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".

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.

BRAF mutation in colorectal carcinomas with signet ring cell component.

OBJECTIVE: : Signet ring cell carcinoma is a rare subtype of colorectal carcinoma (CRC) with an associated BRAFV600E mutation. We investigated frequencies of BRAF mutation in 28 CRCs containing variable signet ring cell component and their relation with clinicopathologic parameters. METHODS: : According to the presence of signet ring cell component, tumors were categorized into groups as follows: 0%-9%, 10%-24%, 25%-49%, and >50%. Genomic DNA was isolated and analyzed for BRAF V600E gene mutation by polymerase chain reaction-restriction fragment length polymorphism. Eleven of 28 cases (39.3%) showed BRAFV600E mutation, which was also confirmed by Sanger sequencing. To elucidate the importance of existence of signet ring cell component at the molecular level, we separated cases into two groups with cut-off levels of 10% and 50%, which pertain to percentages of signet ring cells. RESULTS: : Seven of 19 cases (36.8%) under the threshold of 50% and four of nine cases (44.4%) over this threshold value demonstrated BRAF mutation. Three of 7 cases (42.8%) featuring <10% signet ring cell component and eight out of 21 cases (38.1%) showing >10% were BRAF mutated. CONCLUSIONS: : BRAF mutation must be closely associated with the presence of malignant signet ring cells regardless of their percentages.

Keratoacanthoma of the conjunctiva in a young patient.

Keratoacanthomas rarely occur in the conjunctiva. We report a case of a 24-year-old man with a rapidly growing conjunctival mass. The tumor was excised with a safety margin to exclude squamous cell carcinoma and was histopathologically diagnosed as a keratoacanthoma. There has been no recurrence over 2 years of follow-up. To the best of our knowledge, he is the youngest patient to be diagnosed with conjunctival keratoacanthoma who had no known risk factors such as skin disorders, trauma, surgery, or infection. In similar cases, we recommend complete early surgical excision and careful follow-up to exclude malignancy.

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.

Keratoacanthoma of the conjunctiva in a young patient / Ceratoacantoma da conjuntiva em um paciente jovem

ABSTRACT Keratoacanthomas rarely occur in the conjunctiva. We report a case of a 24-year-old man with a rapidly growing conjunctival mass. The tumor was excised with a safety margin to exclude squamous cell carcinoma and was histopathologically diagnosed as a keratoacanthoma. There has been no recurrence over 2 years of follow-up. To the best of our knowledge, he is the youngest patient to be diagnosed with conjunctival keratoacanthoma who had no known risk factors such as skin disorders, trauma, surgery, or infection. In similar cases, we recommend complete early surgical excision and careful follow-up to exclude malignancy.

RESUMO Ceratoacantoma raramente ocorre na conjuntiva. Nós relatamos o caso de um homem de 24 anos de idade, com uma massa conjuntival de rápido crescimento. O tumor foi retirado com uma margem de segurança para excluir carcinoma de células escamosas. Ele foi diagnosticado histopatologicamente como sendo ceratoacantoma. Não houve recidiva em dois anos de seguimento. Ele é o paciente mais jovem com ceratoacantoma conjuntival que não tinham fatores de risco conhecidos como doenças de pele a ser descrito. Em casos semelhantes, recomendamos excisão cirúrgica precoce completo e um acompanhamento cuidadoso para excluir malignidade.

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.

APOBEC3B expression in drug resistant MCF-7 breast cancer cell lines.

APOBEC3B belongs to a protein family of cytidine deaminases that can insert mutations in DNA and RNA as a result of their ability to deaminate cytidine to uridine. It has been shown that APOBEC3B-catalysed deamination provides a chronic source of DNA damage in breast cancers. We investigated APOBEC3B expression in four drug resistant breast cancer cell lines (Doxorubicin, Etoposide, Paclitaxel and Docetaxel resistant MCF-7 cell lines) using a novel RNA in situ hybridization technology (RNAscope) and compared expression levels with drug sensitive MCF-7 cell line. After RNAscope staining, slides were scanned and saved as digital images using Aperio scanner and software. Quantitative scoring utilizing the number of punctate dots present within each cell boundary was performed for the parameters including positive cell percentage and signal intensity per positive cell. In Doxorubicin and Etoposide resistant MCF-7 cell lines, APOBEC3B expression was approximately five-fold increased (23% and 24% respectively) with higher signal intensity (1.92 and 1.44 signal/cell, respectively) compared to drug sensitive MCF-7 cell line (5%, 1.00 signal/cell) with statistical significance. The increase of APOBEC3B expression in Docataxel resitant and Paclitaxel resistant MCF-7 cell lines was not very high. In conclusion, APOBEC3B expression was increased in some population of tumor cells of drug resistant cell lines. At least for some drugs, APOBEC3B expression may be related to drug resistance, subjecting to some tumor cells to frequent mutation.

The relation between percentage of immunostained cells and amplification status in breast cancers with equivocal result for Her2 immunohistochemistry.

We analyzed Her2 amplification in breast cancers with equivocal IHC staining to investigate the significance of percentage of Her2 immunostained tumor cells. We especially included the breast cancers with complete/incomplete membrane staining at moderate intensity in less than 10% of the invasive tumor cells. Of 1804 breast cases, 180 had moderate complete/incomplete membrane Her2 immunostaining. According to 2013 ASCO/CAP guideline, 124 were in IHC score 2+ and 56 in 1+ category. The percentage of Her2 immunostained invasive tumor cells were determined by visual estimation at the time of diagnosis and categorized into three groups; <10%, 10-50%, and >50% for this review. FISH was performed by dual DNA probe and data of Her2/cep17 ratio, Her2/cell and Cep17/cell were recorded applying 2013 ASCO/CAP criteria. There were 22 cases (12.2%) in >50% group, 102 (56.7%) in 10-50% group, and 56 (31.1%) in <10% group. Overall Her2 amplification was 25.5%. Her2 was amplified in 12 (54.5%) cases in >50% group; 26 (25.4%) in 10-50% and 8 (14.3%) in <10%. Her2 amplification was more frequent in cancers with >50% moderately immunostained cells in IHC equivocal group. However, most of Her2 IHC equivocal breast cancers contain moderate amount (10-50%) of immunostained cells. Relatively small but non-neglectable number (14%) of cases in <10% group was Her2 amplified by FISH which approaches to overall incidence of Her2 overexpression (15-20%) in all breast cancer. Breast cancers with moderate complete/incomplete membrane Her2 IHC staining in <10% of invasive tumor cells should be regarded as equivocal and reflex FISH should be performed in these cases.

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.

A case of mucosal leishmaniasis: Mimicking intranasal tumor with perforation of septum.

A 79-year-old male suffering from nasal congestion was referred to our hospital. Endoscopic examination revealed a hyperemic mass obstructing the left nasal passage. The lesion's surface was smooth. The findings of imaging studies were consistent with a benign tumor despite the erosion and perforation of the septum. The lesion originated from the middle concha and was attached to it with a thin stalk. It was removed easily by endoscopic resection. Histopathology revealed significant infiltration of mononuclear inflammatory cells, mostly lymphocytes and histiocytes, into the edematous subepithelial connective tissue. High-power magnification showed numerous Leishmania amastigotes in the cytoplasm of the histiocytes. A polymerase chain reaction experiment for Leishmania also confirmed the morphological diagnosis. No relapse was observed in the 12 months after surgery and the patient was doing well.

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.

Chitosan magnetic nanoparticles for pH responsive Bortezomib release in cancer therapy.

The use of nanotechnology in cancer treatment offers exciting opportunities, including the possibility of destroying tumors with minimal damage to healthy tissue by novel targeted drug delivery systems. pH differences between healthy and tumor microenvironment provide pH responsive release of drugs at tumor site via smart nanoparticles. In this study, chitosan coated superparamagnetic iron oxide nanoparticles (CS MNPs) were in situ synthesized by ionic crosslinking method as nanocarrier systems and loaded with the drug Bortezomib (Velcade(®)). The drug loading capacity, drug release and stability of CS MNPs were analyzed. CS MNPs were visualized inside the cells by fluorescence microscopy. The cytotoxicity of Bortezomib, CS MNPs and Bortezomib loaded CS MNPs were tested by XTT analyses in vitro. Gene expression analyses revealed that pro-apoptotic PUMA and NOXA genes were upregulated while anti-apoptotic BCL-2, SURVIVIN and cIAP-2 genes were downregulated at Bortezomib loaded CS MNP treated cells. Immunocytochemical analyses demonstrated an increase in p53 tumor suppressor protein levels at treated cells, which supports the upregulation of PUMA and NOXA genes, while Survivin protein level did not significantly change. This study points out that the pH responsive magnetic targeting of Bortezomib is more efficacious than free drug treatment. Moreover, targeted delivery of Bortezomib would reduce the frequency of drug administration by lowering the required amount of drug dose.

Chalkley method in the angiogenesis research and its automation via computer simulation.

The aim of this study was to develop a computer simulation evaluating microvessel density according to the Chalkley method on digital images taken from neovascular hot spots. An image analysis algorithm has been developed using ImageJ, an extensible, open source image processing and analysis software. The idea was to create a virtual Chalkley point array graticule, and to calculate Chalkley counts automatically by stepwise angular rotation of it on the superimposed images containing properly segmented microvessels. This eliminates the necessity of having the Chalkley graticule, an accessory that has to be mounted on the microscope's ocular. The proposed method is a faithful simulation of the original Chalkley counting procedure. It gives pathologists who do not have the Chalkley graticule an opportunity to evaluate microvessels quantitatively according to the basic principles underlying Chalkley counting. Evaluating microvessel densities in solid tumors is a frequent procedure in angiogenesis research. A few standard methods, including Chalkley counting, are used for the estimation of microvessel density. Several independent studies have shown that the Chalkley counting is more consistent and may provide useful data on prognosis. The obvious disadvantages lie in the facts that this method is time-consuming and requires a special hardware. Computer simulation may overcome these obstacles.

Experimental assessment of the neo-vascularisation of acellular dermal matrix in the wound bed pretreated with mesenchymal stem cell under subatmospheric pressure.

Neo-vascularisation of the acellular dermal matrix (ADM) is an essential procedure if a full-thickness wound is closed with ADM and skin is grafted over the ADM. In this study, we aimed to improve the neo-vascularisation of ADM by combining the effects of negative pressure wound therapy (NPWT) and mesenchymal stem cells (MSCs) on angiogenesis. In this study, 28 female Sprague-Dawley rats were used and divided into four groups. Full-thickness dorsal skin defects were created in 2 × 2 cm dimensions. The wounds were treated with only the ADM in group 1, the ADM and NPWT in group 2, the ADM and MSCs in group 3 and the ADM, NPWT and MSCs in group 4. By the ninth day of surgery, the excisional biopsy samples were histologically examined to identify the rates of ADM adherence to the recipient bed; the newly formed blood vessels which penetrate the ADM vertically and vascularisation were evaluated by immunohistochemical staining. The graft adherence rates were higher in group 4 than in the other groups statistically, p = 0.003. The numbers of cluster of differentiation 31 (CD31)-stained newly formed microvessels were higher in group 4 than in the other groups statistically, p < 0.05. All subjects in group 4 had the vertical vessels in normal calibration with open lumen vessels which penetrate the ADM. These findings suggest that MSC transplantation induces angiogenesis more efficiently than NPWT. The combination of the NPWT with MSC in this study has shown a synergistic effect on angiogenesis and has affected the neo-vascularisation of the ADM significantly.

The protective effect of melatonin and S-methylisothiourea treatments in nitrogen mustard induced lung toxicity in rats.

OBJECTIVES: Mustard is highly toxic to the lung. Its toxic effects are associated with inflammatory cell accumulation and increased pro-inflammatory cytokines as well as reactive oxygen and nitrogen species. In this study, we aimed to investigate the efficiency of melatonin (MEL) and S-methylisothiourea (SMT) on mechlorethamine (MEC) induced lung toxicity. METHODS: Thirty-six male rats were randomly divided into four groups: control, MEC, MEC+MEL, and MEC+SMT. Control group was given saline only via transdermal route. Other groups were exposured to a single dose of MEC (3.5 mg/kg) via transdermal route. MEL (100 mg/kg) was administered intraperitoneally 30 min after the application of MEC, and after the same dose of MEL was given every 12 h for a total of six doses. SMT (50 mg/kg) was also given intraperitoneally 30 min after the application of MEC. RESULTS: MEC injection resulted in alveolar epithelial injury, hemorrhage, inflammation, edema and interalveolar septal thickening in the lung tissues. The tissue TNF-α, IL-1ß, and nitrate/nitrite (NOx) levels were found significantly different for all groups (p<0.001). TNF-α and IL-1ß levels increased significantly with MEC exposure, and MEL and SMT ameliorated these increases in lung tissues. MEC also elevated NOx levels in lung tissue. Melatonin showed meaningful protection against lung injury. But protection of SMT was weaker. CONCLUSION: Inflammation plays an important role in the MEC induced lung toxicity as well as oxidative and nitrosative stress. Melatonin has also anti-inflammatory properties similar to SMT, as well as anti-oxidant properties. But melatonin treatment was found more efficient than SMT treatment.

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.

The effects of splenectomy on lipid peroxidation and neuronal loss in experimental spinal cord ischemia/reperfusion injury.

AIM: The aim of this study is to investigate the effects of prior splenectomy on oxidative stress and neuronal loss following spinal cord ischemia and reperfusion injury. MATERIAL AND METHODS: Twenty-one Sprague Dawley rats were randomly divided into three groups as sham laparatomy (n=7), spinal cord ischemia/reperfusion (SCIR) injury (n=7) and splenectomy+spinal cord ischemia/reperfusion (SSCIR) injury (n=7). In the latter group, splenectomy was performed 3 days before the SCIR injury. The activity of lipid peroxidation in the spinal cord was assessed by malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities. The difference between the 3 groups was compared using Kruskal-Wallis test. The histological differences were assessed by counting the viable neurons. RESULTS: SCIR injury resulted in a decrease of tissue lipid peroxidation activities. There was statistically significance between the three groups (p < 0.05), but there was not any significance between the SCIR and SSCIR injury groups (p > 0.05). The number of viable neurons was higher in SSCIR group when comparing with SCIR group (p < 0.05). CONCLUSION: SCIR injury affects lipid peroxidation in rats. Prior splenectomy does not attenuate lipid peroxidation, but prevents neuronal loss after SCIR injury.

The efficacy of bioceramics for the closure of burr-holes in craniotomy: case studies on 14 patients.

PURPOSE: Bioceramics are currently in use to cover bone defects in orthopedics and craniofacial surgery. But their compatibility and efficacy in cranium were not investigated in detail. The aims of this study were to produce, characterize, and assess the biocompatibility and osteointegration of Si-HA, Si-Sr-HA, HA-Wollastonite, and HA-Wollastonite-Frit bioceramics. METHODS: Bioceramics were implanted into the burr holes of 14 craniotomy patients who were followed up from three to 24 months. Radiologic and scintigraphic examinations were performed. RESULTS: Osteoblastic activity quantified by scintigraphy increased from 6.865 to 22.991±1.682 from four to eight months in the HA-Woll group. Adding fritt into HA-Woll decreased osteoblastic activity at 10 months. Si-Sr-HA displayed significantly higher osteoblastic activity when compared to the craniotomy site at 12 months. The scintigraphic ratio of the bioceramic implanted regions to the craniotomy sites varied between 1.10 and 1.57. Osteoblast formation and establishment of the trabecular pattern of bone was observed in the surroundings of bioceramics in two patients. CONCLUSION: These bioceramics can be safely used to cover the burr holes of craniotomy patients, as well as to close the cranial bone defects.