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AIM: Our aim was to evaluate the efficacies of different nomogram approaches, including the Memorial Sloan Kettering Cancer Centre (MSKCC), Stanford University, Tenon Hospital, Cambridge University and TR methods, in patients operated for breast cancer. MATERIAL AND METHOD: The study included 60 breast cancer patients who were operated on for breast cancer at Ankara Numune Training and Research Hospital, A2 General Surgery Clinic, between 2007 and 2012. All patients were sentinel lymph node (SLN)-positive and had undergone axillary lymph node dissection (ALND). Five different scoring systems were applied retrospectively to these 60 patients. Receiver operating characteristics (ROC) curves were created for the nomograms and the area under the curve (AUC) sensitivity and specificity results were calculated. RESULTS: Twenty-two patients (37%) had axillary non-SLN metastases. AUC values of MSKCC, Stanford, Cambridge, Tenon and TR nomogram were calculated as 0.646, 0.644, 0.62, 0.595, and 0.66, respectively. A significant difference was found between the groups with and without non-SLN metastasis in terms of SLN metastasis size (p = 0.013). CONCLUSION: The MSKCC, Stanford, Cambridge, Tenon, and TR nomogram models were found to have insufficient power to discriminate between patients with and without non-SLN metastases in patients with SLN-positive breast cancer (AUC values

Background: The MF07-01 trial is a multicenter, phase III, randomized, controlled study comparing locoregional treatment (LRT) followed by systemic therapy (ST) with ST alone for treatment-naïve stage IV breast cancer (BC) patients. Methods: At initial diagnosis, patients were randomized 1:1 to either the LRT or ST group. All the patients were given ST either immediately after randomization or after surgical resection of the intact primary tumor. Results: The trial enrolled 274 patients: 138 in the LRT group and 136 in the ST group. Hazard of death was 34% lower in the LRT group than in the ST group (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.49–0.88; p = 0.005). Unplanned subgroup analyses showed that the risk of death was statistically lower in the LRT group than in the ST group with respect to estrogen receptor (ER)/progesterone receptor (PR)(+) (HR 0.64; 95% CI 0.46–0.91; p = 0.01), human epidermal growth factor 2 (HER2)/neu(–) (HR 0.64; 95% CI 0.45–0.91; p = 0.01), patients younger than 55 years (HR 0.57; 95% CI 0.38–0.86; p = 0.007), and patients with solitary bone-only metastases (HR 0.47; 95% CI 0.23–0.98; p = 0.04). Conclusion: In the current trial, improvement in 36-month survival was not observed with upfront surgery for stage IV breast cancer patients. However, a longer follow-up study (median, 40 months) showed statistically significant improvement in median survival. When locoregional treatment in de novo stage IV BC is discussed with the patient as an option, practitioners must consider age, performance status, comorbidities, tumor type, and metastatic disease burden. © 2018, Society of Surgical Oncology.

Objectives: The best protection against breast cancer, the most common cancer in women, is early detection. The most commonly used risk assessment tools, identifying women at high risk of developing breast cancer, are the Gail model and its modifications, National Surgical Adjuvant Breast and Bowel Project (NSABP) and National Cancer Institute (NCI) models. We aimed to evaluate the sensitivities of these models. Materials and Methods: We retrospectively evaluated 1333 patients who had been diagnosed with breast cancer at Ankara Numune Education and Research Hospital and Ankara University Medical Faculty between April 1998 and December 2014. Results: The Gail model identified 32.52% of the patients as being at high risk. The model NSABP identified 15.48% as being at high risk and the NCI identified 19.39 %. Conclusion: Comparison of the sensitivity of three models revealed Gail model as the most sensitive one, but it only identified 32.52 % of the patients who developed breast cancer as being at high risk. There was a correlation between the results, but results were significantly different. We conclude that these three models are not applicable to Turkish women due to their low sensitivity and poor concordance. There is a need to develop a new risk assessment model with the addition of different parameters for Turkish women. Giriş: Kadınlarda en sık görülen kanser olan meme kanserine karşı en iyi koruma erken tanıdır. Meme kanseri gelişimi için yüksek riskli bireyleri tanımlamak için en sık kullanılan risk değerlendirme yöntemleri Gail ve modifikasyonları olan National Surgical Adjuvant Breast and Bowel Project (NSABP) ve National Cancer Institute NCI modelleridir. Araştırmamızda bu modellerin duyarlılıklarını değerlendirmeyi amaçladık. Materyal ve Metot: Ankara Numune Eğitim ve Araştırma Hastanesi ve Ankara Üniversitesi Tıp Fakültesi’nde, Nisan 1998 ile Aralık 2014 tarihleri arasında, meme kanseri tanısı almış 1333 hastayı retrospektif olarak değerlendirdik. Bulgular: Gail modeli hastaların %32,52’ sini yüksek riskli olarak tanımladı. NSABP %15,48 ve NCI modeli %19,39 hastayı yüksek riskli olarak tanımladı. Sonuç: Üç modelin duyarlılığını karşılaştırdığımızda Gail modeli en duyarlısıdır; fakat zaten meme kanseri gelişmiş olan hastaların sadece %32,52’ sini yüksek riskli olarak tanımlayabilmiştir. Sonuçlar arasında korelasyon vardı; ama anlamlı derecede farklı idi. Biz, bu üç modelin, düşük duyarlılık ve zayıf uyuşmalarına bağlı olarak, Türk kadınlarına uygun olmadığına karar verdik. Türk kadınları için, farklı parametreler eklenerek yeni bir risk değerlendirme modeli geliştirilmesine ihtiyaç vardır.

Ribosomal RNA (rRNA) expression, one of the most important factors regulating ribosome production, is primarily controlled by a CG-rich 45 S rDNA promoter. However, the DNA methylation state of the 45 S rDNA promoter, as well as its effect on rRNA gene expression in types of human cancers is controversial. In the present study we analyzed the methylation status of the rDNA promoter (-380 to +53 bp) as well as associated rRNA expression levels in breast cancer cell lines and breast tumor-normal tissue pairs. We found that the aforementioned regulatory region was extensively methylated (74-96%) in all cell lines and in 68% (13/19 tumor-normal pairs) of the tumors. Expression levels of rRNA transcripts 18 S, 28 S, 5.8 S and 45 S external transcribed spacer (45 S ETS) greatly varied in the breast cancer cell lines regardless of their methylation status. Analyses of rRNA transcript expression levels in the breast tumor and normal matched tissues showed no significant difference when normalized with TBP. On the other hand, using the geometric mean of the rRNA expression values (GM-rRNA) as reference enabled us to identify significant changes in the relative expression of rRNAs in the tissue samples. We propose GM-rRNA normalization as a novel strategy to analyze expression differences between rRNA transcripts. Accordingly, the 18S rRNA/GM-rRNA ratio was significantly higher whereas the 5.8S rRNA/GM-rRNA ratio was significantly lower in breast tumor samples than this ratio in the matched normal samples. Moreover, the 18S rRNA/GM-rRNA ratio was negatively correlated with the 45 S rDNA promoter methylation level in the normal breast tissue samples, yet not in the breast tumors. Significant correlations observed between the expression levels of rRNA transcripts in the normal samples were lost in the tumor samples. We showed that the expression of rRNA transcripts may not be based solely on promoter methylation. Carcinogenesis may cause dysregulation of the correlation between spliced rRNA expression levels, possibly due to changes in rRNA processing, which requires further investigation.

Background The MF07-01 trial is a multicenter randomized study comparing locoregional treatment (LRT) followed by systemic therapy (ST) with ST alone in de novo stage IV breast cancer (BC) patients. The aim of this study is to evaluate the importance of LRT in patients who lived at least 5 years after the diagnosis of de novo Stage IV BC. Methods At initial diagnosis, patients were randomized 1:1 to either the LRT or ST group. All the patients were given ST either immediately after randomization or after surgical resection of the intact primary tumor. Continuous and categorical variable differences between LRT and ST groups were analyzed using t-test and Chi-square test, respectively. Overall survival (OS) and 5-year survival rates were compared using Kaplan-Meier log-rank tests. Univariate and multivariate Cox models were used to estimate hazard ratios. Results During 124 months of follow-up, 26% of patients in LRT group and 11% of patients in ST group remained alive. Median survival was 46 months for LRT (n = 134) and 35.5 months for ST (n = 132) [HR:0.65, 95%CI;0.49-0.85, p = 0.002]. Solitary bone metastasis patients’ median survival was 14.5 months longer in the LRT group compared with the ST group [HR:0.53, 95%CI; 0.29-0.98, p = 0.04]; 22% of solitary bone metastasis patients in the LRT group and 5% in the ST group were alive. Regarding the patients who lived at least 5 years since randomization, LRT (p = 0.004), hormone receptor positivity (p = 0.007), hormonotherapy (p = 0.0001), bisphosphonates usage (p = 0.02), T2 tumor (p = 0.0008) and 2 or more organ metastases (p = 0.007) were associated with OS in univariate analysis, and in a multivariate Cox proportional model with a significant baseline and clinical characteristics, LRT [OR = 1.75, p = 0.05)], bisphosphonates usage [OR = 1.93, p = 0.05), T2 tumor [OR = 3.5, p = 0.003), and 2 or more organ metastases [OR = 0.48, p = 0.03] were found to be significantly related with OS. Conclusions In the current analysis, patients at the diagnosis of de novo stage IV BC who underwent LRT followed by ST had a 75% higher chance to live at least 5 years compared with the patients who received only ST. Longer follow-up of the study discloses that LRT should be presented to the patient when discussing treatment options. Clinical trial identification NCT00557986. Legal entity responsible for the study Turkish Federation of Breast Diseases Societies. Funding Turkish Federation of Breast Diseases Societies. Disclosure All authors have declared no conflicts of interest.

Objective: Sentinel lymph node (SLN) scintigraphy is used widespread in breast cancer, but the effect of the radionuclide agent, injection technique, the method of biopsy, tumor localization, breast size remain controversial. We examined the effects of the excisional biopsy in the rate of the SLN identification with lymphoscintigraphy (LS) and intraoperative gamma probe (IGP). Material and Methods: One hundred patients (age range: 28-79 yr) with breast cancer were included in the study. They consisted of two groups: Group 1; there were 58 patients without excisional biopsy Group 2; there were 42 patients with excisional biopsy LS: 2 hours before the operation, 37 MBq/ ml Tc 99m colloidal rhenium sulphide was injected at the periaerolar region intradermally Anterior and lateral static images were acquired. IGP: The hot spot of greatest radioactivity were marked on the skin during the surgery with IGP and removed. Excised SLNs were examined with frozen section. After that histopathological and immunohistochemical examinations were performed. Results: SLNs were found in all patients in group 1 (100%), in 39 patients of group 2 (93%) with LS. SLNs were excised in 57 of the 58 patients of group 1 (98%), in 38 of the 42 patients of group 2 (90%) with IGF. Metastases were found in SLNs in 27 patients (28%). Axillary dissection was performed in these patients. Conclusion: According to results of our study the excisional biopsy was not the only factor but also other factors such as breast mass, calcified or metastatic lymph node may be affected the success rate of the SLN. Conflict of interest:None declared.

Background CpG hypermethylation in gene promoters is a frequent mechanism of tumor suppressor gene silencing in various types of cancers. It usually occurs at early steps of cancer progression and can be detected easily, giving rise to development of promising biomarkers for both detection and progression of cancer, including breast cancer. 5-aza-2′-deoxycytidine (AZA) is a DNA demethylating and anti-cancer agent resulting in induction of genes suppressed via DNA hypermethylation. Results Using microarray expression profiling of AZA- or DMSO-treated breast cancer and non-tumorigenic breast (NTB) cells, we identified for the first time TAGLN gene as a target of DNA hypermethylation in breast cancer. TAGLN expression was significantly and frequently downregulated via promoter DNA hypermethylation in breast cancer cells compared to NTB cells, and also in 13/21 (61.9 %) of breast tumors compared to matched normal tissues. Analyses of public microarray methylation data showed that TAGLN was also hypermethylated in 63.02 % of tumors compared to normal tissues; relapse-free survival of patients was worse with higher TAGLN methylation; and methylation levels could discriminate between tumors and healthy tissues with 83.14 % sensitivity and 100 % specificity. Additionally, qRT-PCR and immunohistochemistry experiments showed that TAGLN expression was significantly downregulated in two more independent sets of breast tumors compared to normal tissues and was lower in tumors with poor prognosis. Colony formation was increased in TAGLN silenced NTB cells, while decreased in overexpressing BC cells. Conclusions TAGLN gene is frequently downregulated by DNA hypermethylation, and TAGLN promoter methylation profiles could serve as a future diagnostic biomarker, with possible clinical impact regarding the prognosis in breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13148-015-0138-5) contains supplementary material, which is available to authorized users.

Breast cancer is one of the most important causes of cancer-related deaths worldwide in women. In addition to gene expression studies, the progressing work in the miRNA area including miRNA microarray studies, brings new aspects to the research on the cancer development and progression. Microarray technology has been widely used to find new biomarkers in research and many transcriptomic microarray studies are available in public databases. In this study, the breast cancer miRNA and mRNA microarray studies were collected according to the availability of their data and clinical information, and combined by a newly developed ranking-based meta-analysis approach to find out candidate miRNA biomarkers (meta-miRNAs) that classify breast cancers according to their grades and explain the relation between miRNAs and mRNAs. This approach provided meta-miRNAs specific to breast cancer grades, pointing out let-7 family members as grade classifiers. The qRTPCR studies performed with independent breast tumors confirmed the potential biomarker role of let-7 family members (meta-miRNAs). The concordance between the meta-mRNAs and miRNA target genes specific to tumor grade (common genes) supported the idea of mRNAs as miRNA targets. The pathway analysis results showed that most of the let-7 family miRNA targets, and also common genes, were significantly taking part in cancer-related pathways. The qRT-PCR studies, together with bioinformatic analyses, confirmed the results of meta-analysis approach, which is dynamic and allows combining datasets from different platforms. © 2015 Oztemur et al.

Background: Hernia repair is one of the most frequent procedures in surgery. The aim of this study is to compare Lichtenstein procedure and non-mesh suture repair of primary inguinal hernias with respect to quality of life.Methods: Between August 2000 and December 2003, 70 patients scheduled for repair of a unilateral primary inguinal hernia were prospectively evaluated by Short Form 36 (SF-36) to assess quality of life after 6 months of operation. Registrars under supervision of consultants did all operations.Results: Among 70 patients, 24 patients (34.2%) had undergone non-mesh suture repair and 46 patients (65.8%) had undergone Lichtenstein procedure. SF-36 questionnaire showed a signifi-cant difference in physical function, pain and global health parameters of the test in favour of the Lichtenstein procedure 6 months postoperatively.Conclusion: We conclude that long-term quality of life following Lichtenstein procedure is supe-rior to non-mesh suture repair in primary inguinal hernias.

BACKGROUND: Breast cancer is a remarkably heterogeneous disease. Luminal, basal-like, "normal-like", and ERBB2+ subgroups were identified and were shown to have different prognoses. The mechanisms underlying this heterogeneity are poorly understood. In our study, we explored the role of cellular differentiation and senescence as a potential cause of heterogeneity. METHODOLOGY/PRINCIPAL FINDINGS: A panel of breast cancer cell lines, isogenic clones, and breast tumors were used. Based on their ability to generate senescent progeny under low-density clonogenic conditions, we classified breast cancer cell lines as senescent cell progenitor (SCP) and immortal cell progenitor (ICP) subtypes. All SCP cell lines expressed estrogen receptor (ER). Loss of ER expression combined with the accumulation of p21(Cip1) correlated with senescence in these cell lines. p21(Cip1) knockdown, estrogen-mediated ER activation or ectopic ER overexpression protected cells against senescence. In contrast, tamoxifen triggered a robust senescence response. As ER expression has been linked to luminal differentiation, we compared the differentiation status of SCP and ICP cell lines using stem/progenitor, luminal, and myoepithelial markers. The SCP cells produced CD24+ or ER+ luminal-like and ASMA+ myoepithelial-like progeny, in addition to CD44+ stem/progenitor-like cells. In contrast, ICP cell lines acted as differentiation-defective stem/progenitor cells. Some ICP cell lines generated only CD44+/CD24-/ER-/ASMA- progenitor/stem-like cells, and others also produced CD24+/ER- luminal-like, but not ASMA+ myoepithelial-like cells. Furthermore, gene expression profiles clustered SCP cell lines with luminal A and "normal-like" tumors, and ICP cell lines with luminal B and basal-like tumors. The ICP cells displayed higher tumorigenicity in immunodeficient mice. CONCLUSIONS/SIGNIFICANCE: Luminal A and "normal-like" breast cancer cell lines were able to generate luminal-like and myoepithelial-like progeny undergoing senescence arrest. In contrast, luminal B/basal-like cell lines acted as stem/progenitor cells with defective differentiation capacities. Our findings suggest that the malignancy of breast tumors is directly correlated with stem/progenitor phenotypes and poor differentiation potential.

Quantitative gene expression measurements from tumor tissue are frequently compared with matched normal and/or adjacent tumor tissue expression for diagnostic marker gene selection as well as assessment of the degree of transcriptional deregulation in cancer. Selection of an appropriate reference gene (RG) or an RG panel, which varies depending on cancer type, molecular subtypes, and the normal tissues used for interindividual calibration, is crucial for the accurate quantification of gene expression. Several RG panels have been suggested in breast cancer for making comparisons among tumor subtypes, cell lines, and benign/malignant tumors. In this study, expression patterns of 15 widely used endogenous RGs (ACTB, TBP, GAPDH, SDHA, HPRT, HMBS, B2M, PPIA, GUSB, YWHAZ2, PGK1, RPLP0, PUM1, MRPL19, and RPL41), and three candidate genes that were selected through analysis of two independent microarray datasets (IL22RA1, TTC22, ZNF224) were determined in 23 primary breast tumors and their matched normal tissues using qRT-PCR. Additionally, 18S rRNA, ACTB, and SDHA were tested using randomly primed cDNAs from 13 breast tumor pairs to assess the rRNA/mRNA ratio. The tumors exhibited significantly lower rRNA/mRNA ratio when compared to their normals, oil average. The expression of the studied RGs in breast tumors did not exhibit differences in terms of grade, ER, or PR status. The stability of RGs was examined based on two different statistical models, namely GeNorm and NormFinder. Among the 18 tested endogenous reference genes, ACTB and SDHA were identified as the most Suitable reference genes for the normalization of qRT-PCR data in the analysis of normal matched tumor breast tissue pairs by both programs. In addition, the expression of the gelsolin (GSN) gene, a well-known downregulated target in breast tumors, was analyzed using the two most suitable genes and different RG combinations to validate their effectiveness as a normalization factor (NF). The GSN expression of the tumors used in this study was significantly lower than that of normals showing the effectivity of using ACTB and SDHA as suitable RGs in this set of tumor-normal tissue panel. The combinational use of the best performing two RGs (ACTB and SDHA) as a normalization factor can be recommended to minimize sample variability and to increase the accuracy and resolution of gene expression normalization in tumor-normal paired breast cancer qRT-PCR studies.

BackgroundAccuracy in the diagnosis of breast cancer and classification of cancer subtypes has improved over the years with the development of well-established immunohistopathological criteria. More recently, diagnostic gene-sets at the mRNA expression level have been tested as better predictors of disease state. However, breast cancer is heterogeneous in nature; thus extraction of differentially expressed gene-sets that stably distinguish normal tissue from various pathologies poses challenges. Meta-analysis of high-throughput expression data using a collection of statistical methodologies leads to the identification of robust tumor gene expression signatures.MethodsA resampling-based meta-analysis strategy, which involves the use of resampling and application of distribution statistics in combination to assess the degree of significance in differential expression between sample classes, was developed. Two independent microarray datasets that contain normal breast, invasive ductal carcinoma (IDC), and invasive lobular carcinoma (ILC) samples were used for the meta-analysis. Expression of the genes, selected from the gene list for classification of normal breast samples and breast tumors encompassing both the ILC and IDC subtypes were tested on 10 independent primary IDC samples and matched non-tumor controls by real-time qRT-PCR. Other existing breast cancer microarray datasets were used in support of the resampling-based meta-analysis.ResultsThe two independent microarray studies were found to be comparable, although differing in their experimental methodologies (Pearson correlation coefficient, R = 0.9389 and R = 0.8465 for ductal and lobular samples, respectively). The resampling-based meta-analysis has led to the identification of a highly stable set of genes for classification of normal breast samples and breast tumors encompassing both the ILC and IDC subtypes. The expression results of the selected genes obtained through real-time qRT-PCR supported the meta-analysis results.ConclusionThe proposed meta-analysis approach has the ability to detect a set of differentially expressed genes with the least amount of within-group variability, thus providing highly stable gene lists for class prediction. Increased statistical power and stringent filtering criteria used in the present study also make identification of novel candidate genes possible and may provide further insight to improve our understanding of breast cancer development.

The RNASEL G1385A variant was recently found to be implicated in the development of prostate cancer. Considering the function of RNase L and the pleiotropic effects of mutations associated with cancer, we sought to investigate whether the RNASEL G1385A variant is a risk factor for breast cancer.A total of 453 breast cancer patients and 382 age- and sex-matched controls from Greece and Turkey were analyzed. Genotyping for the RNASEL G1385A variant was performed using an Amplification Refractory Mutation System (ARMS).Statistical evaluation of the RNASEL G1385A genotype distribution among breast cancer patients and controls revealed no significant association between the presence of the risk genotype and the occurrence of breast cancer.Although an increasing number of studies report an association between the RNASEL G1385A variant and prostate cancer risk; this variant does not appear to be implicated in the development of breast cancer.