages as integrity losses and local fragmentations. The results provide evidence for development of an atherosclerotic process in the neonatal period, even in prenatal stage, long before the formation of smoke-related cardiovascular diseases.

Is neopterin a diagnostic marker of acute appendicitis?

BACKGROUND: The diagnosis of acute appendicitis, even for experienced surgeons, can sometimes be complex. A delay in diagnosis increases the complication rate. This experimental study aimed to investigate the suitability and significance of neopterin as a marker for acute appendicitis. METHODS: The levels of neopterin were measured using an acute appendicitis animal model in 35 New Zealand male rabbits. They were divided into 5 groups as Group 1= control; Group 2= sham; and Groups 3 (12-hour); 4 (24-hour); and 5 (48-hour) (based on the elapsed time period before their appendectomies). The neopterin levels of each group were measured by neopterin enzyme immunoassay kit in blood samples (taken before the appendectomies in Groups 3, 4 and 5). RESULTS: For the diagnosis of acute appendicitis, the optimal cut-off point was 34.475 nmol/L. The probability of acute appendicitis was found to be 4.667 times higher when the neopterin level was greater than 34.475 nmol/L. CONCLUSION: This study was an experimental animal study; however, it provides valuable clues useful in clinical assessment. Neopterin seems to have great potential as a new diagnostic marker for the diagnosis of acute appendicitis.

Towards Development of a Standard Terminology of the World Health Organization Classification of Tumors of the Central Nervous System in the Turkish Language, and a Perspective on the Practical Implications of the WHO Classification for Low and Middle Income Countries.

In our manuscript, we propose a common terminology in the Turkish language for the newly adopted WHO classification of the CNS tumors, also known as the WHO CNS 5th edition. We also comment on the applicability of this new scheme in low and middle income countries, and warn about further deepening disparities between the global north and the global south. This division, augmented by the recent COVID-19 pandemic, threatens our ability to coordinate efforts worldwide and may create significant disparities in the diagnosis and treatment of cancers between the "haves" and the "have nots".

The effect of intravesical acetylsalicylic acid instillation on tissue prostaglandin levels after partial bladder outlet obstruction in rabbits.

AIMS: To examine whether obstruction changes the expression of prostaglandins (PGs) in bladder, intravesical low-dose aspirin could be used as a new route of drug administration, this way of administration influences PGs' expression, and contractile function of the bladder is protected after treatment. METHODS: Eighteen rabbits were divided into three groups. Sham-operated group (group 1) included 6 rabbits. Twelve rabbits were partially obstructed for 70 days. Six of these 12 rabbits not receiving any treatment constituted obstructed group (group 2). The remaining six rabbits received 2 mg/kg/day aspirin (group 3). One rabbit in each group was evaluated on 1st, 7th, 14th, 28th, 42nd, and 70th days following obstructive surgery. After scarification, the percentage of collagenous area and concentrations of PGE2 and PGF2-alpha were measured. Contractile responses to field stimulation (EFS), carbachol, and potassium chloride (KCl) were determined. RESULTS: Wet tissue PGE2 and PGF2-alpha levels were higher in obstructed group than the other groups. Aspirin decreased the percentage of collagenous area in group 3 compared to the group 2, but this difference was not statistically significant. The strips from aspirin groups resulted in better contractile response to cholinergic stimulation with KCl, but this difference was not statistically significant between the obstructed and aspirin groups. Similarly, carbachol did not elicit significantly greater concentration-dependent contraction in strips from obstructed group compared to those from aspirin groups. Maximum responses to EFS were not significant in aspirin group compared to those from obstructed group. CONCLUSIONS: Intravesical aspirin may have protective effect on partially obstructed bladder.

The levels of nitric oxide and asymmetric dimethylarginine in the rat endometriosis model.

AIM: To investigate the levels of nitric oxide (NO) and asymmetric dimethylarginine (ADMA) in all the rat endometriosis models. MATERIAL & METHODS: Forty-one rats with endometriotic implants were divided into four groups (1 to 4) and administered infliximab, etanercept, letrozole and control, respectively. There were 11 rats in group 5 (normal). The size of implants, plasma ADMA and nitrate/nitrite (NO(x) ) levels and histological score were assessed. RESULTS: In groups 1, 2 and 3, plasma ADMA levels were higher than groups 4 and 5, 296.8 ± 66.2, 285.9 ± 35.7, 200.3 ± 41.0, 125.3 ± 16.7, 111.3 ± 6.5 µmol/L, respectively, while NO(x) levels were lower than groups of control and normal 19.6 ± 3.8, 19.8 ± 4.4, 39.3 ± 6.1, 80.5 ± 5.3, and 91.1 ± 5.0 µmol/L, respectively. CONCLUSIONS: Infliximab, etanercept and letrozole have regressed endometriotic implants, decreased plasma NO(x) levels, and increased plasma ADMA levels.

A comparative study of histopathological analysis of filum terminale in patients with tethered cord syndrome and in normal human fetuses.

BACKGROUND: The structural changes in filum terminale (FT) may be responsible for tethered cord syndrome (TCS) in children. Although the histological changes in FT related to TCS are well-known, there is no comparative study of the changes which occur in TCS and normal fetal FT samples. The aims of this study are to compare the histological changes which occurred in FT samples of TCS and in fetuses, and to point out these changes. METHODS: During the last 2 years, 14 cases of TCS were operated on, the FT was cut and the spinal cord was released. Among them, 6 samples of FT were obtained for histopathological examination. Moreover, 1 FT from an adult cadaver and 4 samples from fetal FT were obtained for the same examination. RESULTS: While adipose tissue, fibrosis, hyalinization, and meningothelial proliferation were observed in FT samples of TCS, none of these findings were observed in fetal samples. Elastic fibers were present in all TCS specimens and the adult cadaver, but were not observed in fetuses. Peripheral nerves, ganglion cells and ependymal cells were observed in fetal FT samples. CONCLUSION: These changes probably begin at birth.

The association between neopterin and acetaminophen-induced nephrotoxicity.

INTRODUCTION: In large dosages, acetaminophen (APAP) produces acute kidney necrosis in most mammalian species. High neopterin levels have been accepted as strong indicators for the clinical severity of some diseases. In this study, we aimed to evaluate whether neopterin is a biomarker in the identification of APAP-induced nephrotoxicity. MATERIALS AND METHODS: Thirty adult male Wistar rats were randomly divided into three groups: control, APAP-1, and APAP-2 groups. APAP-1 and APAP-2 group rats were given a single dose of 1 and 2 g/kg body weight of APAP by gastric tube, respectively. Kidney tissues and blood samples were obtained for biochemical and histopathological analyses. Biochemical parameters, serum and kidney neopterin levels, and the grade of tubular injury were compared in the control, APAP-1, and APAP-2 group animals. RESULTS: APAP treatments caused tubular necrosis in the kidney and increase in serum creatinine concentrations accompanied by elevated serum and kidney neopterin levels. In the rats of groups APAP-1 and APAP-2 when compared with that of the control group (109.1 pmol/mg protein), median kidney neopterin concentrations were 162.1 (p = 0.089) and 222.2 (p < 0.001) pmol/mg protein, respectively. The grade of tubular injury of the APAP-1 and APAP-2 groups was higher than the group of control (both p < 0.001). CONCLUSIONS: Serum and kidney neopterin levels could be sensible alternative to evaluate the risk to have nephrotoxicity because of APAP overdose. The elevated serum and kidney neopterin in the APAP-induced tubular necrosis might be a marker of acute histological kidney injury.

[Progressive multifocal leukoencephalopathy in an elderly patient with no obvious immunosuppression]. / Belirlenebilen bir immünyetmezligi olmayan yasli bir hastada gelisen progresif multifokal lökoensefalopati.

Progressive multifocal leukoencephalopathy (PML) which is a severe demyelinating disease of the central nervous system (CNS), is caused by a human polyomavirus known as JC virus (JCV). PML is seen primarily in immunosuppressed (AIDS, organ transplant or malignancy) patients. In this report, a case of PML that developed in a 75-years-old female patient with no known immunosuppression was presented. The patient was admitted to the emergency department with complaints of headache and burning sensation in head. Cerebrospinal fluid (CSF) examination revealed increase in lymphocytic cells. Since lesions compatible with tuberculoma were detected in brain tissue by magnetic resonance imaging, antituberculous therapy initiated empirically. The disease exhibited a progressive course and all the serological, molecular, microbiological and biochemical tests performed in blood and CSF failed to identify the causative agent. Pathological and immunohistochemical examination of the brain biopsy specimens demonstrated demyelinating disease. Brain biopsy, CSF, serum and urine specimens were investigated by real-time polymerase chain reaction specific for JCV and JCV-DNA was detected in the urine samples. Follow-up visits of the patient indicated a progressive course. In conclusion, after ruling out the other primary causes, JCV should be investigated in patients with demyelinating CNS disease even in the absence of significant immunosuppressive condition. Elderly patients should be considered in the risk group for demyelinating disease of CNS due to JCV.

Protective effect of sulfhydryl-containing antioxidants against ischemia/reperfusion injury of prepubertal rat intestine.

BACKGROUND AND AIM: Reactive oxygen species generated during reperfusion of the tissue are known to play an important role in the basic pathophysiology of ischemia/reperfusion (I/R) injury. The aim of this study was to investigate and compare the protective effects of three sulfide-based antioxidants, N-acetylcysteine (NAC), erdosteine (ERD), and alpha-lipoic acid (LA), on I/R injury of the small intestine tissue. METHODS: Forty male Sprague-Dawley rats weighing between 100-150 g were divided into five groups (n = 8 for each): control (sham operated), I/R, I/R + NAC, I/R + ERD, and I/R + LA. Intestinal ischemia was provided by occluding the superior mesenteric artery via a special microvascular clamp; ischemia for 30 min and reperfusion for 3 days were carried out. Ileal specimens were obtained to determine the tissue levels of malondialdehyde (MDA), protein carbonyl contents (PCO), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities and histological changes. RESULTS: The rats subjected to intestinal I/R exhibited an increase in tissue MDA and PCO; the levels could hardly be ameliorated in the treatment groups. SOD and GPx activities were significantly decreased in the I/R group, whereas their reduction was less expressed in the treatment groups. Additionally, the histopathological injury scores of the disulfide-treated groups were lower than those of the I/R group. CONCLUSION: All of the sulfhydryl-containing antioxidants used in this study exhibited a significant role in attenuating intestinal I/R injury; however, the outcome of the LA-treated group was significantly marked than that of the others.

The selective inhibition of type IV phosphodiesterase attenuates the severity of the acute pancreatitis in rats.

Phosphodiesterases (PDEs) are enzymes primarily responsible for regulation of the intracellular cyclic nucleotides. Among these enzymes, the type 4 PDE is highly expressed in most immune and inflammatory cells and its inhibition causes the suppression of immune and inflammatory cell activity, including production of cytokines. This study was designed to investigate the efficacy of the type 4 PDE inhibitor rolipram on acute pancreatitis in rats. Rats were divided into three groups--treatment, control, and sham. In the treatment and control groups, rats were pretreated with rolipram and vehicle before acute pancreatitis was induced. The pretreatment of rats with rolipram significantly reduced the amylase (P<0.0001) and IL-1ß levels (P=0.002) compared to vehicle treated rats. Also, mean histopathological scores were significantly reduced by rolipram treatment (P<0.005). It can be concluded that rolipram ameliorates severity of pancreatitis in rats.

Solitary fibrous tumour extending both supratentorially and infratentorially.

Solitary fibrous tumours (SFT) of the central nervous system are rare. Such lesions are mesenchymal neoplasms that resemble meningioma. To date, 73 cases of SFT have been reported in the literature, but there is no reported case of an SFT that extends into both the supratentorial and infratentorial spaces. A 76-year-old man presented with headache, dysarthria and ataxia of 2 months' duration. MRI revealed a right cerebellar tumour, extending superiorly to the occipital lobe. During surgery, a huge, solid and well-capsulated tumour was observed. The tentorium cerebelli was also damaged by the tumour. Histological and immunohistochemical studies confirmed the diagnosis of SFT. This is the first reported case of SFT located in both the infratentorial and supratentorial spaces. SFT are spindle cell neoplasms with a characteristic immunohistochemical profile of CD34, vimentin and bcl-2 positivity.

Intracavitary amphotericin B in the treatment of intracranial aspergillosis.

Intracranial aspergillosis is a rare infectious disease of the central nervous system with high mortality rates. Our aim is to present 3 cases of intracranial aspergillosis who were surgically treated with intracavitary amphotericin B administration. First case was a 21-year-old male patient. Allogeneic stem cell transplantation treatment was performed because of aplastic anemia and vocal cord paralysis developed 10 days after treatment. Multiple aspergillosis abscesses were observed in the cranial magnetic resonance imaging (MRI). Cerebral lesions were excised and 0.3 cc of amphotericin B was applied locally. Second case was a 18-year-old male patient treated for acute lymphocytic leukemia. MRI was performed on the development of consciousness change during treatment and right frontal abscess was detected. The abscess was excised and amphotericin B was applied locally. Third case was a 45-year-old woman with mastectomy. She had chemotherapy after surgery and had blood stem cell transplantation because of pancytopenia. Two months after treatments, MRI was performed on the development of ataxia and a cerebellar abscess was detected. The abscess was surgically excised and local amphotericin B was applied. The first case deceased 2 weeks after surgery and the second case died 2.5 years later due to multi-organ failure. The third case is stil alive and neurologically stable after 14 years of surgical treatment. In intracranial aspergillosis, intracavitary amphotericin B therapy may be used as an adjunct after the surgical excision of abscess. This procedure may contributes to the regression of abscess or prevention of the recurrence. But comparative clinical studies are needed for more accurate conclusions.

Arachnoid cyst of the cerebellopontine angle associated with gliosis of the eighth cranial nerve.

The clinical syndrome produced by a cyst in the cerebellopontine angle (CPA) may closely mimic that of an acoustic neuroma, with sensorineural hearing loss, impaired corneal reflex, and cerebellar signs with increased intracranial pressure. Facial palsy is seldom reported. Gliosis of the eighth nerve is common but its association with CPA arachnoid cyst is very rare and not previously reported. We report a patient with a CPA arachnoid cyst associated with gliosis of the eighth cranial nerve. He presented with right peripheral facial palsy, and gliosis of the eighth nerve was diagnosed intraoperatively. CPA arachnoid cysts should be included in the differential diagnosis of peripheral facial palsy and the eighth cranial nerve should be examined during the resection and fenestration of the arachnoid cyst.

Idiopathic pulmonary hemosiderosis in an adult patient responded well to corticosteroid therapy.

Idiopathic pulmonary hemosiderosis (IPH) is a very rare disorder of unknown etiology characterized by recurrent or chronic hemorrhage and accumulation of hemosiderin in the lung parenchyma. It is most common in children but can occur in adults. Clinical manifestations of the disease include iron deficiency anemia without any known cause, pulmonary symptoms such as hemoptysis, dyspnea and cough, and parenchymal lesions on chest X-ray. The clinical course of the disease may vary from patient to patient however, in general, the prognosis of the disease is worse. Treatment is symptomatic and supportive. Corticosteroids and other immune suppressive agents were used for the therapy of IPH. Since it is seen rarely in adults and the clinical course of the disease vary from patient to patient we presented an adult male patient with IPH responded well to steroid therapy clinically and radiologically.