The contribution of the WNT pathway to the therapeutic effects of montelukast in experimental murine airway inflammation induced by ovalbumin and lipopolysaccharide.

The wingless/integrase-1 (WNT) pathway involved in the pathogenesis of inflammatory airway diseases has recently generated considerable research interest. Montelukast, a leukotriene receptor antagonist, provides therapeutic benefits in allergic asthma involving eosinophils. We aimed to investigate the role of the WNT pathway in the therapeutic actions of montelukast (MT) in a mixed type of allergic-acute airway inflammation model induced by ovalbumin (OVA) and lipopolysaccharide (LPS) in mice. Female mice were sensitized with intraperitoneal OVA-Al(OH)3 administration in the initiation phase and intranasal OVA followed by LPS administration in the challenge phase. The mice were divided into eight groups: control, asthmatic, and control/asthmatic treated with XAV939 (inhibitor of the canonical WNT pathway), LGK-974 (inhibitor of the secretion of WNT ligands), or MT at different doses. The inhibition of the WNT pathway prevented tracheal 5-HT and bradykinin hyperreactivity, while only the inhibition of the canonical WNT pathway partially reduced 5-HT and bradykinin contractions compared to the inflammation group. Therefore, MT treatment hindered 5-HT and bradykinin hyperreactivity associated with airway inflammation. Furthermore, MT prevented the increases in the phosphorylated GSK-3ß and WNT5A levels, which had been induced by airway inflammation, in a dose-dependent manner. Conversely, the MT application caused a further increase in the fibronectin levels, while there was no significant alteration in the phosphorylation of the Smad-2 levels in the isolated lungs of the mice. The MT treatment reversed the increase in the mRNA expression levels of interleukin-17A. An increase in eosinophil and neutrophil counts was observed in bronchoalveolar lavage fluid samples obtained from the mice in the inflammation group, which was hampered by the MT treatment. The inhibition of the WNT pathway did not alter inflammatory cytokine expression or cell infiltration. The WNT pathway mediated the therapeutic effects of MT due to the inhibition of GSK-3ß phosphorylation as well as the reduction of WNT5A levels in a murine airway inflammation model.

The effect of the change in hemoglobin-albumin-lymphocyte-platelet scores occurring with neoadjuvant chemotherapy on clinical and pathological responses in breast cancer.

INTRODUCTION: Breast-cancer is a common-cause of death in women.(1) We investigated the effects of before/after-NACT on hemoglobin-albumin-lymphocyte-platelet (HALP) scores and of changes therein on clinical/pathological-responses. MATERIALS AND METHODS: One-hundred-twenty-seven breast-cancer-patients receiving-NACT between December 2009 - January 2019 were investigated retrospectively. RESULTS: The mean - age was 50.3±12.3 (min 27 - max 79), and 125 patients (98.4 %) were women. Fifty-four (42.5 %) were premenopausal and 71 (55.9 %) postmenopausal. Invasive-ductal-carcinoma was present in 111 patients (92.5 %). Eighty patients (70.2 %) were ≤ T2 and 34 (29.8 %) > T2. Lymph-node-status was positive in 99 patients (83.2 %) and negative in 20 (16.8 %). Ki-67 was ≤ 10 % in 22 (28.9 %), 11-20 % in 23 (30.3 %), and > 20 % in 31 (40.8 %). Complete clinical response was observed in 27 (21.3 %), partial-response in 76 (59.8 %), stable-disease in 21 (16.5 %), and progressive-disease in 3 patients (2.4 %). The objective-response-rate (ORR) was 103 (81.1 %). Pathological-complete-response (pCR) was observed in 24 patients (18.9 %). ORR was higher in Ki-67 > 20 % compared to ≤ 10 % and 10-20 % (90.3 % vs 59.0 % / 78.3 %, respectively, p: 0.027), but no difference occurred in pCR. Neutrophil-lymphocyte-ratio (NLR), platelet-lymphocyte-ratio (PLR), prognostic-nutritional-index (PNI), and HALP were measured before/after NACT. Associations with ORR and pCR were investigated via changes in these with NACT (excepting-PNI), but no-significant results emerged. CONCLUSIONS: Higher ORR occurred post-NACT in patients with Ki-67 >20 %, while NLR, PLR, PNI, and HALP before/after-NACT and post-NACT-changes (excepting-PNI) had no-effect on ORR/pCR (Tab. 5, Ref. 21). Text in PDF www.elis.sk Keywords: breast cancer, objective response rate (ORR), pathological complete response (pCR), hemoglobin-albumin-lymphocyte-platelet (HALP) score.

PD-L1 expression in invasive solid papillary breast carcinomas.

Background: Invasive solid papillary carcinomas (ISPC) are rare malignant neoplasms in the classification of WHO 2019 breast tumors. Aims: We aimed to investigate the correlations between programmed cell death ligand-1 (PD-L1) expression status of tumor and immune cells and clinicopathological parameters by molecular classification of this rare morphological subtype. This study will contribute to the literature about the PD-L1 expression state of ISPCs for the first time. Material and Methods: The study included 19 invasive solid papillary carcinoma cases diagnosed between 2009 and 2019 in Pathology Department. Molecular subtyping was performed in 19 cases by immunohistochemical studies (ER/PR, Her-2/neu, Ki-67), and PD-L1 expression was evaluated in neoplastic and immune cells. Results: PD-L1 expression was detected in 4 (21%) cases, 3 (75%) of them were in luminal B and 1 (25%) were in the luminal A group. The correlation between molecular subtypes and PD-L1 expression was statistically significant (P = 0.016). Patients with PD-L1 expression had a higher Ki-67 index than patients without PD-L1 expression (P = 0.037). In addition, there was a statistically significant correlation between PD-L1 expressions of intratumoral lymphocytes and PD-L1 expressions of neoplastic cells (P = 0.004). Conclusions: While predicting the group that will benefit more from immunotherapy in solid papillary carcinoma cases, not only PD-L1 expression of tumor cells but also PD-L1 expression in tumor infiltrating lymphocyte (TIL) can help. In addition, PD-L1 staining rates of tumor cells as well as clinicopathological parameters (molecular subtype, high Ki-67 index, presence of TIL) can be predictive about immunotherapy.

The status of HER2 in colorectal carcinoma and the relation of HER2 with prognostic parameters and MSI.

Background: Colorectal cancer (CRC) is the third most commonly occurring cancer in men and the second most common cancer in women. Despite advances in surgical techniques and chemotherapeutic regimens, CRC continues to be one of the main causes of cancer-related deaths in the world. Aims: The aim of the study was to evaluate the immunohistochemical expression of human epidermal growth factor receptor 2 (HER2) and the relationship between HER2, clinicopathological parameters, and microsatellite instability (MSI). Materials and Methods: Two hundred and forty resected CRCs at our institution between 2016 and 2019 were included in the study. Tumors were re-evaluated and classified according to the World Health Organization. Tissue macroarray techniques were used to generate tissue samples. HER2 antibody was performed using the automated system. Results: HER2 antibody was score 3 positive in only 5 cases. Score 2 was observed in 13 cases, score 1 in 27, score 0 in 195. All of the HER2-positive cases were metastatic. All of them were tubular adenocarcinoma. HER2 positive cases were well and moderately differentiated. Four of the HER2 positive cases were T3 stage, and one was T4. Conclusion: A total of 2.1% of CRCs were positive for HER2 antibody. There was a positive correlation between HER2 and distant metastasis. There was no significant relationship between MSI, other prognostic parameters, and HER2.

Effectiveness of Hypericum perforatum Extract in the Treatment of Corrosive Esophageal Burns.

PURPOSE: The purpose of our study is to determine the effectiveness of "Hypericum perforatum" extract in corrosive esophageal burns and to shed light on the search for new treatments. MATERIALS AND METHODS: A total of 32 Sprague Dawley rats were separated into 4 groups. A standard esophageal burn model was created. Group 1 was identified as the sham group. Group 2 was burned and no treatment was performed afterward. Group 3 was burned and then 2 cc/day H. perforatum extract was given for 21 days. Group 4 was not applied any process and 2 cc/day H. perforatum extract was given for 21 days. The rats were sacrificed and biopsy specimens were taken for histopathological examination for the presence of inflammation, fibrosis, and necrosis. RESULTS: There was a significant difference between groups in terms of inflammation, fibrosis, and necrosis. Furthermore, in the bilateral comparisons between the groups, there was a meaningful difference in terms of inflammation and fibrosis between Group 2 and Group 3. However, there was no meaningful difference between the same groups in terms of necrosis. CONCLUSION: H. perforatum extract may be effective on inflammation, fibrosis, and necrosis in corrosive esophageal burns.

Investigation of the relationship between immune checkpoints and mismatch repair deficiency in recurrent and nonrecurrent glioblastoma

Background/aim: Microsatellite instability tests and programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) in the immune checkpoint pathway are the tests that determine who will benefit from immune checkpoint inhibitor therapy. We aimed to show the expression of DNA mismatch repair proteins and PD-1/PD-L1 molecules that inhibit immune checkpoints, to explain the relationship between them, and to demonstrate their predictive role in recurrent and nonrecurrent glioblastoma. Materials and methods: We analyzed 27 recurrent and 47 nonrecurrent cases at our archive. We performed immunohistochemical analysis to determine expressions of PD-1, PD-L1, and mismatch repair proteins in glioblastoma. We evaluated the relationship between these two group and compared the results with the clinicopathological features. Results: The mean age of diagnosis was significantly lower in recurrent glioblastoma patients. Median survival was longer in this group. We found that PD-L1 expression was reduced in recurrent cases. Additionally, recurrent cases had a significantly higher rate of microsatellite instability. Loss of PMS2 was high in both group but was substantially higher in recurrent cases. Conclusion: The presence of microsatellite instability and low PD-L1 levels, which are among the causes of treatment resistance in glioblastoma, were found to be compatible with the literature in our study, with higher rates in recurrent cases. In recurrent cases with higher mutations and where immunotherapy resistance is expected less, low PD-L1 levels thought that different combinations with other immune checkpoint inhibitors can be tried as predictive and prognostic marker in GBM patients.

Alpha-lipoic acid: A promising adjuvant for nonsteroidal anti-inflammatory drugs therapy with improved efficacy and gastroprotection.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in a wide variety of diseases due to their analgesic and anti-inflammatory effects, but their usage have been limited due to significant ulcerogenic side effects. In the present study, we aimed to evaluate the effect of α-lipoic acid (ALA) treatment on the anti-inflammatory activity of indomethacin (Indo) as well as the possible therapeutic effect of ALA on high dose Indo-induced gastropathy in female mice. Mice were treated with Indo (5 or 30 mg/kg, p.o) alone or in combination with ALA (50, 100 or 200 mg/kg, i.p). in vivo anti-inflammatory effect was evaluated by formalin-induced paw edema measured as paw thickness and edema. Gastric damage was evaluated macroscopically and histologically by scoring mucosal hemorrhage, erosion, edema and inflammation. To our results, Indo was ineffective at 5 mg/kg, but co-treatment with Indo and ALA significantly reduced paw edema, implying that ALA augmented the anti-inflammatory effect of subtherapeutic dose of Indo. However, ALA was not able to induce a further increase in the anti-inflammatory effect of Indo at 30 mg/kg. Unlike the treatment with Indo at 5 mg/kg, Indo at 30 mg/kg caused severe gastric damage that prevented by co-treatment with ALA. These results suggest that combination of ALA with NSAIDs can both increase anti-inflammatory effect and prevent NSAIDs-induced gastric damage. ALA would be promising adjuvant that can reduce dose for effective NSAID therapy, which improves safety profile of NSAIDs especially in cases long-term administration of high dose needed.

Structural Characteristics in the γ Chain Variants Associated with Fibrinogen Storage Disease Suggest the Underlying Pathogenic Mechanism.

Particular fibrinogen γ chain mutations occurring in the γ-module induce changes that hamper γ-γ dimerization and provoke intracellular aggregation of the mutant fibrinogen, defective export and plasma deficiency. The hepatic storage predisposes to the development of liver disease. This condition has been termed hereditary hypofibrinogenemia with hepatic storage (HHHS). So far, seven of such mutations in the fibrinogen γ chain have been detected. We are reporting on an additional mutation occurring in a 3.5-year-old Turkish child undergoing a needle liver biopsy because of the concomitance of transaminase elevation of unknown origin and low plasma fibrinogen level. The liver biopsy showed an intra-hepatocytic storage of fibrinogen. The molecular analysis of the three fibrinogen genes revealed a mutation (Fibrinogen Trabzon Thr371Ile) at exon 9 of the γ chain in the child and his father, while the mother and the brother were normal. Fibrinogen Trabzon represents a new fibrinogen γ chain mutation fulfilling the criteria for HHHS. Its occurrence in a Turkish child confirms that HHHS can present in early childhood and provides relevant epidemiological information on the worldwide distribution of the fibrinogen γ chain mutations causing this disease. By analyzing fibrinogen crystal structures and calculating the folding free energy change (ΔΔG) to infer how the variants can affect the conformation and function, we propose a mechanism for the intracellular aggregation of Fibrinogen Trabzon and other γ-module mutations causing HHHS.

Investigation of Relationship Between Hypoxic Process and Cancer Stem Cells in Meningioma.

AIM: To investigate the relationship between cancer stem cells (CD133 and CD44) and HIF1? expression in meningioma. MATERIAL AND METHODS: In an immunohistochemistry experiment, three expert pathologists examined 100 meningioma slides stained for HIF1?, CD133, and CD44 antibodies. Statistical analyses were performed using the SPSS 23 Statistics packet program. P values < 0.05 were statistically significant. RESULTS: HIF1? staining was correlated with high grade (Grade 2) meningioma. Cytoplasmic staining was negatively correlated with meningioma grade. High grade meningioma was positive for nuclear HIF1? and showed increased cytoplasmic expression of CD44 and CD133. CONCLUSION: In accordance with previous studies, the level of hypoxia and HIF1? were correlated with meningioma grade. Furthermore, expression of HIF1? was correlated with expression of CD133 and CD44, which are cancer stem cell surface markers, as well as with meningioma grade. In light of these data, new treatment modalities related to CD44 and CD133 stem cell markers and to HIF1? may be developed.

Choroid plexus papilloma in extragonadal teratoma with predominantly neurogenic elements: a case report and review of the literature.

BACKGROUND: Teratoma is a germ cell tumor that develops gonadal or extragonadal. Benign or malign somatic tumors can develop in teratoma. Choroid plexus papilloma is a benign, grade I intraventricular neoplasm that occur mostly in children. Choroid plexus papilloma in a teratoma is not often seen. CASE: We present the fifth case of a choroid plexus papilloma in a teratoma in the English literature. It was extragonadal and localized on the right side of the neck. It included only neuroglial tissue. CONCLUSION: It is important to separate a teratoma with normal choroid plexus from a teratoma with choroid plexus tumor. Pathologists need to be aware of this entity in the distinction from other papillary neoplasms that may be primary or metastatic.

A comparison between unifocal papillary thyroid microcarcinoma with noninvasive follicular thyroid neoplasm with papillary-like nuclear features and other patterns: A retrospective clinicopathological study.

BACKGROUND: Papillary thyroid microcarcinoma (mPTC) is defined as a tumor with low malignancy potential. Different treatment protocols have been used at different centers for analyzing this tumor which has common recurrence and metastasis rates. Consequently, in 2016, the definition of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was accepted which included the lesions > cm. It is important to explain the clinical course and appropriate treatment options for mPTC and its subtypes. AIMS: In this study, we aimed to describe the clinical course of mPTC with and without NIFTP and to determine different risk groups among these subtypes. MATERIAL AND METHODS: We performed microscopic reexamination of about 280 unifocal mPTCs retrieved from our archives between 2007-2018 and analyzed the results of morphological and clinical comparison among these cases that had 0-11-years of clinical follow-up. RESULTS: Among 280 unifocal mPTCs, 127 cases (45.4%) had classical morphology, 58 (20.7%) had NIFTP, 53 (18.9%) had infiltrative pattern, 27 (9.6%) had oncocytic pattern, 12 (4.3%) showed capsular invasion, and 3 (1.1%) showed other morphologies. Seven patients were detected with lymph node metastasis and one with distant metastasis at diagnosis. Lymph node metastasis (recurrence) was postoperatively detected in five patients. All patients with recurrence were women. Moreover, three of these patients were in their 30s and two in 70s. The median diameter of the tumor was 3 mm. Both invasive and noninvasive cases have recurred. CONCLUSION: Contrary to the results of the previous studies, the results of our study did not confirm the indolent course of mPTC with NIFTP. However, metastasis was detected both at the time of diagnosis and during the postoperative period. The malignancy potential of these tumors may not be low. Therefore, more clinicopathological and molecular studies are needed to determine the biological behavior of mPTC cases with different histology.

Interobserver Variability in Mitotic Count for Meningioma Grading: How Can We Reduce It?

AIM: To evaluate the interobserver variability in determining the number of mitoses in 10 high-power field (HPF) and thus the tumor grade, and to investigate how to reduce grade discordance between the observers and the most useful method to identify the patients who would receive an additional treatment. MATERIAL AND METHODS: Two hundred and seventy cases with meningioma were re-evaluated by three experienced pathologists and five senior residents. They determined the number of mitotic figures in 10 HPF in each slide. Re-evaluation of the cases, which were found of different grades from the reference observers was requested by full scan method. Statistical analysis was performed by using SPSS V23.0. RESULTS: A moderate agreement was found between the observers and the reference observer. After the evaluation of mitotic activity with the full scan method, the mean numbers of mitoses found by the observers in 10 HPF were increased. In the first evaluation, 4?6 cases were defined as Grade II by the observers. Whereas, 23?27 cases were defined as Grade II after the full scan method. CONCLUSION: If there are less than 16 mitotic figures throughout the slide, it is more difficult to find the 10 HPF including 4 or more mitosis. Interobserver variability in mitotic figure counting can be reduced by full scan method, and examining the hematoxylin and eosin stained slides by the full scan method helps us to determine the true histologic grade of meningiomas in most cases, who would receive an additional treatment.

Ileocolonic Lymphonodular Hyperplasia in Children Related to Etiologies Ranging from Food Hypersensitivity to Familial Mediterranean Fever.

OBJECTIVE: We aimed to share our observations on the demographics, clinical characteristics, and outcomes of lymphonodular hyperplasia (LNH) in children. SUBJECTS AND METHODS: The study included children on whom colonoscopy was performed between January 2015 and May 2018 (n = 361). Demographics, treatment modalities, and outcomes of the patients with LNH were recorded. RESULTS: LNH was found in 66 patients (18.3%; mean age 8.6 ± 5.96 years, 59.1% male). We found that the etiologic factors were food hypersensitivity (FH) in 25 (37.8%), nonspecific colitis in 12 (18.2%), irritable bowel syndrome in 10 (15.2%), familial Mediter-ranean fever in 7 (10.6%), primary immunodeficiency in 4 (6.1%), and intestinal dysmotility, oxyuriasis, Crohn's disease, and giardiasis in 1 (1.5%) patient. Additionally, in the genetic analysis of patients with idiopathic LNH (n = 4), we detected heterozygote MEFV mutations in all. Cow's milk and egg (25%) were the most common allergens in patients with FH. Symptoms of all patients (n = 25) improved after an elimination diet. CONCLUSIONS: LNH is a common finding in pediatric colonoscopies with a variety of etiologies ranging from FH and familial Mediterranean fever to immunodeficiency.

Constitutional Mismatch Repair Gene Defect Syndrome Presenting With Adenomatous Polyposis and Cafe au Lait Spots: A Case Report.

INTRODUCTION: Adenomatous polyps in the gastrointestinal system rarely occur in childhood and are accompanied by syndromes such as Familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MUTYH-associated polyposis, Gardner and Turcot syndrome, and also mismatch repair (MMR) gene defects. In this article, we want to present a rare patient who had adenomatous polyposis and in situ carcinoma and was detected biallelic MMR gene defect. CASE: A 16-year-old female patient admitted with painless rectal bleeding, chronic abdominal pain, and anorexia for 1 year. Her physical examination was notable for multiple cafe au lait spots. The colonoscopic and histopathologic examination revealed multiple adenomatous polyps that one of them contains low-high grade dysplasia and in situ carsinoma. Genetic analysis revealed a homozygous mutation in the PMS2 gene [c.1164delT (p.H388Qfs*10) (p.His388GInfsTer10)] and she was diagnosed with constitutional MMR gene defect syndrome. Polypectomy was performed 4 times in 2 years period. Then, the patient's last colonoscopic examination revealed a large broad polyp in the rectum and multiple polyps in the other colon segments, and she underwent colectomy because of high risk of colorectal cancer. CONCLUSIONS: Adenomatous polyps are very important in childhood because of rarity. In particular, the presence of cafe au lait spots and a history of malignancy detected in relatives at an early age must be considered for CMMRD.

WITHDRAWN:Interobserver Variability in Mitotic Count for Meningioma Grading: How Can We Reduce It?

Ahead of Print article withdrawn by publisher.

Incidental retroperitoneal oncocytoma (Ectopic oncocytic adrenocortical adenoma): Case report and review of the literature.

Ectopic adrenocortical tissue may be present in many anatomical localizations. Hyperplasia, adenoma or carcinoma can occasionally develop from the ectopic adrenal tissue. Therefore, it should be surgically excised when it is detected. Adrenocortical tumors are the most common type of adrenal neoplasms. Ectopic adrenocortical adenomas are rarely seen. A total of 34 cases of ectopic adrenocortical adenoma (14 of which are oncocytomas) have been reported at different localizations in English literature. Most of them are non-functional. Differential diagnosis is required with other benign or malign oncocytic neoplasms. We report a 56-year-old male patient, who presented with a retroperitoneal mass. Our case is the seventh case of ectopic retroperitoneal adrenal adenoma with oncocytic cells.

Evaluation of the Extent of Vessel Avulsion Injury: An Experimental Study Using a Rabbit Model.

BACKGROUND: Determining the extent of damage in vascular avulsion type injuries still represents a challenge for the microsurgeon. Excision of the damaged section is critical for the success of anastomosis. The purpose of this study was to determine which among vascular endothelial and adventitia damage findings is most effective in determining the extent of avulsion injury. METHODS: Varying degrees of avulsion were applied to the aorta of 12 (n = 12) adult female New Zealand rabbits. Avulsion was first determined using adventitial findings and then with endothelial findings. The definitive extent of damage was determined histopathologically. RESULTS: The mean area of the histopathological sections was 16.7 ± 6.9 mm. The extent of damage measured from the adventitia was 15.8 ± 7.9 mm (the difference in histopathological examinations was not significant, p = 0.590, paired t-test), while the extent of damage from the lumen was 13.3 ± 8.2 mm (the difference in histopathological examinations was significant p = 0.004, paired t-test). CONCLUSION: Excision based on adventitia findings is more effective in case of avulsion injury.

Endoscopic Findings of Children with Familial Mediterranean Fever.

PURPOSE: Familial Mediterranean fever (FMF) is an auto inflammatory disease characterized by periodic fever, synovitis and serositis. Patients may be admitted to gastroenterology units due to gastrointestinal symptoms. In this study; we aimed to analyze endoscopic findings and diagnostic utility of endoscopic procedure in children with FMF. METHODS: Patient with FMF that was performed endoscopy for the gastrointestinal symptoms were included to the study (39 of 164 patients, 53 procedure). A control group was randomly designed as age and gender matched four endoscopic procedures per one endoscopic procedure of patients with FMF (n=212). RESULTS: No different was found between the patients and control group in esophagogastroscopy findings. However, the diagnosis of gastrointestinal pathology was made by esophagogastroscopy in 46.2% patients. Colonoscopic examination revealed that the frequency of inflammatory bowel disease (IBD) was higher in undiagnosed patients compared to both the control group (50.0% vs. 6.9%, p<0.05, odds ratio [OR]:13.4 and 95% confidence inteval [95% CI]: 2.1-84.3) and the patients under colchicine treatment (50.0% vs. 8.3%, p<0.05, OR: 11 and 95% CI: 0.8-147.8). Colonoscopic procedure that was made after the diagnosis was found to provide contribution by 16.7% in determining the etiology of the additional symptoms. CONCLUSION: Patients with FMF may be admitted to pediatric gastroenterology outpatient clinic prior to diagnosis or during the follow-up period. The frequency of IBD is high in undiagnosed patients with FMF. Endoscopic procedures may be helpful in these patients for the diagnosis accompanying mucosal lesions.