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Background: Recent studies have shown a lower likelihood of locoregional recurrences in patients with low 21-gene recurrence score (RS). In this single institutional study, we investigated any associations between different cut-off values of 21-gene RS and histopathological factors and outcome in patients with long-term follow-up. Methods: Between February 2010 to February 2013, 61 patients with early stage clinically node-negative hormone receptor-positive and HER2-negative breast cancer tested for the 21-gene RS assay, were included into the study. The clinicopathological, treatment and outcome characteristics were analyzed. Results: Median age was 48 (range, 29-72). Of those, 53 patients were diagnosed with Stage 1 (86.9%) and 8 patients were Stage 2 (13.1%) following surgery. Patients with high histologic grade (HG), or with Ki-67>=25% were significantly more likely to have intermediate/high RS based on RS >11 and >18 (Table 1). Based on the 21-gene RS assay, only 19 patients (31%) received adjuvant chemotherapy. At a median follow-up of 112 months, 3 patients developed local recurrences (4.9%) treated with endocrine therapy alone. Among patients treated with endocrine treatment alone (n=42), the clinicopathological characteristics including age < 40, age < 50, high histologic or nuclear grade, high Ki67-scores (>=20%, >=25%, >=30%), presence of lymphovascular invasion, luminal-A type tumor, multifocality, lymph node positivity, tumor size more than 2 cm, RS>=18 or RS>11 were not significantly found to be associated with 10-year locoregional recurrence free survival (LRRFS). However, patients with a RS >=16 have significantly shown a poorer 10-year LRRFS cpmpared to those with RS < 16 (RS < 16; 100% vs RS>=16; 75%, p=0.039, Table 2). Conclusions: These results suggest that Oncotype DX assay may be of little value in patients with high histologic grade or high Ki67 scores (>= 25%) as treatment decision criteria to determine any benefit from chemotherapy. Furthermore, patients with a RS >=16 are more likely to benefit from adjuvant chemotherapies, whereas those with a RS < 16 have an excellent outcome and local control on long term follow-up with endocrine treatment alone. Further prospective studies should be performed to validate these findings in future. Table 1. Correlation of 21-gene Recurrence Score (RS) including different cut-off values with Ki-67 scores and histopathological factors Table 2. Clinicopathologic factors and 21-gene Recurrence Score (=RS) associated with disease free survival (DFS) and locoregional recurrence free survival free survival (=LRRFS). (DFS is equal to LRRFS since none of the patients developed distant metastases) Citation Format: Cihan Uras, Neslihan Cabıoğlu, Fatma Tokat, Halil Kara, Ozlem ER, Taner Korkmaz, Nuran Bese, Umit Ince. FAVORABLE LOCOREGIONAL CONTROL IN CLINICALLY NODE-NEGATIVE HORMONE-RECEPTOR POSITIVE BREAST CANCER WITH LOW 21-GENE RECURRENCE SCORES: A SINGLE INSTITUTIONAL STUDY WITH 10-YEAR FOLLOW-UP [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-31.

Introduction: The OSNA technique is based on reverse transcription loop-mediated DNA amplification for the detection of cytokeratin 19 (CK19) messen-ger RNA (mRNA). The purpose of our paper, which represents the first study in the literature, is to test the accuracy of this method in the detection of lymph node metastases in patients undergoing robotic radical prostatectomy with lymph node dis-section. Methods: Our cohort consisted of patients that have undergone robotic radical prostatectomy with extended lymph node dissec-tion. Lymph nodes were evaluated with imprint technique and then with frozen section examination. The remaining tissue was evaluated by OSNA method. Lymph nodes were defined as ‘neg-ative’ or ‘positive’ according to mRNA copy number. Results: 7 patients and 25 lymph nodes were included in our cohort. Two patients were found negative with all pathology methods. In one patient the standard stains revealed a suspi-cious outcome but it was positive for micrometastasis with OSNA. In another patient the outcome was positive for standard stains and negative for OSNA. Finally, 2 patients were found positive for OSNA and negative for imprint methods. Conclusions: One Step Nucleic Acid Amplification (OSNA) method using CK19 seems to fail in detection of lymph node metastases in prostate cancer patients undergoing radical prostatectomy and lymph node dissection.

In women with unexplained infertility (UI) and recurrent in vitro fertilization (IVF) failures, the etiology is often unclear. Endometrial immune perturbations and the use of immune markers associated with these dysregulations are of great interest in the diagnosis and treatment of UI. However, reliable biomarkers and standardized quantification methods are lacking. Here, to address endometrial immune dysregulation in UI patients with recurrent IVF failures, we performed endometrial tissue sampling and immunostaining of CD56 (uNK), CD138, and BCL-6. Of these cases, 57.9% had positive CD56 in the endometrial stroma, while 46.1% had positive BCL-6 in the glandular epithelium, and 14.5% of the cases were found to be positive for CD138. Combined staining rates were 60.5%, 68.4%, and 71.05% for (CD56 or BCL-6), (CD56 or CD138), and (CD56, BCL-6, or CD138), respectively. There was a significant correlation between CD56 and BCL-6 positivity, while CD138 positivity was an independent parameter. After the recommended targeted therapy, pregnancy rates were found to increase from 58.5% to 61.6% and 73.8% in CD56-positive, (CD56- or BCL-6-positive), and (CD56-, BCL-6-, or CD138-positive) cases, respectively. Notably, a retrospective evaluation of digital pathology and light microscopy results showed a significant correlation. This study suggests that the examination of CD56, BCL-6, and CD138 in the same endometrial sample may be an effective method in determining the etiology of UI and reaching an early diagnosis and treatment options. Moreover, digital pathology can be used in the evaluation of CD56 and BCL-6 to provide objective, rapid, and reliable results.

Background The progression to gastric cancer has been linked to chronic infection with Helicobacter pylori (H. pylori). Immune checkpoint inhibitors (programmed cell death -1, PD-1; programmed cell death –ligand 1, PD-L1) have a role in cancer immune escape. The relationship between H. pylori virulence factors with PD-1, PD-L1 T helper 1 (Th1), T helper 17 (Th17), and regulatory T cell (Treg) response genes, has not been thoroughly investigated in the development of gastric cancer. Therefore, we evaluated how H. pylori virulence factors influence the expression levels of immune-related genes in the development of gastric immunopathology. Methods A total of 92 gastric tissues of normal controls and patients with gastritis, gastric ulcer, and gastric cancer were examined for the expression of immune-checkpoint inhibitor genes (PD-1 PD-L1), Th1 (interferon- γ, IFN-γ), Th17 (interleukin- 17, IL-17, Retinoic-acid-receptor- related orphan nuclear receptor gamma t, RORγ-t), and Treg (Forkhead box P3, FOXP3) response genes with quantitative real-time PCR (qRT-PCR). Furthermore, correlation of H. pylori virulence factors’ (cytotoxin-associated gene A, cagA; vacuolating cytotoxin gene A, vacA (s1,s2,m1,m2); blood group antigen-binding adhesin gene A, babA, duodenal ulcer promoting gene A, dupA; the putative neuraminyllactose-binding hemagglutinin homolog, hpaA; neutrophil-activating protein A napA; outer inflammatory protein A, oipA; urease A, ureA; and urease B, ureB) genotypes with a degree of inflammation and density of H. pylori were investigated. Next, the relationship between H. pylori virulence factors and immune-checkpoint inhibitor genes, and T-cell response genes was evaluated. Eventually, a decision tree model was developed to determine the clinical outcome of patients using expression data. Results The intensity of PD-1 and PD-L1 mRNA expression was increased significantly in gastric tissue of patients with gastric ulcer (PD-1: 2.3 fold, p=0.01; PD-L1: 2.1 fold, p=0.004), and gastric cancer (PD-1: 2 fold, p= 0.04; PD-L1: 1.8 fold, p=0.05) compared with control subjects. Also, PD-1: PD-L1 expression was significantly higher in patients with gastritis, who were infected with a marked density of H. pylori compared with its mildly infected counterparts. Furthermore, a novel negative correlation was found between PD-1 (r= -0.43) and PD-L1 (r= -0.42) with FOXP3 in patients with gastritis. CagA-positive H. pylori strain's negative association with PD-L1 expression (r=-0.34) was detected in patients with gastritis. Interestingly, PD-1 mRNA expression correlated positively with vacA s2/m2, in gastritis (r=0.43) and ulcer (r=0.43) patients. Furthermore, PD-1: PDL1 expression negatively correlated with vacA m1/m2 (r=-0.43 for PD-1; r=-0.38 for PD-L1) in gastritis patients. Moreover, an inverse correlation of PDL1 was present with vacA m1 (r=0.52) and vacA s1/m1 (r=0.46) versus vacA m2 (r=-0.44) and vacA m1 (r=0.52) and vacA s1/m2 (r=-0.14) in ulcer patients, respectively. Also, a correlation of vacA m2 (r=-0.47) and vacA s1/s2 (r= 0.45) with PD-1 was detected in ulcer patients. In addition, a novel negative correlation between FOXP3 mRNA levels and napA was shown in patients with gastritis and ulcer (r=-0.59). Finally, a computer-based model that was developed showed that knowing the expression levels of PD-L1, RORγ-t, and vacA s1/m2 would be useful to detect the clinical outcome of a patient. Conclusion Our results suggested that PD-1:PD-L1 immune checkpoint inhibitors were increased in gastric pre-cancerous lesions that progress to gastric cancer. Herein, we report the relationship between H. pylori virulence factors and expression of host immune checkpoint inhibitors for diagnostic prediction of gastric malignancies using computer-based models.

Background: Recent studies have shown a lower likelihood of locoregional recurrences in patients with low 21-gene recurrence score (RS). In this single institutional study, we investigated any associations between different cut-off values of 21-gene RS and histopathological factors and outcome in patients with long-term follow-up. Methods: Between February 2010 to February 2013, 61 patients with early stage clinically node-negative hormone receptor-positive and HER2-negative breast cancer tested for the 21-gene RS assay, were included into the study. Demographic, clinicopathological, treatment and outcome characteristics were analyzed.Results: Median age was 48 (range, 29-72). Of those, 53 patients were diagnosed with Stage 1 (86.9%) and 8 patients were Stage 2 (13.1%) following surgery. Patients with high histologic grade (HG), or with Ki-67>25%were more likely to have intermediate/high RS based on RS >11 and >18. Based on the 21-gene RS assay, only 19 patients (31%) received adjuvant chemotherapy. At a median follow-up of 112 months, 3 patients developed local recurrences (4.9%) treated with endocrine therapy alone. Among patients treated with endocrine treatment alone (n=42), the clinicopathological characteristics including age >20%, >25%, >30%), presence of lymphovascular invasion, luminal-A type, multifocality, lymph node positivity, tumor size more than 2 cm, RS>18 or RS>11 were not significantly found to be associated with 10-year locoregional recurrence free survival (LRRFS). However, patients with a RS >16 have significantly shown a poorer 10-year LRRFS compared to those with RS >16; 75%, p=0.039). Conclusions: These results suggest that Oncotpe DX assay may be of little value in patients with high histologic grade or high Ki67 scores (>25%) as treatment decision criteria to determine any benefit from chemotherapy. Furthermore, patients with a RS >16 are more likely to benefit from adjuvant chemotherapies, whereas those with a RS

Objective In the present study, preliminary outcomes of the in vivo assessment of a Leishmania donovani/L. infantum hybrid isolated from a hospitalised patient with visceral leishmaniasis in Manisa and identified through analysis of the Leishmania-specific ITS-1, hsp70 and cpb gene regions are presented in comparison with reference strains of L. donovani and L. infantum. Methods Three different study groups [(SG); n=16 mice each] and a control group (n=8 mice) were established with female Balb/C mice weighing 25-30 g. Reference L. donovani (MHOM/IN/1980/DD8), reference L. infantum (MHOM/TN/1980/IP1) and a L. donovani/L. infantum hybrid (MHOM/TR/2014/CBVL-LI/ LD), stored in liquid nitrogen, were thawed, cultured and incubated at 25 °C. A 15-μL dose of 1x108/mL promastigotes of three strains was applied to the tail veins of mice in the SG. After the mice were sacrificed, the liver and spleen tissues were removed and stored for immunological, immunohistochemical and pathological analyses. Results The presence of infection in the liver and spleen tissues of mice was detected both by a specific enzyme-linked immunosorbent assay test and from the recovery of Leishmania promastigotes from liver and spleen tissues in NNN medium. However, Leishmania amastigotes were not observed in the touch biopsy smears of livers or spleens in either of the SGs. In addition, no evidence of tissue damage was identified in the SGs after immunohistochemical staining (with antibodies against IL-9, CD-117, MBP, CD163, CD4, CD8 and CD31). Conclusion The obtained results show that hybrid Leishmania and reference L. donovani and L. infantum strains reached the liver and spleens of Balb/C mice in SGs but were of no pathological consequence. Yet, these three Leishmania isolates caused skin lesions when applied subcutaneously in Balb/C mice in another study. The findings presented in this study will be reassessed upon completion of the project, once the final results are obtained.

Background Signs of inflammation including epidermal interface changes, spongiosis and dermal inflammation as well as pagetoid dyskeratosis are rarely described in fibrous papule (FP). We aimed to describe the inflammatory parameters, the rate of pagetoid dyskeratosis, along with CD163 immunohistochemical staining as an adjunctive diagnostic tool in FP. Methods Histopathology samples of all biopsy-proven FP cases were retrieved from archives and investigated for inflammatory parameters, presence of pagetoid dyskeratosis, as well as CD163, CD10 and CD34 immunostaining pattern of dermal spindle/stellate or multinucleate cells (graded from 0 to 4). Results Thirty-two cases of FP were identified. A high rate of inflammatory parameters including interface changes (20/32), spongiosis (31/32), and dermal lymphocytic inflammation (31/32) were detected. Pagetoid dyskeratosis was identified in eight out of 32 cases (25%). A grade 4 staining revealing a strong dendritic pattern was confirmed in all FP cases with CD163 immunohistochemistry including atypical variants such as granular FP, compared with CD10 (11/32) and CD34 (3/32). Conclusion The dendritic cellular proliferation in FP may represent an inflammatory response to various stimuli; pagetoid dyskeratosis is a relatively common and underrecognized epidermal feature and CD163 immunostaining may be used as an adjunctive diagnostic tool in unusual histopathological subtypes. This article is protected by copyright. All rights reserved.

Amaç: Bu çalışmanın amacı, sıçanlarda maternal uterin arter ligasyonuna bağlı olarak gelişen intrauterine büyüme geriliğinde kondrogenez ve osteogenezin Wnt/β-catenin ve S100 ekspresyonlarının immünohistokimyasal ve histomorfometrik olarak değerlendirilmesi.Gereç ve Yöntem: Gebe sıçanlar 3 gruba ayrıldı (n=5). Kontrol grubuna cerrahi veya anestezi uygulanmadı. Deney grubunda, 18. gebelik gününde bilateral maternal uterin arterlere ligasyon yapıldı. Sham grubuna uterin arter ligasyonu dışındaki tüm cerrahi işlem uygulandı. Fetuslar gebeliğin 20. gününde alındı, sol proksimal tibiadan büyüme plağı ve zonların kalınlıkları, trabeküler sayı ve kalınlıkları, kortikal kalınlıklar histomorfometrik olarak değerlendirildi. Büyüme plağında β-catenin ve S100 ekspresyonları immunohistokimyasal olarak değerlendirildi.Bulgular: Deney grubunda büyüme plağı (p0.05). Aynı zamanda daha düşük sayıda trabekülar yapı (p, Aim: The aim of this study is to investigate the effects of intrauterine growth retardation depending on maternal uterine artery ligation, Wnt/β-catenin and S100 expression immunohistochemistry and histomorphometrically on chondrogenesis and osteogenesis of fetal rats.Materials and Methods: Maternal rats were randomly divided into 3 groups (n=5). No surgery or anesthesia were applied in control group. Bilaterally the maternal uterine arteries were ligated on gestational day 18 in experimental group. Although all surgical procedures were performed in sham group, the uterine artery ligation were not made. Fetuses were taken on gestational day 20, thicknesses of growth plate and zones, trabecular number and thickness and cortical thickness were evaluated with the histomorphometrically in samples from left proximal tibia. The expressions of β-catenin and S100 immunohistochemically were evaluated in the growth plate.Results: Thicknesses of growth plate (p0.05). Also trabecular numbers were lower (p

Background Recent studies have shown a lower likelihood of locoregional recurrences in patients with a low 21-gene recurrence score (RS). In this single-institution study, we investigated whether there are any associations between different cutoff values of 21-gene RS, histopathological factors, and outcome in patients with long-term follow-up. Methods The study included 61 patients who had early-stage (I-II) clinically node-negative hormone receptor-positive and HER2-negative breast cancer and were tested with the 21-gene RS assay between February 2010 and February 2013. Demographic, clinicopathological, treatment, and outcome characteristics were analyzed. Results The median age was 48 years (range, 29–72 years). Patients with high histologic grade (HG), Ki-67 ≥ 25%, or Ki-67 ≥ 30% were more likely to have intermediate/high RS (≥ 18). Based on the 21-gene RS assay, only 19 patients (31%) received adjuvant chemotherapy. At a median follow-up of 112 months, 3 patients developed locoregional recurrences (4.9%), which were treated with endocrine therapy alone. Among patients treated with endocrine treatment alone (n = 42), the following clinicopathological characteristics were not found to be significantly associated with 10-year locoregional recurrence free survival (LRRFS): age 11. However, patients with RS ≥ 16 had significantly poorer 10-year LRRFS compared to those with RS p = 0.039). Conclusions The results suggest that patients with clinically node-negative disease and RS ≥ 16 are more likely to benefit from adjuvant chemotherapies. However, those with RS

BACKGROUND The detection rate of clinically significant prostate cancer has improved with the use of multiparametric magnetic resonance imaging (mpMRI). Yet, even with MRI-guided biopsy 15%-35% of high-risk lesions (Prostate Imaging-Reporting and Data System [PI-RADS] 4 and 5) are histologically benign. It is unclear if these false positives are due to diagnostic/sampling errors or pathophysiological alterations. To better understand this, we tested histologically benign PI-RAD 4 and 5 lesions for common malignant epigenetic alterations. MATERIALS AND METHODS MRI-guided in-bore biopsy samples were collected from 45 patients with PI-RADS 4 (n = 31) or 5 (n = 14) lesions. Patients had a median clinical follow-up of 3.8 years. High-risk mpMRI patients were grouped based on their histology into biopsy positive for tumor (BPT; n = 28) or biopsy negative for tumor (BNT; n = 17). From these biopsy samples, DNA methylation of well-known tumor suppressor genes (APC, GSTP1, and RARβ2) was quantified. RESULTS Similar to previous work we observed high rates of promoter methylation at GSTP1 (92.7%), RARβ2 (57.3%), and APC (37.8%) in malignant BPT samples but no methylation in benign TURP chips. Interestingly, similar to the malignant samples the BNT biopsies also had increased methylation at the promoter of GSTP1 (78.8%) and RARβ2 (34.6%). However, despite these epigenetic alterations none of these BNT patients developed prostate cancer, and those who underwent repeat mpMRI (n = 8) demonstrated either radiological regression or stability. CONCLUSIONS Histologically benign PI-RADS 4 and 5 lesions harbor prostate cancer-associated epigenetic alterations.

Background: Thyroid cancer accounts for 1% of cancer cases in developed countries, in which papillary thyroid carcinoma (PTC) is the most common type. There are multiple variants of PTC described to date, some of them with aggressive behavior and poor clinical outcome. These variants are well described and accepted in recent guidelines of many international societies, and the prognostic and management implications are well laid out. Due to their established clinical importance and to guide appropriate surgical management, it is now imperative in clinical practice, including cytopathology, to differentiate aggressive variants from nonaggressive ones. This review aims to describe the variants of PTC and to provide a practical algorithmic approach to facilitate the cytological diagnosis of these variants. Summary: Subtyping PTC variants on fine needle aspiration cytology (FNAC) is challenging even for the most experienced cytopathologist. To facilitate a correct subtyping on FNAC, we propose a stepwise approach that is mainly designed for conventional smear methodology. This approach requires first to stratify the lesions into oncocytic and nononcocytic features before analyzing further details in cell morphology and pattern. Key Messages: (1) Subtyping in PTC is possible on cytopathology. (2) The main aim of the cytopathologist is to differentiate aggressive from nonaggressive variants. (3) The subtyping of PTC can help in the surgical management of the patients.

The number of breast cancer cases and mortality rate has been on the rise globally. For effective treatment and curbing the mortality rate, early diagnosis is paramount. To evaluate the effectiveness of treatment, a fundamental step is histopathological examination of the state of nuclei. However this is a challenging task for various reasons. Accordingly, we perform nuclei detection in breast cancer histopathology images using RetinaNet with a ResNet-152 as the feature extractor. The data used for training and validation of the model was carefully collected at our partner teaching hospital. A mean Average Precision (mAP) of 78% was achieved by optimizing the Focal Loss. Thus outperforming current state-of-the-art methods which have been reported in the literature.

Objective: High levels of endonuclease III-like 1 (NTHL1) DNA glycosylase, which plays a role in the first step of the base excision repair pathway, has been related to cancer initiation and progression. 5-hydroxyuracil (5-OHU) oxidative base damage is a substrate for NTHL1 and endonuclease VIII-like 1 enzyme 1 (NEIL1) DNA glycosylases. This study investigates the association of 5-OHU incision activity with the risk of disease progression in patients with non-muscle-invasive bladder cancer (NMIBC) regarding grade and stage. Materials and Methods: During transurethral resection of 17 NMIBC patients, the papillary tumour before monopolar resection and healthy bladder mucosal tissue from the same person were obtained using cold cup biopsy. Both the normal mucosa and NMIBC tumour were pathologically confirmed. The histological grade and stage were also determined. The 5-OHU incision activity of all tissues was measured using a radiolabelled 5-OHU modified base containing DNA substrate. Results: 5-OHU incision activity was significantly higher in all high-grade NMIBC tissue extracts compared with the corresponding normal tissues (p=0.001). However, we found no significant difference in 5-OHU incision activity in low-grade NMIBC tissues (p=0.89). There was also a significant increase in 5-OHU incision activity at the Ta/T1 stage compared with the corresponding normal tissue (p=0.001). Conclusion: The increase in 5-OHU incision activity according to the histological grade of NMIBC tissue indicates that this activity (mainly performed by NTHL1 and NEIL1 DNA glycosylases) might play a role in NMIBC prognosis. Thus, it could be used as a potential prognostic biomarker for NMIBC.

In an effort to ease the job of pathologists while examining Hematoxylin and Eosin stained breast tissue, this study presents a deep learning-based classifier of nuclear pleomorphism according to the Nottingham grading scale. We show that high classification accuracy is attainable without pre-segmenting the cell nuclei. The data used in the experiments was acquired from our partner teaching hospital. It consists of image patches that were extracted from whole slide images. Using the labeled data, we compared the performance of three state-of-the-art convolutional neural networks and tested the trained model on the unseen testing data. Our experiments revealed that the densely connected architecture (DenseNet) outperforms the residual network (ResNet) and the dual path networks (DPN) in terms of accuracy and F1 score. Specifically, we reached an overall validation accuracy and F1 score of over 0.96 and 0.94 respectively.

The SARS-CoV-2 virus caused the most severe pandemic around the world, and vaccine development for urgent use became a crucial issue. Inactivated virus formulated vaccines such as Hepatitis A, oral polio vaccine, and smallpox proved to be reliable approaches for immunization for prolonged periods. During the pandemic, we produced an inactivated SARS-CoV-2 vaccine candidate, having the advantages of being manufactured rapidly and tested easily in comparison with recombinant vaccines. In this study, an inactivated virus vaccine that includes a gamma irradiation process for the inactivation as an alternative to classical chemical inactivation methods so that there is no extra purification required has been optimized. The vaccine candidate (OZG-38.61.3) was then applied in mice by employing the intradermal route, which decreased the requirement of a higher concentration of inactivated virus for proper immunization, unlike most of the classical inactivated vaccine treatments. Hence, the novelty of our vaccine candidate (OZG-38.61.3) is that it is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. Efficiency and safety dose (either 1013 or 1014 viral copy per dose) of OZG-38.61.3 was initially determined in Balb/c mice. This was followed by testing the immunogenicity and protective efficacy of OZG-38.61.3. Human ACE2-encoding transgenic mice were immunized and then infected with a dose of infective SARS-CoV-2 virus for the challenge test. Findings of this study show that vaccinated mice have lower SARS-CoV-2 viral copy number in oropharyngeal specimens along with humoral and cellular immune responses against the SARS-CoV-2, including the neutralizing antibodies similar to those shown in Balb/c mice without substantial toxicity. Subsequently, plans are being made for the commencement of Phase 1 clinical trial of the OZG-38.61.3 vaccine for the COVID-19 pandemic.

Amaç: ERK 1/2 (ekstraselüler sinyalle düzenlenen kinaz 1, 2) ve p38α’nın, FGFR1 Ser 777’yi fosforile etmek yoluyla anti-tümörojenik etki göstermesi muhtemeldir. Ser777 fosforilasyonunun ise FGFR1 aktivasyonunu inhibe ettiği bilinmektedir. Dolayısıyla Ser777’nin mutasyona uğramasının FGFR1’i aktive ederek; karsinogenez ile bunu devam ettirebilecek mekanizmaları harekete geçirebileceği düşünülmüştür. Bu kapsamda gerçekleştiren çalışmada; mesane kanseri ile FGFR1 Ser777 mutasyonu arasındaki ilişkinin tespiti amaçlanmıştır. Yöntem: Çalışmada; mesane kanseri tümör dokusu (n=62) ve kontrol grubu örneklerinde (n=30) DNA izolasyonunun ardından, FGFR1 Ser777 mutasyon analizi, DNA dizi analizi yöntemi ile gerçekleştirilmiştir.Bulgular: Bildiğimiz kadarıyla ilk defa çalışılan söz konusu mutasyon, incelenen hasta ve kontrol grubu örneklerinde tespit edilememiştir.Sonuç: Elde edilen bulgular, Ser777’nin mesane kanserinde mutasyona uğramadığını düşündürmüştür. Literatürde konuyla ilgili başka çalışma bulunmadığı göz önüne alındığında, çalışma sonuçlarının literatüre önemli katkı sağlayabileceği düşünülmektedir. Dahası, diğer kanser türlerinde de FGRF1 Ser777 mutasyonunun çalışılmasının farklı bakış açıları ortaya koyabileceğini düşünmekteyiz., Objective: The ERK 1/2 (extracellular signal-regulated kinase 1, 2) and p38α probably have an anti-tumorigenic effect by phosphorylating FGFR1 Ser 777. The Ser777 phosphorylation is known to inhibit FGFR1 activation. Therefore, the Ser777 mutation was suggested to trigger the carcinogenesis, and the other continued mechanisms by activating the FGFR were suggested. We aimed to determine the relationship between FGFR1 Ser777 mutation and bladder cancer were aimed to be determined in this context.Methods: After the DNA isolation of bladder cancer tumor tissues (n = 62) and control group samples (n = 30), the DNA sequence analysis was performed for the FGFR1 Ser777 mutation in the study carried out for this purpose. Results: The mutation which has been studied for the first time to the best of our knowledge was not detected in the patient and control group samples in the current study.Conclusion: As a conclusion the data suggested that Ser777 did not mutate in bladder cancer. Considering that there are no other studies on the subject in the literature, it is thought that the results of the study might make a significant contribution to the literature. Moreover, in our opinion, studying the FGRF1 Ser777 mutation in the other types of the cancer will reveal different points of view.

The molecular mechanisms underlying the development and progression of bladder cancer (BC) are complex and have not been fully elucidated. Alterations in base excision repair (BER) capacity, one of several DNA repair mechanisms assigned to preserving genome integrity, have been reported to influence cancer susceptibility, recurrence, and progression, as well as responses to chemotherapy and radiotherapy. We report herein that non-muscle invasive BC (NMIBC) tissues exhibit increased uracil incision, abasic endonuclease and gap-filling activities, as well as total BER capacity in comparison to normal bladder tissue from the same patient (p

Relapsed and refractory CD19-positive B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) are the focus of studies on hematological cancers. Treatment of these malignancies has undergone recent transformation with the development of new gene therapy and molecular biology techniques, which are safer and well-tolerated therapeutic approaches. The CD19 antigen is the most studied therapeutic target in these hematological cancers. This study reports the results of clinical-grade production, quality control, and in vivo efficacy processes of ISIKOK-19 cells as the first academic clinical trial of CAR-T cells targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey.We used a lentiviral vector encoding the CD19 antigen-specific antibody head (FMC63) conjugated with the CD8-CD28-CD3ζ sequence as a chimeric antigen receptor (CAR) along with a truncated form of EGFR (EGFRt) on human T-lymphocytes (CAR-T). We preclinically assessed the efficacy and safety of the manufactured CAR-T cells, namely ISIKOK-19, from both healthy donors’ and ALL/NHL patients’ peripheral blood mononuclear cells.We showed significant enhancement of CAR lentivirus transduction efficacy in T-cells using BX-795, an inhibitor of the signaling molecule TBK1/IKKƐ, in order to cut the cost of CAR-T cell production. In addition, ISIKOK-19 cells demonstrated a significantly high level of cytotoxicity specifically against a CD19+ B-lymphocyte cancer model, RAJI cells, in NOD/SCID mice.This is the first report of preclinical assessment of efficacy and safety analysis of CAR-T cells (ISIKOK-19) targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey.Relaps/refrakter CD19-pozitif B-hücreli akut lenfoblastik lösemi (ALL) ve Hodgkin dışı lenfoma (NHL), hematolojik kanserlerle ilgili çalışmaların odak noktasıdır. Bu malignitelerin tedavisi, daha güvenilir ve iyi tolere edilen terapötik yaklaşımlar olan, yeni gen terapisi ve moleküler biyoloji tekniklerinin geliştirilmesi ile son zamanlarda dönüşüm geçirmiştir. CD19 antijeni, bu hematolojik kanserlerde en çok çalışılan terapötik hedeftir. Bu çalışma, Türkiye’de relaps/refrakter ALL ve NHL hastalarında, ilk akademik klinik deneme için kullanılması amacıyla, CD19 eksprese eden B hücrelerini hedefleyen CAR-T (ISIKOK-19) hücrelerinin klinik sınıf üretimi, kalite kontrolü ve in vivo etkinlik süreçlerinin sonuçlarını bildirmektedir.Bu çalışmada, insan T-lenfositleri (CAR-T) üzerinde kesilmiş EGFR (EGFRt) formu ile birlikte kimerik bir antijen reseptörü (CAR) olarak CD8-CD28-CD3ζ sekansı ile konjuge CD19 antijene özgü antikor başını (FMC63) eksprese eden bir lentiviral vektör kullandık. Hem sağlıklı donörlerin hem de ALL/NHL hastalarının periferal kan mononükleer hücrelerinden üretilen CAR-T (ISIKOK-19) hücrelerinin etkinliğini ve güvenliğini klinik öncesi olarak değerlendirdik.CAR-T hücre üretiminin maliyetini düşürmek için sinyal molekülü TBK1/IKKƐ’nın bir inhibitörü olan BX-795 kullanarak T-hücrelerinde CAR lentivirüs transdüksiyon etkinliğinin önemli ölçüde arttığını gösterdik. Ek olarak, ISIKOK-19 CAR-T hücrelerinin, NOD/SCID farelerinde özellikle bir CD19 + Blenfosit kanser modeli olan RAJI hücrelerine karşı önemli ölçüde ve yüksek seviyede sitotoksisite gösterdiğini değerlendirdik.Bu çalışma, Türkiye’de relaps/refrakter ALL ve NHL hastalarında CD19 eksprese eden B-hücrelerini hedefleyen CAR-T hücrelerinin ilk akademik klinik çalışması olarak ISIKOK-19 hücrelerinin klinik sınıf üretimi, kalite kontrolü ve in vivo etkinlik süreçlerinin sonuçlarını bildirmektedir.

BACKGROUND Recently a new system for reporting salivary gland fine-needle aspiration (FNA) cytology was proposed, the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC). Herein, we evaluated diagnostic accuracy of salivary gland FNA, comparing the system previously used in our hospital with the Milan system. METHODS Salivary gland specimens obtained between 2011 and 2017 were reclassified according to MSRSGC. Risk of malignancy for each diagnostic category was determined. Diagnostic yield of both classifications was evaluated. RESULTS The cases (n = 388) were classified according to the old system: nondiagnostic (n = 28), benign (n = 246), atypical (n = 36), neoplastic (n = 57), suspicious for malignancy (n = 7) and malignant (n = 14). The lesions were distributed according to the MSRSGC: nondiagnostic (n = 28), non-neoplastic (n = 89), atypia of undetermined significance (n = 39), benign neoplasm (n = 156), neoplasm of uncertain malignant potential (n = 55), suspicious for malignancy (n = 7) and malignant (n = 14). When considering only benign and malignant cases, both classifications showed the same sensitivity (62.5%), specificity (100%) and similar accuracy (95.8%). Comparison between the two systems showed no significant difference. CONCLUSIONS Salivary gland FNA has high diagnostic accuracy and assists clinical management independently of the reporting system used, however, in some cases, the use of Milan system could be beneficial, since it allows an enhanced category stratification.

Graphical abstract, Highlights • IQGAP proteins demonstrated differential expression between CV-PTC and FV-PTC. • Proteome similarities between benign and FV-PTC hampered accurate unsupervised clustering. • Changes in actin cytoskeleton proteins play predominant roles in thyroid pathology., Introduction Fine Needle Aspiration Biopsy (FNAB) allows the cytological differentiation of benign and malignant thyroid nodules. However, the method itself is not adequate in determining some cases. For example, the diagnosis of Follicular Variant Papillary Thyroid Carcinoma (FV-PTC) can be challenging. In the current study we investigate the protein profiles of FV-PTC and classical variant PTC (CV-PTC) with no lymph node metastasis and compare it with benign thyroid tissue. Method We used CV-PTC (n = 6), FV-PTC (n = 6) and benign thyroid tissues (n = 6) to prepare tissue lysates. Proteins from each group were trypsin and lys-C digested. The samples were analyzed on a Q Exactive Orbitrap mass spectrometer. Results We identified 2560 proteins across all 18 specimens. Protein profiles revealed that there was no clear distinction between benign and FV-PTC samples. However, further examination of our data showed that proteins in energy metabolism have altered in FV-PTC. Proteomic pathway analysis showed marked alteration of the actin cytoskeleton proteins, especially several members of Arp2/3 complex were significantly increased in CV-PTC. We made the novel observation that IQGAP1 protein was significantly increased in CV-PTC, whereas IQGAP2 protein was highly expressed in FV-PTC lesions, suggesting differential roles of IQGAP proteins in thyroid pathology. Conclusion In the present study, mass spectrometry based label free quantification approach was applied to investigate the protein profiles of FV-PTC, CV-PTC and benign thyroid tissues. This study pointed out that actin cytoskeleton proteins, IQGAP proteins and changes in energy metabolism play predominant roles in thyroid pathology.

Peripheral nerve injury is a common, important problem that lacks a definitive, effective treatment. It can cause neurologic deficits ranging from paresthesia to paralysis. This study evaluated the effect of ozone therapy on sciatic nerve crush injury in rats.Twenty-four male rats were divided into control sham surgery, sciatic nerve injury, and sciatic nerve injury with ozone groups (each n = 8). The sciatic nerve injury was inflicted via De Koning's crush-force method. The sciatic nerve injury group received medical air and the sciatic nerve injury ozone group received 0.7 mg/kg ozone. Sciatic nerve samples were obtained 4 weeks after injury. Vascular congestion, vacuolization, edema formation, S100 expression, and the thicknesses of the perineurium and endoneurium and diameter of the injured sciatic nerves were evaluated.The diameter of the sciatic nerve and thicknesses of the perineurium and epineurium were significantly greater in the sciatic nerve injury group (P 0.05) and significantly less in the sciatic nerve injury with ozone group (P0.001). High S100 immunoreactivity was seen in the sciatic nerve injury group compared with the other 2 groups (P0.05). The distributions of vascular congestion and vacuolization were significantly less in the sciatic nerve injury with ozone group (P 0.05).Ozone therapy improved sciatic nerve injury recovery without causing an increase in fibrotic tissue. Ozone reduced fibrosis, vascular congestion, vacuolization, and edema in rodents. Ozone treatment might be used to assist in sciatic nerve injury.

Non-small cell lung cancer (NSCLC) is a frequent tumor entity with high mortality. Although several newly discovered chromosomal translocations and mutations opened new horizons for targeted therapy, literature still lacks large series of NSCLC with chromosomal abberations and their correlations with histological and clinical features. We present a case of echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation positive adenocarcinoma of the lung with an unusual metastatic pattern in a 29-year-old young woman. Conclusion: Young adult non-smoker female patients with an unexplained pleural effusion and signs of metastatic disease should alert the physicians straight away for all types of malignancies including lung cancer. Any skin lesions should be evaluated carefully, biopsies should be done to exclude metastasis in urgency. On the other hand, an uncommon clinical presentation of a lung cancer requires corresponding molecular testing rapidly in order to offer the best treatment option. (C) 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license.

Introduction: The Acibadem Health Group (AHG) has been using telepathology/digital pathology stations since 2006. In 2013, the system was changed from videoconferencing to digital pathology (whole-slide imaging) utilizing 3DHISTECH scanners and software. In 2017, digital cytology started to be used for routine cytopathologic diagnosis for thyroid fine-needle aspiration (FNA) cases. Material and Methods: Two hundred and twenty-seven thyroid cases were received for analysis using telecytology (TC) during the period from November 2017 to May 2018. Rapid on-site evaluation was performed at the Atakent Hospital of the AHG by a cytotechnologist and scanned on the same day. For every case, there were Diff-Quik- and Papanicolaou-stained FNA smears. Each glass slide was digitized with a 3DHISTECH whole-slide scanner in 1 focal Z-plane at ×40 magnification. Results: Two hundred and twenty-seven thyroid FNA specimens were retrieved, of which 25 had histologic follow-up. Samples were classified as nondiagnostic in 3%, benign in 74%, atypia of undetermined significance/follicular lesion of undetermined significance in 13%, suspicious for follicular neoplasia/follicular neoplasia in 3%, suspicious for malignancy in 4%, and malignant in 3%. When only the “suspicious for malignancy” and “malignancy” categories were considered positive tests, cytology sensitivity and specificity using TC for diagnosis was 100%. Conclusions: Our data demonstrate that TC is suitable to provide a primary diagnosis in daily routine cytology practice. Despite the promising results, there were some challenges stemming from the novelty of using TC for the primary diagnosis. The study also addresses both advantages and disadvantages of TC in daily practice to increase the efficiency of the technique in primary diagnosis.

Introduction: The lack of papillary structures and faint and/or unclear core features of follicular variant of papillary thyroid carcinoma (FV-PTC) may hamper the definitive fine needle aspiration biopsy -based diagnosis. Recently, the nomenclature of noninvasive encapsulated FV-PTC was revised to "noninvasive follicular thyroid neoplasms with papillary-like nuclear features" (NIFTP). However, it remains inconclusive whether or not the peptide patterns differ between NIFTP and encapsulated FV-PTC. The main objectives of this study were to investigate the viability of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) in the pathological assessment of NIFTP and to evaluate the discriminatory power of MALDI MSI for the classification of classical variant of PTC (CV-PTC), NIFTP, and encapsulated FV-PTC. Methods: MALDI MSI was employed to investigate the changes in peptide profiles from 21 formalin-fixed paraffin-embedded (FFPE) tissue samples (n = 7 from each group of CV-PTC, NIFTP, and FV-PTC). Six out of seven FV-PTC FFPE tissue samples were encapsulated FV-PTC; only one was infiltrative FV-PTC. Liquid chromatography-tandem mass spectrometry was used for the identification of the peptide signals detected in MALDI MSI. Results: Using receiver operating characteristics analysis, 10 peptide signals distinguished NIFTP from normal thyroid parenchyma (area under the curve [AUC] >0.80). To evaluate the discriminatory power of MALDI MSI, statistically significant peptide signals (n = 88) within three groups were used for hierarchical clustering. The method had high discriminatory power for distinguishing CV-PTC from NIFTP and FV-PTC (encapsulated and infiltrative). The majority of the NIFTP and encapsulated FV-PTC were clustered together, indicating that NIFTP could not be distinguished from encapsulated FV-PTC. However, infiltrative FV-PTC FFPE tissue samples had the furthest distance from all the NIFTP cases. High signal intensities of S100-A6, vimentin, and cytoplasmic actin 1 were detected in FV-PTC, prelamin A/C in CV-PTC, and 60S ribosomal protein L6 and L8 in NIFTP tissues. Conclusions: MALDI MSI, a powerful tool combining histological and mass spectrometric data, enabled the differentiation of NIFTP from normal thyroid parenchyma. Although NIFTP is a recent definition that replaces noninvasive encapsulated FV-PTC, the peptide profiles of NIFTP and encapsulated FV-PTC were found to be similar.

Objective: to investigate the role of mammalian target of rapamycin (mTOR) in human granulosa cell ovarian tumors and the therapeutic effect of rapamycin in COV434 mitotic granulosa cell lines. Material and Methods: a retrospective evaluation of the medical records and pathologic sections of patients with granulosa cell ovarian carcinoma was performed. mTOR and p-mTOR expression was immunohistochemically investigated. A COV434 cell culture were treated with 0.5, 1, 2, and 5 mu M rapamycin. Real-time growth curve analysis via xCELLigence system and apoptotic cell analysis via YO-PROT-1 Iodide were performed to assess the therapeutic effect of rapamycin on cancer cells. Results: a total of twenty patients were evaluated. mTOR staining was detected in 18 (90%) patients. Mild, moderate, intense, and very intense staining was observed in three (15%), eight (40%), six (30%), and one (5%) sample, respectively. The mean mTOR staining ratio was 59 +/- 41%. P-mTOR staining was observed in two ( 10%) patients. One (5%) patient had 5% staining, and one (5%) patient had 100% staining for p-mTOR. Both of the latter patients had very intense staining. Rapamycin caused a dose-dependent growth arrest and induced apoptosis in COV434 mitotic granulosa cells. The real-time growth curves of the cells treated with these drugs were distinguished by a marked reduced slope after exposure for several hours, indicating a rapid onset of apoptosis. Live/dead cell analysis with YO-PRO-1 staining showed that rapamycin induced apoptosis in 24% of the cells when used at 1 mu M concentration, whereas the rate increased to 61% and 72% when the cells were treated with 2 mu M and 5 mu M rapamycin, respectively. Conclusion: mTOR expression is observed in various degrees in 90%, and p-mTOR expression is observed in only 10% of patients with granulosa cell ovarian carcinoma. Rapamycin caused a dose-dependent growth arrest and apoptosis in COV434 mitotic granulosa cells., İstanbul University, Scientific Research Fund

WOS: 000392717800006 PubMed ID: 27654016 Introduction. Many patients of all ages are admitted to hospital due to bone fractures. The etiology of fracture has a very wide spectrum, ranging from motor accidents to pathological conditions such as tumors, osteoporosis, and others. Bone fracture healing is a well-programmed and well-organized process, but is also long and intractable. The outcome of this process is therefore affected by many factors, such as the patient's age, ethnicity, nutritional status, and extent of the fracture. At present, regional analgesic techniques are frequently applied in order to avoid the complications of systemic opioid administration, central block applications. Femoral block is one of the regional analgesic techniques frequently applied by anesthesiologists when the lower extremities are involved. In this study, we evaluated the effect of femoral nerve block on the healing of an experimental non-stabilized femur fracture via expression of TGF-beta, VEGF, and beta-catenin and bone histomorphometry in rats. Material and methods. In the control group, only the femoral fracture was performed and the bone was not fixated, similarly as in other groups. In the One-Day Block group, a one-time femoral nerve block was applied after the femoral fracture. In the Three-Day Block group, a daily femoral nerve block was performed for three days after the femoral fracture. On Days 4, 7, and 13, femurs were excised. The bone sections were stained with hematoxylin-eosin to evaluate bone tissue and Safranin O to assess callus tissue, cartilaginous tissue, and new bone areas. TGF-beta, VEGF, and beta-catenin were assessed by immunohistochemistry. Results. Histomorphometric analysis revealed that femoral block application had a positive impact on bone healing. TGF-beta expression in the One-Day and Three-Day Block Groups was significantly higher than in the control group at all times, as was also the case with VEGF expression. On day 13, beta-catenin expression was significantly higher in the Three-Day Block group than the others. Conclusions. The results of the study suggests that the applications of a femoral nerve block for perioperative analgesia, for either one day or three days, resulted in better and more rapid bone healing. Turkish Regional Anesthesia Association at 13th National Regional Association Congress This study was awarded with Best Free Paper by Turkish Regional Anesthesia Association at 13th National Regional Association Congress, 2013.

Currently, the gold standard for breast biopsies is open excision of the suspected lesion. However, an excisional biopsy inevitably leaves a scar behind. The cost and morbidity associated with this procedure have prompted many physicians to evaluate less invasive and alternative procedures (1–3). Clustered suspicious microcalcifications can be a very early sign of malignancy, particularly typical for ductal carcinoma in situ (DCIS). Microcalcifications are usually detected on screening mammographies, and most of them cannot be identified on ultrasonography (US). Lesions detected only on mammography require stereotactic guidance for biopsy, and vacuum-assisted breast biopsy (VABB) is currently the biopsy method of choice for stereotactic biopsies. VABB is considered to be a safe procedure and is comparable to surgical biopsy for the characterization of microcalcifications (4, 5). Studies have shown that it is a very accurate biopsy method and is characterized by high-quality specimens, high calcification retrieval, and low rates of false-negative results (6–10). In case of microcalcifications, complete percutaneous excision is frequently possible, which leads to a decrease in sampling error as well as a decrease in upgrade rate, imaging-pathology discordance, and re-biopsy rate. The likelihood of subsequent growth on follow-up is also diminished. VABB is not a therapeutic procedure for malignant lesions; however, using VABB for diagnosis rather than surgical biopsy decreases the number of operations required (11–13). Vacuum biopsy can be used for the histopathologic diagnosis of all nonpalpable breast lesions; however, it is mostly reserved for mammographically detected lesions, mainly microcalcifications. In this paper, we aim to present our biopsy method and retrospectively evaluate the results, upgrade rate, and follow-up findings of stereotactic-guided VABB procedures performed over a six-year period in our clinic.

Background: The BRAFV600E mutation is common in papillary thyroid cancer (PTC). Lymph node metastasis (LNM) may be associated with poor prognosis. However, the LNM mechanism remains unclear. Objectives: Our aim was to evaluate the prevalence of the BRAFV600E mutation in primary tumors and accompanying LNM at the time of diagnosis. Methods: This retrospective study included 51 PTC patients (40 women, 11 men; mean age 40.0 ± 16.5 years; range 6-81) who underwent total thyroidectomy accompanied by a lateral neck dissection due to preoperatively detected LNM. Real-time PCR was used for the detection of the BRAFV600E mutation in specimens from primary thyroid tumors and metastatic lymph node tumors. Results: The prevalence of the BRAFV600E mutation was 64.7% (n = 33) in primary tumors and 47.1% (n = 24) in metastatic lymph nodes. Of 33 patients with BRAFV600E-positive primary tumors, 18 (54.5%) had BRAFV600E-positive metastatic lymph nodes. Of 18 patients with BRAFV600E-negative primary tumors, 6 (33.3%) had BRAFV600E-positive metastatic lymph nodes. The presence of the BRAFV600E mutation in the primary tumor did not affect the tumor size, but the diameter of metastatic lymph nodes significantly increased (by nearly 3 mm) with the presence of BRAFV600E in LNM (p = 0.01). Conclusions: In our study, the BRAFV600E mutation did not show a one-to-one correspondence. This indicates that the presence of BRAFV600E in the primary tumor is not clonal and addresses the role of intratumor heterogeneity in PTC tumorigenesis. This supports the theses that mutations occur in the later stages of tumorigenesis, might be subclonal, and develop de novo, or that some other factors may be involved in the development of metastasis.

Background/aims Human Papilloma Virus (HPV) infection can be a predisposing condition for the development of squamous cell papilloma (SCP) of the esophagus, which can progress to dysplasia and to carcinoma as a result of chronic infection. The aim of the present study was to search for the presence of HPV in the esophageal SCP, and to genotype the detected HPV. Materials and methods Data from patients with definite diagnosis of SCP of the esophagus were identified from pathology records for two years period at different Hospitals. Slides from each patient were reviewed and samples with satisfactory papilloma tissues were submitted to molecular analysis. DNA has been isolated. DNA sequencing has been performed for genotyping HPV for all types. Results Our study group consisted of 21 women and 17 men (a total of 38 patients), mean age was 41 years (range 17-67 years). Most of the papillomas were located at mid-esophagus (68%). Eight out of 38 patients (21%) had associated erosive esophagitis, and fourteen patients (36.8%) had Helicobacter Pylori (H. pylori). Of the 38 SCP analyzed, seven (19%) were positive for HPV DNA. Three of them were of genotype 6, whereas four were of genotype 16, 18, 31, 81 that are known as highly oncogenic. There were no correlations between the presence of HPV and the patient's age, the presence of reflux esophagitis or H. pylori, smoking habit and the location of the papillomas. Conclusion The presence of high-risk type HPV in esophageal SCP may implicate a role of the virus in the pathogenesis of the esophageal tumor.

Mesotherapy is widely used for its lipolytic effect as an alternative procedure to surgical methods. Although many benefits of lipolytic mesotherapy have been observed, numerous side effects have also been reported. Here, we report a case of cutaneous foreign body granulomas that occurred after lipolytic mesotherapy.

Background Malaria is known to cause acute and deadly complications. However, malaria can cause unforeseen pathologies due to its chronicity. It increases the risk of endemic Burkitt Lymphoma development by inducing DNA damage in germinal centre (GC) B cells, and leading higher frequency of Epstein–Barr virus (EBV)-infected cells in GCs. EBV is well known for its tropism for B cells. However, less is known about EBV’s interaction with T cells and its association with T cell lymphoma. Case presentation A 43-year-old Sudanese male admitted to hospital in Istanbul, Turkey, a non-endemic country, with hyperpigmented painful skin rashes on his whole body. A complete blood count and a peripheral blood smear during admission revealed large granular lymphocytes (LGLs) with abnormally higher CD8 T cell numbers. Additional skin biopsy and pathology results were compatible with CD8+ T cell lymphoproliferative disorder with skin involvement. Patient was treated and discharged. However, a pathologist noticed unusual structures in skin tissue samples. Careful evaluation of skin biopsy samples by polarized microscopy revealed birefringent crystalloid structures resembling malarial haemozoin mainly loaded in macrophages and giant histiocytes. After purification of DNA from the skin biopsy samples, nested PCR was performed for the detection of Plasmodium parasites and Plasmodium falciparum DNA was amplified. Because, the co-presence of EBV infection with malaria is a well-known aetiology of lymphoma, EBV-early RNA (EBER) transcripts were investigated in paraffin-embedded tissue samples and found to be positive in macrophage-like histiocytes. Conclusions This is a unique case of malaria and EBV infection in a T-LGL lymphoma patient who presented in a non-endemic country. This case emphasizes the clinical importance of EBV monitoring in T-LGL patients with skin involvement. Notably, Plasmodium infection should be examined in patients from malaria endemic regions by pathological and molecular investigations.

Tekant, Gonca A Topuzlu/0000-0002-6231-9792; Tekant, Gonca Topuzlu/0000-0002-6231-9792; Arslan, Aydan/0000-0002-6073-1927 WOS:000459395400016 PubMed ID: 30875294 Leiomyomas are benign, slow-growing, smooth muscle tumors, which can occur at many locations in the body. The male genitourinary tract is seldom affected and scrotal leiomyomas are extremely rare. Most of the scrotal leiomyomas are localized in the testis, epididymis, spermatic cord, subcutaneous tissue, tunica albuginea, and scrotal skin and only a few of them are reported in the origin of isolated tissue without paratesticular structures in the paratesticular region. We are presenting a case of solitary paratesticular leiomyoma in a child, which is very rare in terms of lesion location and patient age, and describing the imaging features of this lesion.

PubMed ID: 30008986, Involvement of high cholesterol and oxidative stress in cardiovascular diseases is well studied, as it can be hypothesized that various products originated from lipid peroxidation, such as oxysterols, or affected protein expression might lead to cardiomyocyte damage followed by the pathological modifications. Although oxidation of excessive cholesterol to oxysterols in elevated stress conditions is identified by a number of studies, the role of a high cholesterol diet in regulating fatty acid and oxysterol accumulation, together with scavenger receptor mRNA levels, in the heart remains little investigated. Our study provides a detailed analysis of the changes in fatty acid, oxysterol, and scavenger receptor profiles and its relation with histological alterations in the heart tissue. We evaluated alterations of fatty acid composition, by the GC-MS method, while 4ß-, 25-, and 27-hydroxycholesterol and 7-ketocholesterol levels by means of LC-MS/MS in high cholesterol diet-fed rabbits. Additionally, a number of proteins related to lipid metabolism and scavenger receptor mRNA expressions were evaluated by Western blotting and RT-PCR. According to our in vivo results, a high cholesterol diet enhances a number of unsaturated fatty acids, oxysterols, and LXR?, in addition to CD36, CD68, CD204, and SR-F1 expressions while ?-tocopherol supplementation decreases LXR? and SR expressions together with an increase in 27-hydroxycholesterol and ABCA1 levels. Our results indicated that the high cholesterol diet modulates proteins related to lipid metabolism, which might result in the malfunction of the heart and ?-tocopherol shows its beneficial effects. We believe that this work will lead the generation of different theories in the development of heart diseases.

Background In 2016, the Papanicolaou Society of Cytopathology (PSC) issued a new classification scheme for respiratory cytology. We aim to evaluate our samples according to this classification and to assess risk of malignancy and diagnostic yield of different cytological modalities. Methods Respiratory specimens (sputum, bronchial wash/brush, BAL and FNA) obtained between 2007 and 2016 were reclassified according to PSC guidelines. Risk of malignancy for each diagnostic category was determined. Diagnostic yield was evaluated based on three-categorical approach. Results One thousand, two hundred and ninety respiratory specimens were retrieved, of which 280 had histologic follow-up. Samples were reclassified as nondiagnostic 16%, negative for malignancy 53%, atypical 5.4%, neoplastic (benign neoplasm/low-grade carcinoma) 0.4%, suspicious for malignancy 2.1% and malignant 23.1%. Risk of malignancy for each category was 64.01% for ND, 48.27% for NM, 59.09% for A, 100% for N-B-LG; 90% for SM and 89.74% for M. When only malignant cases were considered positive tests, cytology sensitivity was 55% and specificity 88%. Conclusion Our results were in line with PSC guidelines, but the use of multiple cytological techniques may cause some discrepancies in overall diagnostic yield and in estimated risks of malignancy, which is important due to the widespread utilization of different cytological procedures.

Background: Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare vascular proliferative disorder mainly located in the periauricular region. The etiopathogenesis of ALHE is unknown, and it is still controversial as to whether the entity represents a benign vascular neoplasm or an inflammatory process. Aim: Recently, the intracytoplasmic staining pattern of Wilms tumor 1 (WT1) on immunohistochemistry has highlighted true vascular neoplasms, such as microvenular hemangioma, tufted angioma, and spindle cell hemangioma, which has made it helpful to distinguish ALHE from vascular malformations, as there is a negative staining pattern in the other entities. We aimed to investigate the immunoreactivity of ALHE specimens for WT1 as well as glucose transporter protein 1 (GLUT1) immunohistochemistry, an important and sensitive marker for the diagnosis of infantile hemangioma, which recently has been described to label other hemangiomas, such as verrucous hemangioma. Material and methods: Clinical data and histopathological specimens from patients diagnosed with ALHE were reviewed, and immunohistochemical staining and microscopic analysis for WT-1 and GLUT1 were performed. Results: Intracytoplasmic endothelial staining of WT1 was detected in 19 of 20 ALHE specimens. GLUT1 was not detected in any ALHE specimen. Conclusions: We conclude that ALHE may represent a true hemangioma (i.e., benign vascular neoplasia) characterized by an eosinophil- and lymphocyte-rich inflammatory component as opposed to the reactive inflammatory dermatosis with a positive intracytoplasmic staining pattern for WT1. As far as we are aware, WT1 staining for ALHE has not been described to date.

Granulosa cell tumor of the ovary (GCT) is a very rare tumor, accounting for only 2% of all ovarian tumors. It originates from sex cords in the ovary and can be divided into adult (95%) and juvenile (5%) types based on histologic findings. To date, no clear etiologic process has been identified other than a missense point mutation in the FOXL2 gene. Our previous works showed that c-Jun N-terminal kinase (JNK) pathway plays critical role in cell cycle progression and mitosis of normal and immortalized granulosa cells and follicle growth in rodent ovaries. These findings led us to investigate the role of JNK pathway in the granulosa cell tumor of the ovary. We used two different GCT cell lines (COV434 and KGN) and fresh GCT samples of adult and juvenile types obtained from the patients during surgery. We have discovered that endogenous kinase activity of JNK is markedly enhanced in the GCT samples and cell lines, whereas it was almost undetectable in mitotic non-malignant human granulosa cells. The inhibition of JNK pathway in GCT cell lines with two different pharmacologic inhibitors (SP600125 and AS601245) or siRNA resulted in a dose-dependent reduction in in vitro cell growth, increased apoptosis and diminished estradiol and AMH productions. JNK inhibition was also associated with a decrease in the number of cells positive for mitosis marker phospho-histone H3(Ser) 10 in the asynchronous cells; and diminished EdU uptake during S phase and cell cycle arrest at G2/M-phase transition in the synchronized cells. Ex vivo treatment of patient-derived GCT samples with JNK inhibitors for 24 h significantly decreased their in vitro growth and estradiol and AMH productions. Furthermore, in human GCT xenograft model, in vivo tumor growth was significantly reduced and plasma AMH levels were significantly decreased in SCID mice after administration of JNK inhibitors and siRNA. These findings suggest that targeting JNK pathway may provide therapeutic benefit in the treatment of granulosa cell tumors for which currently no curative therapy exists beyond surgery., Republic of Turkey Ministry of Development Research Infrastructure Support Program

Together with complex genetic and environmental factors, increased serum cholesterol and ox-LDL levels are considered as major triggering factors of atherosclerosis. Mononuclear cell infiltration to the arterial wall and uptake of ox-LDL, which is facilitated by CD36 receptor through an uncontrolled manner, play a key role in foam cell formation followed by atherogenesis development. The aim of this study was to analyze if CD36 expression in peripheral blood mononuclear cells reflect its aortic tissue level in hypercholesterolemia. In this study, CD36 protein expression was evaluated in aortic specimens of cholesterol or cholesterol plus Vitamin E treated animals in relation to the immunohistochemical analyses for the HNE-protein adducts, as well as for smooth muscle actin and vimentin. The CD36 mRNA expression was determined by RT-PCR in PBMC of hypercholesterolemic rabbits and hypercholesterolemic versus normocholesterolemic individuals. Immunohistochemistry findings revealed that smooth muscle actin, smooth muscle vimentin, HNE-protein conjugates, and CD36 protein expressions were significantly increased in aorta of hypercholesterolemic group where foam cells were present. High cholesterol diet significantly induced CD36 mRNA expression in both rabbit aorta and PBMCs, while positive correlation between aortic and PBMC CD36 expression has been found. In addition, consistent with the rabbit model, CD36 mRNA expression levels in human PBMCs were significantly higher in hypercholesterolemic patients than in normocholesterolemic individuals. Taken together, these results demonstrate that the CD36 mRNA levels of PBMCs could reflect the CD36 mRNA levels in aorta and could be used as a biomarker for diagnosis of atherosclerotic burden. (c) 2018 BioFactors, 44(6):588-596, 2018

BACKGROUND: Differentiation of psoriasis from non-psoriasis psoriasiform dermatitis (NPPD) may be difficult for dermatopathologists, as lack of distinctive histopathological features in a subset of cases may cause confusion in diagnosis. OBJECTIVE: As the prototype of psoriasiform dermatitis, psoriasis is a hyperproliferative skin disorder with increased epidermal turnover compared with NPPD, we investigated the role of proliferation markers, Ki-67 and Cyclin D1 as diagnostic tools to differentiate psoriasis from other psoriasiform dermatitis. METHODS: Histopathological specimens of psoriasis (n = 35) and NPPD (n = 36, 14 pityriasis rubra pilaris, 12 pityriasis rosea and 10 lichen simplex) cases were reviewed and immunohistochemically stained for Ki-67 and Cyclin D1. Ki-67 and Cyclin D1 positive cells were counted for suprabasal, and total epidermal immunostaining per mm(2). RESULTS: Suprabasal and total epidermal cell counts for Ki-67 were found to be significantly higher in the psoriasis group compared with the NPPD group (p < 0.05). An important and interesting feature was the presence of a cut-off value for the suprabasal/total epidermal cell count ratio of 75% for Ki-67 immunostaining, which was higher in all patients having psoriasis (range, 77.1% - 92.4%) and lower in all NPPD cases (range, 21.0% - 73.3%). However, suprabasal Cyclin D1 cell counts were higher in the psoriasis group compared with the NPPD group (p < 0.05), total epidermal Cyclin D1 cell counts were not statistically significant in either group (p = 0.167), and a cut-off value for suprabasal/total epidermal cell count ratio to distinguish these two entities was not detected using this immunostain. CONCLUSIONS: We suggest that Ki-67 is a more sensitive marker than Cyclin D1 in terms of having a cutoff value of 75% for the suprabasal/total epidermal immunoreactive cell count ratio, which we believe could be useful for dermatopathologists in differentiating psoriasis from other psoriasiform dermatitis.

Myxopapillary ependymomas (ME) are rare and slowly growing gliomas usually with spinal cord localization originating from the ectopic ependymal residues. They are commonly located in the conus medullaris, cauda equina and filum terminale. ME is known to be more aggressive in childhood, but has a good prognosis in adults with a very low metastasis risk.(1,2) If successfully excised, ME are usually cured completely. However, in adults, ME at the sacrococcygeal region metastasizing to organs outside central nervous system has rarely been reported so far.(3-5) Herein, we report an extremely rare case of an inguinal lymph node metastasis developed 19 years after removal of primary ME at the sacrococcygeal region, which presented with unusually severe back and hip pain. Because the metastasis of ME to the lymph node after such a long time is rare, our case may contribute to improving the differential diagnosis of extremely rare metastatic ME cases and identifying their unexpected role in the pain of unknown origin.

Purpose To demonstrate a novel frozen section analysis technique during robot assisted radical prostatectomy with 2 distinct advantages: evaluation of the entire circumference and easier reconstruction for whole mount evaluation. Material and methods Istanbul Preserve was performed on patients who underwent robotic prostatectomy with nerve sparing between 10/2014 and 7/2016. Gland was sectioned at 3–4 mm intervals from apex to bladder neck. Entire tissue representing margins (except for the most anterior portion) was circumferentially excised and microscopically analyzed. In margin positivity, approach was individualized based on extent of positive margin and Gleason pattern. A matched cohort was established for comparison. Retrospective analysis of a prospectively maintained database was performed. Impact of FSA on PSM rate was primarily assessed. Results Data on 170 patients was analyzed. Positive surgical margin was reported in 56(33%) on frozen section. Neurovascular bundle was partially or totally resected in 79% and 18%. Conversion of positive margin to negative was achieved in 85%. Overall positive margin rate decreased from 22.5% to 7.5%. Nerve sparing increased from 87% to 93%. Location of positive margin at frozen was at the neurovascular bundle area in 39%; thus Istanbul Preserve detected 61% additional margin positivity compared to other techniques. Reconstruction for whole mount was easy. Conclusion Istanbul Preserve is a novel technique for intraoperative FSA during RARP allowing for microscopic examination of the entire prostate for margin status and easy re-construction for whole mount examination. It guarantees safer margins together with increased rate of nerve sparing.

Exercise training is known to have multiple beneficial effects on type 2 diabetes mellitus (T2DM). The aim of this study was to explore the effects of aerobic exercise frequency on diabetic parameters, the histopathological structure of skeletal muscle, diabetic myopathy, and mitochondrial enzyme activity in an experimental model of T2DM.Sprague-Dawley rats (n = 35) were rendered diabetic by injection of nicotinamide (110 mg/kg) and streptozotocin (65 mg/kg). Rats with blood glucose concentrations between 7 and 17 mmol/L were used. Diabetic rats were randomly allocated to one of the following groups: (i) control sedentary; (ii) diabetic sedentary; (iii) diabetic with continuous exercise (30 min/day, 5 days/week); (iv) diabetic with short bouts of exercise (3 × 10 min/day, 5 days/week); and (v) diabetic rats as "weekend warriors" (35 + 40 min/day, 2 days/week). After 6 weeks swimming exercise (total duration 150 min/week), biochemical tests were performed to measure insulin, glucose, cytokines, serum and muscle myeloperoxidase (MPO), and malondialdehyde (MDA) levels. Histologic analysis (histomorphometric and mitochondrial enzyme analysis) was also performed.Compared with diabetic sedentary rats, significant improvements were observed in all exercise groups in terms of glucose levels, weight loss, tissue MPO and MDA levels, muscular connective tissue, muscle atrophy, mitochondrial enzyme, and all histomorphometric analyses.The results of the study emphasize the effects of training on inflammation, increased oxidative stress, myopathy, and mitochondrial damage in a rat model of T2DM, and demonstrate that there is no major difference between exercise modalities provided that the total duration of exercise remains the same.

The menopause has a negative effect in the skin. Melatonin affects skin functions and structures through actions mediated by cell-surface and putative-nuclear receptors expressed in skin cell. We have therefore determined the effects of melatonin treatment on stem cell in the epidermis and extracellular matrix related molecules in the dermis the skin of postmenopausal rats. A total of 45 female rats were divided into 5 groups: control group, group A [ovariectomy (OVX)], group B (OVX +10 mg/kg/day melatonin), group C (OVX +30 mg/kg/day melatonin), group S (sham operated + 10 mg/kg/day melatonin). Ventral skin samples were excised at 12th week after ovariectomy. Hematoxylin-eosin, periodic acid- methylamine silver, elastic van Gieson staining techniques were used to measure histomorphometrically the thickness of elastic fibers and basement membrane, depths of the epidermis, dermis, and subcutaneous fat layer. Immunohistochemical staining methods were used for fibroblast growth factor β (FGF β), collagen type I, fibronectin, β-catenin, c-kit, c-Myc evaluation. Epidermal thickness, subcutaneous fat layer, and elastic fibers were significantly decreased in group C, and there was a significant increase after melatonin treatment. Although there was no difference in dermal thickness of group C, melatonin also significantly increased the dermal thickness. High FGF β, type I collagen, fibronectin, β-catenin, c-Myc immunoreactivity developed following melatonin in all groups. Thus melatonin treatment of postmenopausal rats was mostly due to the decrease of stem cell and extracellular matrix-related molecules in the skin.

e15538 Background: The aim of this study was to evaluate the prognostic role of microsatellite instability (MSI) status and PD-L1 expression in surgically resected gastric cancer and the relationship of these parameters with clinicopathological features. Methods: Eighty six gastric cancer patients which had curative surgical resection at Acibadem Atakent and Maslak Hospitals between 2010 and 2017 were analysed. Tumor samples were evaluated with MSI and PD-L1 antibodies by immunohistochemical (IHC) methods. PD-L1 IHC scoring was performed using the combined positive score (CPS). Survival analysis was accomplished using the Kaplan-Meier method. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival. Results: The rate of PD-L1 expression in tumor cells was 34.9% (n = 30) and the frequency of PD-L1 expression in immune cells with CPS (≥1%) was 57% (n = 49). MSI-H was detected in 11.6%(n = 10), and more observed in PD-L1 positive cases (p = 0.021). MSI-H status was significantly correlated with older age, increased tumor size, presence of PD-L1 expression, and adenocarcinoma subtype. PD-L1 expression was associated with lymph node metastasis, adenocarcinoma subtype, microsatellite instability, presence of preoperative treatment and improved response to preoperative chemotherapy. In our study, the impact of MSI status on survival was not demonstrated, but PD-L1 expression positivity(≥1%) in both tumor cells (15.7 vs 53.4 months, p = 0.008)and in immune cells (20.4 vs NR; p = 0.027) was associated with short overall survival. PD -L1 expression in tumor cells was an independent prognostic factor for overall survival in multivariate analysis (HR: 2.28, p = 0.047). Conclusions: PD-L1 expression was related to a poor prognosis in patients with gastric cancer and can represent a rational approach for PD-1/PD-L pathway-targeted immunotherapy.

At the cellular level, spinal cord injury (SCI) provokes an inflammatory response that generates substantial secondary damage within the spinal cord but may also contribute to its repair. Besides intracellular antioxydant increase after exactly estimated oxidative stress; oxygen formation and transport is also advanced by ozone. The Wnt family of proteins contributes to the development of the nervous system, influencing cell proliferation. In the present study we evaluated the effect of ozone on spinal cord injury in rats.Twenty-one male Sprague-Dawley rats were used. The rats were randomly allocated into three groups (control, trauma and trauma+ozone). SCI was inflicted using Allen"s spinal cord trauma method. The study was performed to determine the effects of ozone therapy on rats with SCI in terms of locomotor strength clinically and neuronal injury, white matter cavitation, edema, number of blood vessels, and expression of β-catenin immunohistochemically.Comparison of the locomotor strength scores revealed a significant improvement on day 7 in trauma+ozone group. The groups were compared with regard to edema, neuronal injury, and white matter cavitation. Average β-catenin levels were significantly different between the control group (68.11 ± 0.43), trauma+ozone group (37.96 ± 2.16), and trauma group (25.46 ± 1.07) (F = 1677.74, df = 2, p0.0005).The results of this study indicated that ozone therapy accelerates the healing process, increases vascularity, and reduces neuronal damage in rodents, suggesting that ozone therapy may be an adjuvant treatment in patients with SCI.

The BRAFOur aim was to evaluate the prevalence of the BRAFThis retrospective study included 51 PTC patients (40 women, 11 men; mean age 40.0 ± 16.5 years; range 6-81) who underwent total thyroidectomy accompanied by a lateral neck dissection due to preoperatively detected LNM. Real-time PCR was used for the detection of the BRAFThe prevalence of the BRAFIn our study, the BRAF