Hayriye Tatli Dogan

Phenotype 2 familial mediterranean fever: evaluation of 22 case series and review of the literature on phenotype 2 FMF.

Familial Mediterranean fever (FMF) is an autosomal recessive autoimmune disorder characterized by recurrent bouts of fever and serosal inflammation. FMF may be complicated by AA-type amyloidosis, worsening the prognosis, with associated renal failure in some patients. Complication rate varies with race, being as high as 60% in Turks and as low as 2% in Armenians. In a few cases of patients with FMF (phenotype 2), amyloid nephropathy may be the presenting manifestation. This study included 420 patients who were admitted to the Nephrology and Rheumatology Departments of Atatürk Education and Research Hospital with unexplained proteinuria/nephrotic syndrome. The initial screening test for amyloidosis was the presence of significant proteinuria (300 mg/24 h). All MEFV gene exons were screened for causative mutations by direct DNA sequencing to check for any mutations. There were 22 phenotype 2 FMF patients with 27 allelic variants. The most prevalent allelic variants were M694V (10/27, 37%) and E148Q (7/27, 26%). Phenotype 2 FMF is not as rare as it was thought before; this should be kept in mind for all patients with unexplained proteinuria and/or acute phase response in high-risk ethnic groups for FMF.

The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer

Tumor cells develop drug resistance which leads to recurrence and distant metastasis. MicroRNAs are key regulators of tumor pathogenesis; however, little is known whether they can sensitize cells and block metastasis simultaneously. Here, we report miR-644a as a novel inhibitor of both cell survival and EMT whereby acting as pleiotropic therapy-sensitizer in breast cancer. We showed that both miR-644a expression and its gene signature are associated with tumor progression and distant metastasis-free survival. Mechanistically, miR-644a directly targets the transcriptional co-repressor C-Terminal Binding Protein 1 (CTBP1) whose knock-outs by the CRISPR-Cas9 system inhibit tumor growth, metastasis, and drug resistance, mimicking the phenotypes induced by miR-644a. Furthermore, downregulation of CTBP1 by miR-644a upregulates wild type- or mutant-p53 which acts as a ‘molecular switch’ between G1-arrest and apoptosis by inducing cyclin-dependent kinase inhibitor 1 (p21, CDKN1A, CIP1) or pro-apoptotic phorbol-12-myristate-13-acetate-induced protein 1 (Noxa, PMAIP1), respectively. Interestingly, an increase in mutant-p53 by either overexpression of miR-644a or downregulation of CTBP1 was enough to shift this balance in favor of apoptosis through upregulation of Noxa. Notably, p53-mutant patients, but not p53-wild type ones, with high CTBP1 have a shorter survival suggesting that CTBP1 could be a potential prognostic factor for breast cancer patients with p53 mutations. Overall, re-activation of the miR-644a/CTBP1/p53 axis may represent a new strategy for overcoming both therapy resistance and metastasis.

Diagnostic accuracy of Thyroid Imaging Reporting and Data System in the prediction of malignancy in nodules with atypia and follicular lesion of undetermined significance cytologies

Thyroid Imaging Reporting and Data System (TIRADS) is a simple and reliable reporting system for the prediction of malignancy. We aimed to determine the role of TIRADS in the prediction of malignancy in subcategories of Bethesda Category III, atypia of undetermined significance (AUS) and follicular lesion of undetermined significance (FLUS).

Retrospective analysis of oncogenic human papilloma virus and Epstein-Barr virus prevalence in Turkish nasopharyngeal cancer patients.

Nasopharyngeal carcinoma (NPC) is associated with the Epstein-Barr virus (EBV). Human papilloma virus (HPV) has also been detected in NPC cases. In this retrospective study, we analyze the frequency of EBV and HPV infection in 82 Turkish patients with NPC. A total of 82 were evaluated for EBV and HPV. In situ hybridization (ISH) was performed for EBV. HPV-ISH and P16 immunohistochemistry used to determine the HPV status. Seventy-two of the 82 (87%) NPC patients were EBV-positive. The highest rate of EBV-positivity was found in undifferentiated NPC patients, which accounted for 65 of 68 (95.6%) undifferentiated cases. One of the 82 NPC patients whose tumor was non-keratinizing differentiated, contained HPV. Our data shows that EBV is closely associated with NPC in Turkey. We found lower rates of HPV-positivity in NPC patients than in North American populations. In addition, both EBV and HPV-negativity were more associated with decreased survival than EBV-positive cases.

Clinical and pathological features of squamous cell carcinoma of the lip

Lip cancers are one of the most common cancers in the head and neck regions and constitute 25%–30% of all oral cavity cancers (1). Lip cancer is located on the lower lip in 87.2%–90% of the patients (2,3). Squamous cell carcinoma (SCC) constitute 95% of the lip cancers (4-6). Lower lip SCCs are most commonly seen in Caucasian male smokers. They are often seen in the sixth decade of life. Etiology is multifactorial, but prolonged sun exposure has a major role. Histological changes, such as leukoplakia, hyperkeratosis, and actinic cheilitis, are also observed in adjacent tissues. Besides, sun rays, pipe and cigarette smoking, bad dental hygiene, chronic alcoholism, and immunosuppression also contribute to tumor development. The standard treatment for lip cancer is surgical excision and reconstruction (7). Surgical excision should be done carefully and the excisional material and its boundaries should be subjected to histopathological examination in three dimensions to obtain the highest cure rate and the smallest defect size (8). A probability exists of recurrence and regional metastasis in 5%–15% of all lower lip SCCs (9). Distant metastasis is expected in 15% of these patients. Histopathologically, tumor thickness is a determining factor for regional metastasis. Therefore, it is an important criterion in treatment planning (10). In the present study, 40 patients with lip SCC were reported. The purpose of the study was to evaluate these patients in terms of epidemiology, histopathology, and recurrence.

Is there a difference in the number of interstitial cells, neurons, presence of fibrosis and inflammation in ureteropelvic junction tissues of patients with ureteropelvic junction obstruction with and without crossing vessels?

OBJECTIVE We compared the number of interstitial cells (ICs), nerves, presence of fibrosis and inflammation at the level of full-thickness human ureteropelvic junction (UPJ) tissues obtained from normal subjects, and patients with UPJ obstruction with and without crossing vessels. MATERIAL AND METHODS Normal UPJ tissues (n=12) histopathologically confirmed to be without tumor involvement were obtained from subjects who underwent radical nephrectomy for kidney mass. Additional UPJ tissues were obtained from patients who underwent pyeloplasty due to UPJ obstruction. Crossing vessel was identified in 17 patients. In 57 patients, no crossing-vessel was noted. ICs were stained immunohistochemically with anti-human CD117 (c-kit) antibody. Neural tissue was stained with S-100. The numbers of ICs and neurons were compared between the groups: controls with normal UPJ (Group I), Ureteropelvic junction obtruction (UPJO) with crossing vessel (Group II) and UPJ obstruction without crossing vessel (Group III). Groups were also compared in terms of the presence of fibrosis and inflammation. RESULTS The mean age of total population included in the study was 30.5±18.5 years. No significant differences were detected between the three groups regarding mean and median numbers of ICs at the level of UPJ (lamina propria and muscle layer) and mean and median numbers of neurons at the level of lamina propria (p>0.05). Likewise, no significant differences were detected between the three groups regarding the presence of fibrosis and inflammation (p>0.05). CONCLUSION Number of ICs, neurons, presence of fibrosis and inflammation seem to be similar in the intact UPJ and UPJ with obstruction with and without crossing vessel. Cellular function rather than the number ICs might play a role that warrants further research.

Evaluation of p53 and ki67 expression profiles in basal cell carcinomas in a usual and an unusual location

OBJECTIVE Owing to their importance in cell proliferation in cutaneous malignancies, we aimed to immunohistochemically compare the expression profiles of p53 and Ki67 in basal cell carcinoma (BCC) cases in both a usual and an unusual locations in this study. MATERIAL AND METHOD In this study we included 12 in an unusual location of BCC cases and 21 BCC cases in a usual location. Immunohistochemical expression of p53 and Ki67 antibodies were studied in 33 paraffin-embedded tissue specimens of basal cell carcinoma. We compared the p53 and Ki67 staining scores with clinicopathologic features. RESULTS The tumor size was found to be greater in BCC cases in an unusual location than those in a usual location. The relationship between age and tumor size was also evaluated in both groups and it was found that tumor size increased with age. A comparative study between the two groups showed no difference p53 and Ki67 expression percentages. There was a linear correlation between the Ki67 and p53 marker staining rates (ρ=0.420; p=0.015). In the samples taken from cases in a usual region, there was a linear and moderate relationship between the markers (ρ=0.513; p=0.017). Median tumor diameter results were similar to the marker staining score (p > 0.05). CONCLUSION This is the first study comparing the expression profiles of p53 and Ki67 of BCC cases in an unusual and a usual location. No significant difference was found concerning Ki67 and p53 expression levels between the two groups.

Prognostic significance of the programmed death ligand 1 expression in clear cell renal cell carcinoma and correlation with the tumor microenvironment and hypoxia-inducible factor expression

BackgroundClear cell renal cell carcinoma (ccRCC) is the most common renal malignancy. Hypoxia-inducible factors, HIF-1α and HIF-2α, are expressed in the majority of ccRCC. Targeting immune checkpoints with the blockade of PD-1 and its ligand PD-L1 reorganizes T-cell activity in tumor microenvironment and provides important antitumor responses. PD-L1 upregulation has been found to be hypoxia-inducible factor (HIF) dependent. Our aim is to demonstrate the association between PD-L1 and HIF expression and to reveal the role of PD-L1 in prognosis and its association with tumor microenvironment.MethodsSurgical specimens from 145 patients diagnosed with ccRCC, who had undergone radical or partial nephrectomy, were retrospectively analyzed. Immunohistochemistry on tissue microarrays (TMA) was performed to demonstrate expressions of PD-L1, HIF-1α, and HIF-2α in tumor cells and PD-1, CD4, and CD8 in lymphocytes to assess lymphocyte density in tumor microenvironment.ResultsPD-L1 tumor cell expression was detected in 20/125 (13.8%) cases, which correlated with higher levels of PD-1, CD4, CD8 and HIF-2α expression. Low or high expression of HIF-1α was similar in PD-L1-positive cases. When PD-L1-positive cases were compared with negative ones, there was no significant difference in terms of prognostic factors. However, the number of WHO/ISUP grade 3–4 tumors was significantly higher in PD-L1-positive cases than in negative ones.ConclusionPD-L1 tumor cell expression is strongly associated with increased HIF-2α expression and presence of dense lymphocytic infiltration in ccRCCs. Our findings confirm that PD-L1 positivity is associated with high ISUP nucleolar grade. The association between PD-L1, HIF, and lymphocyte density in tumor microenvironment must be clarified and especially taken into account in combination treatment.

Investigation of Heme Oxygenase 2 Enzyme Protein Expression in Keratoconus and Normal Human Corneal Epithelium: An Immunohistochemical Study

ABSTRACT Purpose: To compare heme oxygenase 2 (HO-2) enzyme levels detected by immunohistochemical staining methods in the cornea epithelium obtained from keratoconus patients and normal subjects. Materials and Methods: The keratoconus group included 69 eyes of 69 patients with keratoconus scheduled for cross-linking surgery. The control group included 52 eyes of 52 patients with refractive error scheduled for photorefractive keratectomy surgery. After a detailed ophthalmologic examination, corneal topographic maps of each patient were generated, and then the patients underwent surgery. The corneal epithelium was collected mechanically during the surgery, fixed with formalin, embedded in paraffin blocks, and sectioned by microtomes. HO-2 antibodies were applied to the samples for immunohistochemical evaluation. The intensity of the staining was identified as negative, weak, moderate or strong. The keratoconus group was classified as early (average keratometry (AvrK) ≤ 47 D), moderate (AvrK 47–55 D) and advanced keratoconus (AvrK ≥ 55 D). Finally, intergroup and intragroup comparison analyses were made statistically. Results: In the keratoconus group, 20 (29%) (14 weak and 6 moderate staining) of the 69 corneal epithelial specimens were identified with HO-2 expression. In the control group, 40 (76.9%) (16 moderate and 24 strong staining) of the 52 corneal epithelial specimens were identified with HO-2 expression. HO-2 expression in the corneal epithelial specimens was significantly less in the keratoconus group than in the control group (p < 0.001). There was no substantial difference among the keratoconus subgroups in terms of staining with the HO-2 antibody (p = 0.797). Conclusions: The HO-2 enzyme staining using immunohistochemical methods was at lower amounts in the keratoconic corneal epithelial cells as compared with normal corneal epithelial cells. The HO-2 enzyme may play a role in the etiopathogenesis of keratoconus.

Can cutting-needle biopsy be an alternative to excisional biopsy in lymph node pathologies?

OBJECTIVE We aimed to compare cutting-needle biopsy (CNB) diagnoses with excisional biopsy diagnoses of enlarging lymph nodes and to determine the diagnostic value of CNB. MATERIAL AND METHOD Out of the 291 cases that underwent CNB from lymph nodes between 2010 and 2016, 60 were included in the study in which pathological lymph nodes were excised after CNB. Demographic information, pathology and imaging reports, the diameters of the lymph nodes and the length of the CNBs of these cases were obtained from the hospital registry system. Diagnoses of the CNBs and excisional biopsies were then compared. RESULTS According to the excisional biopsy diagnosis, 7 of the 60 cases (11.7%) were benign and 53 of them (88.3%) were malignant. 28 (53%) of the malignant cases were diagnosed as Hodgkins lymphoma while the others (47%) got a non-Hodgkins lymphoma diagnosis. In the 8 non-diagnostic CNBs, 3(37%) of them were found to be benign/reactive, while 5 (63%) were diagnosed as malign lymphoma in excisional biopsy. Similarly, 7(64%) of the 11 cases diagnosed as benign/reactive in CNB, were found to be malignant with excisional biopsy. When CNB and excisional biopsy were compared, sensitivity and specificity were 90% and 100%; positive predictive value (PPV) and negative predictive value (NPV) were 100% and 0%, respectively, and the diagnostic accuracy rate (DV) was 86.5%. The mean diameter of the benign lymph nodes was 26.1 mm and the mean diameter of the malignant ones was 35.6 mm. There was no significant difference between malignant and benign lymph node size (p > 0.05). There was also no statistically significant difference between CNB length and correct diagnosis (p=0.233). CONCLUSION CNB is a non-invasive procedure. It is an alternative to excisional biopsy because of its low morbidity and low cost. However, the sensitivity of CNB is lower than its specificity, and we recommend the surgical excision of lymph nodes with a clinically strong neoplasm suspicion because of the presence of false negatives in 7 cases.