Mistletoe (Viscum album L.) extract attenuates itraconazole-induced acute oxidative stress and hepatocellular injury in rats.

In the current study, the protective effect of a mistletoe extract (Helixor®, HLX) on Itraconazole (ITZ)-induced hepatocellular injury and acute oxidative stress in rats was aimed to be investigated by histological, biochemical and comet assay methods. Four groups a control group, an HLX group (5mg/kg/14days/intraperitoneally (ip)), an ITZ group (100mg/kg/14days/oral) and an HLX plus ITZ group (5mg/kg/14days/ip+100mg/kg/14days/oral) were all created from 32 female Wistar albino rats. At the end of the experiment, AST and ALT liver enzymes, total oxidant status (TOS) levels and total antioxidant status (TAS) levels, histopathological analysis and comet assay were carried out. Highest genotoxicity, higher levels of plasma AST and ALT, higher TOS, more degeneration of liver histopathology including hepatocyte degeneration, hepatocyte apoptosis and necrosis, portal/periportal inflammation, bile ductus hyperplasia and multinuclear giant cell formation were observed in ITZ group (p<0.05). As opposed to that, administration of HLX plus ITZ improved histopathological changes and DNA damage and showed a dramatic decrease in AST, ALT and TOS levels (p<0.05) and an increase in TAS level (p<0.001) when compared to ITZ group. This study showed that the antioxidant properties of HLX administration significantly decreased acute oxidative stress and hepatocellular damage in rats given ITZ.

First Case Report Of Anca-Associated Vasculitis And Anthracosis Coexistence.

Anthracosis is a type of mild pneumoconiosis secondary to harmless carbon dust deposits. Although anthracosis was previously associated with inhaled coal particles, such as coal workers' pneumoconiosis, this hypothesis was later abandoned; pathology has been associated with inhaled dust particles. Our paper is the first case report of ANCA-associated vasculitis and anthracosis coexistence. In addition, it aims to highlight that histopathologically proven anthracotic granulomatous nodules can show high FDG uptake in PET/CT contrary to expectation. We present a case of a 73-year-old male with p-ANCA-associated vasculitis and anthracotic lung nodules accompanied by radiological and clinical findings. The patient got diagnosis with p-ANCA-associated vasculitis with serological and rheumatological tests. Atypically, the clinical findings of the patient were weak (No dyspnoea, cough or additional pulmonary complaints). Nodules were present on X-ray graphics and nodules' contours were irregular on CT. On PET/CT, SUV values of the nodules were high [12 kBq/mL]. Histopathological specimens showed multiple lung granulomas including anthracosis particles. Until performing the biopsy, we could not exclude the possibility of malignancy. Conclusion: When lung involvement of vasculitis is superimposed by anthracosis, it can create granulomas with high SUV values. The relationship between anthracosis and parenchymal lung diseases is a current topic and many recently published papers are present on this subject. To the best of our knowledge, our paper is the first paper showing the relationship between parenchymal involvement of vasculitis and anthracosis in the literature. Environmental pollution and dust particles are the known reasons for anthracosis particles in the nodules. It is open to future research on whether air pollution triggers new atypical cases or not.

68-months progression-free survival with crizotinib treatment in a patient with metastatic ALK positive lung adenocarcinoma and sarcoidosis: A case report.

INTRODUCTION: Lung cancer still ranks first among the most common and most lethal cancers today. The most common subtype is non-small cell lung cancer, and in this group, adenocarcinoma has the worst prognosis. EGFR, ROS1 and ALK-EML4 gene fusion mutations are common in non-small cell lung cancer. CASE REPORT: A 62-year-old non-smoker patient applied in February 2014 for purulent sputum and pain in the chest. Computed tomography revealed a 39x33 mm mass in the right hilum, multiple parenchymal nodules in the bilateral lung and mediastinal multiple enlarged lymph nodes. The patient was admitted to the lung adenocarcinoma as a result of a biopsy from the mass in the hilum, and sarcoidosis was diagnosed by mediastinal lymph node biopsy. MANAGEMENT & OUTCOME: After 4 cycles of carboplatin-pemetrexed for the first line treatment, progression was detected. The patient did not have EGFR and ROS1 mutations. The patient with positive ALK fusion mutation started crizotinib treatment in July 2014. The patient's last response assessment was in March 2020, with 68-progression-free disease with crizotinib. No toxicity was observed except for Grade 1 weakness. No dose changes were made. The patient is still being followed up without brain metastasis under the treatment of crizotinib. DISCUSSION: In this article, we wanted to share our experience of crizotinib in a 68-months progression-free survival in a 62-years old non-smoking female patient with metastatic lung adenocarcinoma who is also diagnosed with sarcoidosis.

Idiopathic focal organizing pneumonia mimicking malignancy.

Idiopathic FOP is a rare type of COP. What we know on this subject is made up of a few clinical cases published in recent years. Our patient was admitted to the hospital with an intermittent coughing complaint that worsens over time. Due to a suspicion of malignancy, a radiological evaluation was requested including a PET-CT and a transbronchial biopsy was performed. Until the last part of our algorithm, the patient profile was clinically and radiologically in favor of the diagnosis of malignancy but, in the end, the diagnosis of FOP was fixed with a follow-up decision. In conclusion, FOP is a relatively new entity that should be kept in mind in the differential diagnosis of malignancy.

Can TROP2 be used as a prognostic marker in endometrioid endometrial carcinoma?

BACKGROUND: Endometrioid-type endometrial carcinoma is the most common malignancy of the female genital tract in developed countries. The prognosis greatly depends on the grade and stage of the disease. AIMS: In some patients, the disease recurs in a short time after the surgical/medical therapy. Hence, it is important to predict the patients who will have worse prognosis at the beginning, to choose the appropriate treatment; resuming the search of new prognostic markers. Therefore, our study aimed to detect trophoblast cell surface antigen 2 (TROP2) as a new prognostic marker. SETTINGS AND DESIGN: The patients who underwent a hysterectomy and diagnosed with endometrioid-type endometrial carcinoma were evaluated retrospectively and TROP2 immunostain was performed to their tumoral slides. MATERIALS AND METHODS: We evaluated TROP2 expressions in 102 patients immunohistochemically who underwent hysterectomy with the diagnosis of endometrioid-type endometrial carcinoma histopathologically and correlated them with the other generally accepted prognostic parameters. STATISTICAL ANALYSIS: The Kolmogorov-Smirnov test and Q-Q plot test were used to verify the normality of the distribution of continuous variables. The Chi-square/Fisher's exact tests were used for categorical variables. Analyses were performed with SPSS Statistics for Windows, Version 20. RESULTS: High overexpression of TROP2 was seen in larger, higher-grade, deeper-invasive tumors, tumors with vascular invasion, and pelvic-lymph-node metastasis. These results were statistically significant (P ≤ 0.05). CONCLUSION: Overexpression of TROP2 in endometrioid-type endometrial carcinoma seems to be a poor prognostic factor; it may be useful in determining the biologically more aggressive tumors before the treatment. This early determination is very important to choose the appropriate surgery, adjuvant-treatments, and follow-up.

A grading dilemma; Gleason scoring system: Are we sufficiently compatible? A multi center study.

OBJECTIVE: Gleason scoring is the grading system which strongly predicts the prognosis of prostate cancer. However, even being one of the most commonly used systems, the presence of different interobserver agreement rates push the uropathologists update the definitons of the Gleason patterns. In this study, we aimed to determine the interobserver agreement variability among 7 general pathologists, and one expert uropathologist from 6 different centers. METHODS: A set of 50 Hematoxylin & Eosin stained slides from 41 patients diagnosed as prostate cancer were revised by 8 different pathologists. The pathologists were also grouped according to having their residency at the same institute or working at the same center. All pathologists' and the subgroups' Gleason scores were then compared for interobserver variability by Fleiss' and Cohen's kappa tests using R v3.2.4. RESULTS: There were about 8 pathologists from 6 different centers revised all the slides. One of them was an expert uropathologist with experience of 18 years. Among 7 general pathologists 4 had surgical pathology experience for over 5 years whilst 3 had under 5 years. The Fleiss' kappa was found as 0.54 for primary Gleason pattern, and 0.44 for total Gleason score (moderate agreement). The Fleiss' kappa was 0.45 for grade grouping system. CONCLUSION: Assigning a Gleason score for a patient can be problematic because of different interobserver agreement rates among pathologists even though the patterns were accepted as well-defined.

Upregulation of SIRT1 gene in gastric adenocarcinoma.

BACKGROUND/AIMS: SIRT1 gene overexpression is reportedly associated with cancer development, via the triggering of DNA repair impairment, and cell proliferation. The study aimed to investigate SIRT1 expression in patients with gastric cancer and its correlations with the clinical and pathological characteristics of the disease. MATERIALS AND METHODS: All patients (64 patients) who underwent gastric biopsy and were diagnosed with gastric adenocarcinoma and signet ring cell carcinoma between January 2011 and December 2013 were enrolled in the study, and patients with benign gastric biopsy were enrolled in the control group (34 patients). The previously prepared gastric tissues were collected from the pathology department, and SIRT1 gene expressions were evaluated in the gastric tissues of all study patients. Patients were subclassified according to their demographic, clinical, and pathologic features, and the patient and control groups were compared. RESULTS: Sixty-four patients were included in the study (25 females and 39 males). The mean age of the patients was 66±1 (range: 33-88) years. The SIRT1 gene 2' Average delta cycle threshold (CT) value was 0.102 in the control group, whereas it was 0.292 in the patients with gastric cancer (relative risk: 2.86; p=0.014). The SIRT1 gene was upregulated in all tumor stage subgroups except stage I, female patients, young patients (<45 years), and corpus and cardia tumor subgroups compared to the control group. CONCLUSION: SIRT1 gene overexpression is associated with gastric adenocarcinoma, and it can be argued that SIRT1 gene upregulation is associated with unfavorable gastric adenocarcinoma prognosis.

Where do these guests come from? A diagnostic approach for metastatic lymph nodes.

OBJECTIVE: In cases presenting with lymphadenopathies (LAP) without a primary focus detected by simple radiological methods, the primary tumor can be diagnosed by a histopathological evaluation of the metastatic lymph nodes. We aimed to discuss the nonhematological malignancies presenting with lymphadenopathies and the histopathological results for primary tumors. MATERIAL AND METHODS: In this retrospective study, cases diagnosed with metastasis in excisional lymph nodes between January 2013 and June 2016 were assessed for a histopathological diagnostic approach. RESULTS: Among 632 lymph node biopsies, a total of 21 cases, involving 12 male and 9 female patients with a mean age of 57.23 y (range, 33-92 y), of nonhematological solid tumors were included. The most common localizations of the involved lymph nodes were inguinal (n=8), axillary (n=6), cervical (n=4), and supraclavicular (n=3) region. The most common primary tumors were malignant melanoma (n=6), breast carcinoma (n=4), ovarian carcinoma (n=2), squamous cell carcinoma (n=2), and germ cell tumor (n=2). Others were papillary thyroid carcinoma, renal cell carcinoma, urothelial carcinoma, prostate adenocarcinoma, and endometrial adenocarcinoma. CONCLUSION: Nonhematological malignancies presenting with lymphadenopathies are one of the most complicated cases for clinicians. The histopathological evaluation of the excisional metastatic lymph node biopsies is an important method because of cost effectiveness and easy applicability.

A rare soft tissue tumor located in the trunk: Ossifying fibromyxoid tumor.

Ossifying fibromyxoid tumor (OFMT), a rare soft tissue tumor, is generally located in the extremities with a distinct morphology characterized by bland, small cells lying in a fibromyxoid stroma and a peripheral rim of the lamellar bone. These tumors mostly express Leu-7, neuron specific enolase in addition to S-100 and vimentin. Some tumors may have malignant cytological features with aggressive behavior but even in classical morphology, recurrence or metastasis can be detected. Thus, the outcome of the tumor remains a mystery and depends on the different results detected during the follow up. Herein, we report a case of OFMT regarding this entity in the differential diagnosis of subcutaneous masses.

Nodular Fasciitis of the Neck Causing Emergency: A Case Report.

Nodular fasciitis is a benign, reactive, tumor-like lesion composed of fibroblasts and myofibroblasts. It typically occurs in the extremities and the trunk. Head and neck localization is 13-20%. As it grows rapidly, clinicians frequently misdiagnose it as an aggressive or a malignant lesion. Some lesions show moderate cellularity, mild cellular atypia, and mitosis histologically causing pathologists to over-diagnose the lesion as a malignant tumor. It is important to diagnose nodular fasciitis correctly to avoid unnecessary additional surgery and treatment. We report the case of an 82-year-old woman who was admitted to the emergency department with a one-month history of progressive shortness of breath. We found a mass in the patient's neck, invasive to the trachea, which was the cause of her symptom. Complete radical surgery of the mass with the larynx was impossible due to her general status. The mass was treated by local radiotherapy; however, no regression was seen in the size of the mass. The patient is still on follow-up with only symptomatic medical support for airway obstruction.

MTUS1 tumor suppressor and its miRNA regulators in fibroadenoma and breast cancer.

Breast cancer is major public health problem predominantly effects female population. Current therapeutic approaches to deal with breast cancer are still lack of effectiveness. Thus, identifying/developing novel strategies to fight against breast cancer is very important. The frequent deletions at 8p21.3-22 chromosomal location nearby D8S254 marker enabled the discovery of a novel tumor suppressor gene, MTUS1. Subsequently, MTUS1 was demonstrated to be less expressed in a variety cancer types including breast cancer. Also, it is obvious that gene expression is widely regulated by miRNAs. Here, we aimed to report differential expression of MTUS1 and its regulatory miRNAs in breast cancer and fibroadenoma tissues. Dynamic analysis of MTUS1 expression levels and its miRNAs regulators were attained by Fluidigm 96×96 Dynamic Array Expression chips and reactions were performed in Fluidigm BioMark™ HD System qPCR. Consequently, MTUS1 mRNA levels were significantly diminished in breast cancer tissues and elevated in fibroadenoma tissues. Also, among MTUS1 targeting miRNAs, miR-183-5p was identified to be overexpressed in breast cancer and down-regulated in fibroadenoma tissues. Also, expression levels of MTUS1 and miR-183-5p were well correlated with clinical parameters. In particular, MTUS1 expression was found to be diminished and miR-183-5p expression was elevated with the advancing stage. In conclusion, as a potential therapeutic target, miR-183-5p can be a chief regulator of MTUS1 and MTUS1-miR-183-5p axis may have significant influence in the pathology of breast cancer.

MTUS1 and its targeting miRNAs in colorectal carcinoma: significant associations.

Deregulated microRNA (miRNA) expression has been shown to be involved in the pathogenesis of several types of cancers including colorectal cancer (CRC). Thus, determining miRNA targets of genes that play critical role in the malignant transformation is very important. Here, expression levels of tumor suppressor microtubule-associated tumor suppressor 1 (MTUS1) and its regulatory miRNAs were reported. Predicted and validated targets of MTUS1 gene was determined by a computational approach. Expressions of MTUS1 and miRNAs were determined by using 96.96 Dynamic Array™ integrated fluidic circuit (Fluidigm). As a result, MTUS1 levels were found to be diminished in formalin-fixed, paraffin-embedded (FFPE) tissue samples of CRC patients compared to controls. Also, several of MTUS1 targeting miRNAs were found to be upregulated in CRC samples (miR-373-3p, 183-5p, 142-5p, 200c-3p, 19a-3p, -20a-5p, -181a-5p, -184, -181d-5p, -372-3p, 27b-3p, 98-5p, -let-7i-5p, -let-7d-5p, -let-7g-5p, -let-7b-5p, and -let-7c-5p). Of these miRNAs, miR-135b-5p, -373-3p, 183-5p, 142-5p, 200c-3p, 19a-3p showed marked expression levels. In contrast, expression levels of let-7a-5p, 7e-5p, 7f-5p, hsa-miR-125a-5p, and 125b-5p were found to be downregulated in CRC tissues. Accordingly, some of the overexpressed miRNAs especially the miR-135b-5p, -373-3p, 183-5p, 142-5p, 200c-3p, and 19a-3p may play key roles in CRC pathophysiology through MTUS1. In contrast, let-7a-5p, 7e-5p, 7f-5p, miR-125a-5p, and 125b-5p may play important roles in CRC carcinogenesis independent from the MTUS1. In conclusion, MTUS1 targeting miRNAs may play key roles in the development of CRC by downregulating tumor suppressor MTUS1.

Differential expressions of cancer-associated genes and their regulatory miRNAs in colorectal carcinoma.

Colorectal cancer is one of the frequently seen malignancies in the world. To date, several oncogenes and tumor suppressor genes have been identified and linked to colorectal cancer pathogenesis. Although recent advances in the diagnosis and therapy of colorectal cancer are promising, identifying novel genetic contributors is still high priority. In the present study, expression profile of some cancer-related genes and their regulatory miRNA molecules were evaluated by using a high-throughput real-time PCR method. For the study, a total of 54 patients diagnosed with CRC and normal colon tissue samples of 42 healthy controls were included. For the expression analysis, total RNA was extracted from FFPE tissue samples and converted to cDNA. All expression analyses were assessed by using Fluidigm Microfluidic Dynamic Array chips for 96 samples and the reactions were held in Fluidigm BioMark™ HD System Real-Time PCR. As a result of the study, expression of the ADAMTS1, FHIT, RUNX1, RUNX3 and WWOX genes was shown to be significantly altered in CRC tissues in contrast to normal tissue samples. Moreover, miR-378a-3p, miR-155-5p, miR-193b-3p, miR-96-5p, miR-17-5p, miR-27a-3p, miR-133b, miR-203a, miR-205-5p, miR-34c-5p, miR-130a-3p, miR-301a-3p, miR-132-3p, miR-222-3p, miR-34a-5p, miR-21-5p, miR-29a-3p and miR-29b-3p were found to be significantly deregulated in CRC. Consequently, results of the current study strongly suggest the involvement of novel cancer-related genes and their regulatory miRNAs in CRC physiopathology.

Evaluation of the protective effect of silibinin against diazinon induced hepatotoxicity and free-radical damage in rat liver.

BACKGROUND: Diazinon (0,0-Diethyl 0-(1-6-methyl-2-isoprophyl 4 pyrimidinyl) phosphorothioate) (DI) is a very effective organophosphate pesticide, used widely in agriculture. Consequently, data on poisoning cases secondary to DI exposure are important. The DI may affect a variety of tissues, including liver. Silibinin is a pharmacologically active constitute of Silybum marianum, with documented antioxidant activity. OBJECTIVES: The aim of our study was to evaluate both histopathologically and biochemically whether silibinin is protective in DI induced liver damage. MATERIALS AND METHODS: Thirty two Wistar albino rats were divided into four groups, as follows: 1) control group - oral corn oil was given; 2) DI group - rats were administered orally 335 mg/kg in the corn oil solution; 3) Silibinin group - 100 mg/kg/day silibinin was given alone orally, every 24 hours for 7 days; 4) Silibinin + DI group - DI plus silibinin was given. All rats were sacrificed at the end of experiment. Superoxide dismutases (SOD), glutathione peroxidase (GPX), nitric oxide (NO) and myeloperoxidase (MPO) were investigated in serum and liver tissue. In addition, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzyme activities were evaluated. The liver tissue was evaluated histopathologically with Hematoxilin & Eosin dye. RESULTS: Biochemically, ALT, AST, NO, MPO in serum and NO, MPO in liver tissue were found to be significantly higher in DI group, compared to control group (P < 0.001). In Group Silibinin + DI, serum AST, ALT, NO, MPO levels were significantly lower (P < 0.01), and both serum and tissue SOD activities were significantly higher, compared to DI group (P < 0.001). Diazinon induced histopathological changes in liver tissue were: severe sinusoidal dilatation, moderate disruption of the radial alignment of hepatocytes around the central vein, severe vacuolization in the hepatocyte cytoplasm, inflammation around central vein and portal region. In rats receiving both DI and silibinin, the DI induced changes accounted for less sinusoidal dilatation, vacuolization in the hepatocyte cytoplasm and the inflammation around central vein and portal region (P < 0.05). CONCLUSIONS: The DI was found to induce liver damage by oxidative stress mechanisms. Silibinin reduced the oxidative stress by inducing antioxidant mechanisms, thereby showing protective effect against DI induced liver damage. Further studies with silibinin should be performed regarding DI toxicity.

Evaluation of the protective effect of silibinin in rats with liver damage caused by itraconazole.

Itraconazole (ITZ) belongs to the triazole group of antifungals with potent keratinophilic and lipophilic features. Hepatotoxicity is one of its most remarkable features. Silibinin (SIL) is a plant used worldwide which is used in the treatment of many liver diseases and it is especially very well known for its hepatoprotective-cytoprotective effect. The aim of our study was to research the protective effect of SIL in ITZ-induced hepatotoxicity using biochemical and pathological tests. Liver enzymes and antioxidant enzyme activities were measured spectrophotometrically by using commercial kits. ALT and AST levels in ITZ group were significantly increased compared to the group, while the activities of GSH-Px and SOD had decreased (p < 0.05). When ITZ group was compared to ITZ + SIL group, AST, ALT, and levels of NO and MPO were significantly decreased, while the activities of GSH-Px and SOD were increased (p < 0.05). Histopathological evaluation showed that SIL significantly decreased periportal inflammation and parenchymal hepatocyte apoptosis in ITZ and ITZ + SIL groups (p < 0.05). Eventhough not statistically significant, partial improvement with the use of SIL has been detected (p > 0.05) in hepatocyte degeneration and multinuclear giant cell formation. According to the evaluation performed with comet assay method, ITZ leads to DNA damage, and the use of SIL significantly decreases DNA damage (p < 0.05). We have detected that the use of ITZ increases oxidative stress (MPO, NO), decreases antioxidant activity (SOD and GSH-Px), and leads to DNA damage and histopathological liver damage, whereas the use of SIL has a cytoprotective effect on the liver by increasing the antioxidant effect (SOD, GSH-Px) and by decreasing the oxidative stress (NO, MPO). ITZ causes the generation of ROS and leads to DNA damage and liver damage. SIL has a cytoprotective effect on the liver by increasing antioxidant enzyme activities, preventing the formation of ROS.

Bilateral multifocal Warthin tumours.

Warthin tumour, also known as papillary cystadenoma lymphomatosum, is the second most frequent benign tumour of the parotid gland after pleomorphic adenoma. A 57-year-old man was referred to our hospital with bilateral buccal masses without pain. He presented with a 1-year history of the condition and stated that growth of the mass has accelerated during the last 6 months. Ultrasonography examination showed two heterogeneous solid masses. Axial contrast-enhanced CT image revealed bilateral heterogeneous solid masses. The masses showed enhancement after contrast administration (95 HU). Fine needle aspiration cytology was recommended for further analysis and typical benign features of Warthin tumour was obtained. Right parotid gland including the masses was resected completely. 5 weeks later superficial parotidectomy was performed to the left parotid gland. Histological examination revealed cystic tumour in the parenchyma of parotid gland, composed of prominent lymphoid stroma and large epithelial cells with oncocytic features covering it consistent with Warthin tumour.