Are micro-RNA 21 and 143 indicative as prognostic biomarkers in dedifferentiated endometrial adenocarcinoma?

AIM: Dedifferentiated endometrial adenocarcinoma (DEAC) is a rare, aggressive subtype, accounting for 2% of all endometrial cancers. Poor survival in DEAC prompts the need for effective treatment modalities through better prognostic classification. MicroRNAs (miRNA) have essential roles in tumor angiogenesis, which might enable their use as novel biomarkers. In this study, we aimed to reveal the relationship between the expression of miRNA-21 and miRNA-143, which are associated with angiogenesis, and the prognosis of DEAC. METHOD: The study included six cases diagnosed with DEAC. The expression levels of miRNA-21 and miRNA-143 were detected by quantitative real-time PCR. Microvascular density (MVD) was measured by CD34 staining. All data and effects on survival were compared for statistical significance. RESULTS: Six cases diagnosed with DEAC were included in the study. The percentage of undifferentiated components ranged from 50 to 90%. The second component of differentiated carcinoma was detected as endometrioid (3/5 grade I, 1/5 grade II, 1/5 grade III) in five cases and serous in one case. The mean MVD was 27 (range 17-44, SD 9.4). In three cases, miRNA-21 expression was down-regulated in neoplastic areas compared to non-neoplastic areas. On the contrary, it was found to be up-regulated in the remaining three cases. MiRNA-143 expression decreased in four cases and increased in two cases. CONCLUSIONS: Based on these findings, we found a significant irregular expression of miRNA-21 in DEACs. As in other cancers, angiogenesis is significantly associated with survival in DEACs. This study provides initial data for revealing possible implications of miRNAs as prognostic indicators in DEAC.

The association of let-7c, miR-21, miR-145, miR-182, and miR-221 with clinicopathologic parameters of prostate cancer in patients diagnosed with low-risk disease.

BACKGROUND: The diagnostic benefit of prostate specific antigen (PSA) is limited, owing to its lack of specificity, particularly in men with PSA levels of 4.0 to 10.0 ng/mL. Therefore, there is a need for more specific and sensitive biomarkers to improve diagnostic accuracy and to predict prostate cancer (PCa) progression. Assessing the expression levels of specific microRNAs (miRNAs) in patients with PCa may be helpful in detecting cancer and predicting the cancer prognosis and its evolution, and may serve as markers to decide the treatment. We examined the expression levels of five miRNAs (let-7c, miR-21, miR-145, miR-185, and miR-221) on patients with low-risk PCa who had been eligible for active surveillance but underwent radical prostatectomy. We investigated the correlation between the relative expression of miRNAs and clinicopathologic parameters to evaluate their clinical significance. MATERIALS AND METHODS: Total RNA was isolated from the tumor and the corresponding non-neoplastic prostate tissue of 45 patients who underwent radical prostatectomy. Quantitative reverse transcriptase-polymerase chain reaction was used to measure the levels of let-7c, miR-21, miR-145, miR-185, miR-221, and RNU6B expression, using TaqMan MicroRNA Assays. miRNA expression was examined in low-risk PCa, and miRNAs' association with Gleason upgraded (GU) and biochemical recurrent (BR) patients was evaluated. RESULTS: We observed that miR-21 and miR-182 were overexpressed; conversely, let-7c, miR-145, and miR-221 were underexpressed in patients with low-risk PCa. GU patients (n = 16) and non-upgraded patients (n = 28) were compared. miR-145 was downregulated significantly in the GU group (P = 0.03). Similarly, miR-221 was downregulated significantly in patients with BR (n = 14) compared with non-recurrent patients (n = 30) (P = 0.04). Receiver operator characteristics (ROC) curve analysis revealed that miR-221 levels were significantly associated with BR in patients with a cut-off <-1.666, a value at which sensitivity was 70% and specificity 71% (area under curve [AUC] = 0.705, P = 0.030). CONCLUSIONS: There is still a need for a tumor marker with higher sensitivity and specificity than that of PSA. Among the five miRNAs examined, miR-221 was most associated with biochemical recurrence in low-risk PCa.

Efficacy of tocilizumab treatment in cerulein-induced experimental acute pancreatitis model in rats.

BACKGROUND/AIMS: Acute pancreatitis (AP) is a disease that can cause local and systemic complications that may have high morbidity and mortality. Currently, there is not any specific treatment for AP. In this study, we created an experimental model of AP in rats, and we aimed to demonstrate the histological effectiveness of tocilizumab treatment that antagonizes interleukin-6 (IL-6), one of the key cytokines in the development of AP. MATERIALS AND METHODS: Forty-eight rats were divided into six groups for this study. AP model was created by subcutaneous injections of cerulein (20 µg/kg) four times at 1-h intervals. Tocilizumab 4 mg/kg was administered to one of the treatment groups and 8 mg/kg to the other treatment group intraperitoneally. The effects of tocilizumab were revealed by examining pancreatic tissue of the rats histopathologically according to the Schonberg scoring system. RESULTS: A comparison between tocilizumab treatment group and AP control group provides statistically significant improvement in AP (p<0.0001). Furthermore, the dose of 8 mg/kg is shown to be more effective than 4 mg/kg (p=0.004). CONCLUSION: Our study points out that tocilizumab may be an effective agent for pancreatitis treatment.

The presence and prognostic significance of human papillomavirus in squamous cell carcinoma of the larynx.

The aim of the present study was to evaluate the role of HPV in laryngeal squamous cell carcinoma and correlate it with patients' clinicopathological data. In total, 78 laryngeal squamous cell carcinoma patients enrolled in this study. The presence of genotype-specific HPV DNA was evaluated using Genotyping Assay in formalin-fixed paraffin-embedded tissue which was diagnosed between 2005 and 2015. All samples were also evaluated for p16 immunohistochemical staining. HPV DNA and p16 status were assessed in terms of location, smoking, alcohol consumption, lymph node status, tumor stage, overall survival, disease-free survival, perineural invasion, and vascular invasion retrospectively. Five test samples were excluded from the study due to inadequate deoxyribonucleic acid purity. HPV DNA was detected in 19 of 73 (26.02%) in patients with laryngeal squamous cell carcinoma. Human papilloma virus genotyping revealed double human papilloma virus in one case (types 16 and 59) and HPV 16 in the remaining cases. Although HPV-positive cases showed slightly better 3 years survival than HPV-negative ones, this finding was not statistically significant (overall survival p = 0.417, HPV positive: 92.3%, HPV negative: 81.4%, and disease-free survival p = 0.526, HPV positive: 93.8%, HPV negative: 80.9%). The presence of HPV DNA was not significantly associated with any clinicopathological features (p > 0.05). Among 73 patients, only 4 had an immunohistochemical staining of p16 and these patients were also HPV DNA 16 positive. Although our study results revealed a slightly better survival in patients with HPV DNA positivity for HPV 16 compared to the negative ones, the difference was not statistically significant. However, an increasing rate in especially high-risk-type HPV-16 prevalence in laryngeal squamous cell carcinoma by RT-PCR method was observed compared to our previous study. Although the presence of HPV in laryngeal SCCs seems to be associated with slightly better prognosis, additional studies may be needed, since our results were not statistically significant. We believed that HPV is not an adequate biomarker for diagnostic and prognostic purposes in laryngeal squamous cell carcinoma.

BRAF, NRAS, KIT, TERT, GNAQ/GNA11 mutation profile analysis of head and neck mucosal melanomas: a study of 42 cases.

Head and neck mucosal melanoma (HNMuM), which occurs mostly in the sinonasal and oral cavity, constitutes less than 1% of all malignant melanomas. Treatment options fail to improve the prognosis of this aggressive tumour that has low overall survival rates. Thus, development of new targeted therapies is essential. Unfortunately, limited data exist regarding their molecular profile. BRAF, NRAS, KIT, TERT and GNAQ/GNA11 oncogene mutations were investigated in 42 HNMuMs (28 sinonasal, 13 oral, 1 nasopharyngeal). Mutation rates were as follows: BRAF (4.8%), NRAS (4.8%), KIT (9.5%), TERT (7.5%), GNAQ/GNA11 (0%). Among 11 cases that harboured mutations (26%), 10 (91%) were located in sinonasal and one (9%) in the oral cavity. The literature was reviewed with comparison of frequencies based on the gathered data. NRAS and TERT promoter mutation rates were significantly higher in sinonasal than in oral location (p<0.05). Our results indicated that BRAF, NRAS, KIT, TERT and GNAQ/GNA11 gene mutations occur at low frequencies in HNMuMs, and subgroups (oral versus sinonasal) differ in their molecular profile. Low rates of aforementioned mutations and activation of oncogenes by pathways other than sun exposure support the distinctive nature of HNMuMs with regard to their cutaneous counterparts.

Molecular alterations in malignant blue nevi and related blue lesions.

Malignant blue nevi (MBN) are extremely rare dermal melanocytic tumors that arise in association with atypical cellular blue nevi (ACBN), cellular blue nevi (CBN), common blue nevi (BN), or de novo. The frequency of BRAF, NRAS, and KIT mutations in malignant melanoma varies according to histological subtype and localization. These mutations are rarely observed in blue nevi, which have recently been shown to carry activating mutations in GNAQ/GNA11 genes. Only few small molecular studies of MBN have been published. The aim of the present study was to analyze in MBN and related blue lesions such as ACBN, CBN, and BN the prevalence of BRAF, NRAS, KIT, GNAQ, and GNA11 gene mutations and their association with clinicopathological features. We included in our study 12 MBN, 6 ACBN, 29 CBN, and 35 common BN diagnosed between 1996 and 2014. Sanger sequencing method was used for mutation analysis. Overall, GNAQ exon 5 mutation was the most frequent alteration (46 %), in 2 of 12 (17 %) MBN, 1 of 6 (17 %) ACBN, 22 of 29 (76 %) CBN, and 13 of 35 (37 %) common BN. BRAF V600E and GNA11 exon 5 mutations were respectively detected in 3 of 12 (25 %) and in 2 of 12 (17 %) MBN while none in ACBN, CBN, and common BN. None of the cases harbored NRAS exon 2/3, KIT exon 9/11/13/17/18, or GNAQ/GNA11 exon 4 mutations. GNAQ gene exon 5 mutations are rare in MBN and ACBN but frequent in CBN and common BN. Remarkably, BRAF V600E and GNA11 exon 5 mutations were only detected in MBN, whereas none were found in ACBN, CBN, or common BN. Our data contribute new elements to the limited data on molecular alterations in MBN.

BRAF, KIT, NRAS, GNAQ and GNA11 mutation analysis in cutaneous melanomas in Turkish population.

BACKGROUND: KIT and mitogen-activated protein kinase cascade are important for melanomagenesis. In the present study, we analyzed the frequency of BRAF, NRAS, KIT, GNAQ and GNA11 gene mutations and investigated their association with clinicopathological features of melanomas in Turkish population. MATERIALS AND METHODS: Forty-seven primary cutaneous melanomas were included in our study. Sanger sequencing method was used for mutation analysis in all cases. RESULTS: Mean age was 62.1 (29-101) years. Female:male ratio was 17:30. Among 47 melanomas, 14 (29.8%) BRAF, 10 (21.3%) NRAS, 4 (8.5%) KIT and 1(2.1%) GNAQ gene mutations were detected. Two of the KIT mutations were found in acral lentiginous melanoma (ALM). In the head and neck region, mutation frequency was significantly lower than in other locations (P = 0.035). The only GNAQ gene mutation (p.Q209L) was detected in a melanoma arising from blue nevus located on the scalp. None of the melanomas harbored NRAS exon 2, KIT exon 13/17/18, GNAQ exon 4 and GNA11 exon 4/5 mutations. Overall mutation frequency did not show significant difference between metastatic (8/14, 57.1%) and nonmetastatic (18/33, 54.5%) patients. We did not observe any significant association between mutation status and gender or age of various patients. CONCLUSIONS: Our results support that BRAF and NRAS gene mutations are common in cutaneous melanomas. The activating mutations of KIT gene are rare and especially seen in ALM. GNAQ and GNA11 mutations are infrequent in cutaneous melanomas and may be associated only with melanomas arising from blue nevus.

miR-205 and miR-200c: Predictive Micro RNAs for Lymph Node Metastasis in Triple Negative Breast Cancer.

PURPOSE: We examined expression profiles of 16 micro RNAs (miRNAs) in triple negative breast cancers to identify their potential as biomarkers for lymph node metastasis. METHODS: The expression profiles of miR-9, miR-21, miR-30a, miR-30d, miR-31, miR-34a, miR-34c, miR-100, miR-122, miR-125b, miR-146a, miR-146b, miR-155, miR-181a, miR-200c, and miR-205 were examined by using real-time quantitative reverse transcription polymerase chain reaction in tumor samples and corresponding benign breast tissues. Their associations with histopathological features and prognostic parameters were assessed. RESULTS: When compared with the expression in benign breast tissues, seven of the miRNAs (miR-31, miR-205, miR-34a, miR-146a, miR-125b, miR-34c, and miR-181a) were downregulated more than 1.5-fold in tumor tissues, whereas, only miR-21 was found to be upregulated more than 1.5-fold in tumor tissues. Although miR-200c levels were decreased only 1.12-fold in tumor tissues, the reduced expressions of miR-200c and miR-205 were significantly associated with lymph node metastasis (p=0.021 and p=0.016, respectively). CONCLUSION: Our results demonstrate that miR-205 and miR-200c expression levels may be useful in predicting lymph node metastasis in triple negative breast cancer patients.