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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.

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.

The aim of this study was to demonstrate demographics of 39 consecutive Spinal Muscular Atrophy (SMA) type 1 patients diagnosed genetically in a tertiary center between June 2006 and June 2009. There was history of consanguineous marriage in 27 (69%) patients. The average patient lifespan was 251 days (30–726 days). The average patient age at diagnosis was 129 days (33–297 days). A statistically significant correlation was found between the age at diagnosis and the lifespan (p = 0.00). No significant correlation was found between the time spent in intensive care and the lifespan (p = 0.43). Routine physical therapy was found to have no significant impact on the lifespan average (p = 0.17). The cause of death in all of our patients was respiratory issues. Genetic counseling was given to 35 families. A second child with SMA was born in three out of the 14 families who declined prenatal diagnosis. Conclusion: A national program is needed in Turkey for SMA prevention and creation of expert teams for the management of these patients.

The aim of this prospective study was to investigate the effects of early onset rehabilitation program on shoulder mobility, functional status, lymphedema, and the incidence of postoperative complications in patients who had modified radical mastectomy. Fifty-seven women were randomly assigned to either treatment group or home exercise program groups, which were consisted of 27 and 30 patients, respectively. After removal of the drains, the patients were instructed to 15 sessions of individual rehabilitation program and continued with home-based physical activity program. The home exercise program groups only received a form including the exercises, which could be performed by themselves after removal of the drains. Range of motion of the shoulder joint and upper extremity circumferential difference were measured. Functional status was assessed by functional index score. Each patient was assessed preoperatively and then postoperatively at fifth day and first, third, and sixth months. The improvement in measurements of flexion, abduction, and adduction movements of the shoulder joint and the functional questionnaire scores were significantly better in treatment group. There was no statistically significant difference in the development of lymphedema and postoperative complications in both groups. Early onset rehabilitation program after modified radical mastectomy provides improvement in shoulder mobility and functional capacity without causing adverse effect in postoperative period.

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.

Improving the diagnosis of acute appendicitis in order to prevent unnecessary surgery is crucial. This study was intended to identify the role of serum inflammatory markers in patients with preliminary diagnosis of acute appendicitis with a retrospective design. Eighty-five patients with the preliminary diagnosis of acute appendicitis were recruited in this study within the period of November-December 2003. The average age was 31.8 years (ranged from 15 to 85). There were 62 males (72.9%) and 23 females (27.1%). In addition to performing routine tests, preoperative serum samples were obtained from the patients to measure C-reactive protein, interleukin-6, and interleukin-10. All the patients were operated on for a clinical suspicion of acute appendicitis. Depending on the macroscopic evidence during the operation and the histopathological examination of the specimen, the patients were separated into two groups: the ones who did not have acute appendicitis as the cause for acute abdomen (group I; n = 14) and the ones who had acute appendicitis (group II; n = 71). The ones who had acute appendicitis (group II) were further grouped as noncomplicated appendicitis (group IIA; n = 44) and complicated appendicitis (group IIB; n = 27). Being a male with elevated levels of leukocytes (white blood cells, WBC); C-reactive protein (CRP), interleukin-6 (IL-6); and interleukin-10 increased the probability of having acute appendicitis in patients with evidences of acute abdomen. The risk of complication of acute appendicitis significantly increased when patients had increased levels of C-reactive protein, increased erythrocyte sedimentation rate, and increased interleukin-6 levels, had symptoms for more than 24 h, and were female. Interleukin-10 levels within normal range might be helpful in eliminating the possibility of acute appendicitis. Thus, elevated levels of WBC, IL-6 and CRP might be helpful in confirming a potential diagnosis of acute appendicitis. In addition, normal levels of IL-10 might be of additional help to possibly rule out the diagnosis of acute appendicitis.

In patients with gastric carcinomas, the role of the alteration of mucin expression in overall survival has been a matter of some speculation, but few studies have been reported. The aim of our study was to determine the relationship between MUC1, MUC2, and MUC5AC expression and patient survival, with a secondary aim designed to investigate the alteration of MUC expression within various clinicopathologic parameters. Forty-four specimens from gastric carcinoma patients were immunohistochemically evaluated using the monoclonal antibodies for MUC1 (EMA, clone E29), MUC2 (CCP58), and MUC5AC (human gastric mucin, clone 45M1). MUC1 expression increased in gastric carcinoma. MUC1 positivity was determined to be statistically significant, with poor clinicopathological parameters and decreased long-term survival. MUC5AC expression decreased in gastric carcinoma. In addition, patients with MUC5AC-positive tumors also had poor clinicopathological parameters and showed shorter survival than those with MUC5AC-negative tumors. MUC2 expression was not significantly associated with patient survival. We confirmed that the expression of mucins is associated with characteristics of differentiation in gastric carcinoma. Poor patient outcomes were seen in gastric carcinomas with MUC1 mucin expression and MUC5AC positivity.

Overexpression and alterations in the glycosylation of gastric mucins have been described in colorectal carcinoma. The purpose of our study was to confirm aberrant expression of MUC5AC in colorectal carcinoma, to investigate relationships between clinicopathological parameters and MUC5AC expression, and to determine if MUC5AC expression may be a prognostic factor for colorectal carcinoma. Immunohistochemical staining using an antibody against MUC5AC tandem repeat epitopes was performed on colorectal tumor specimens (n = 41), their metastatic tumors in regional lymph nodes (n = 21) and normal colonic mucosa (n = 41). We also documented clinicopathological parameters such as the age and sex of the patient, location, size, Dukes stage, histological type and grade of the tumor, pre-sence and number of metastatic lymph nodes, lymphatic, venous and perineural invasion, presence of preoperative and postoperative metastatic tumors and tumor recurrence. MUC5AC was expressed in 34.1% of tumor samples, 24.4% of normal colonic mucosa samples and 19% of lymph node metastases. MUC5AC showed ectopic expression in colorectal carcinoma and was also expressed strongly in mucinous carcinoma (60%). The number of tumors that expressed MUC5AC was lower in patients older than 60 years, in rectum-localized tumors and in patients who had evidence of recurrence and/or metastasis in the postoperative period. The patients with MUC5AC-negative tumors had a lower incidence of being disease free and of overall survival. In conclusion, the patients with MUC5AC-negative tumors had poor clinicopathological parameters and showed worse survival than patients with MUC5AC-positive tumors. Absence of MUC5AC expression in tumors can be a prognostic factor for more aggressive colorectal carcinoma.

Lymphomas may be localised throughout the whole gastrointestinal tract, from oral cavity to rectum. The rectum is a fairly uncommon site for lymphoma compared to other gastrointestinal sites. Primary rectal lymphoma is the rarest disorder accounting for 0.1–0.6% of all colonic malignancies, and 0.05% of all primary rectal tumours. It is unclear whether surgery, chemotherapy, radiotherapy or combinations of these treatments improve the prognosis and survival rate in such patients. The role of surgery in primary rectal lymphoma of the rectum is still controversial. A case of primary rectal lymphoma treated by a combination of chemotherapy and radiotherapy is described.

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.

Background and Aim: With the introduction of H2 receptor antagonists and proton pump inhibitors, the incidence of elective surgery for peptic ulcer (PU) diseases has decreased, although complications of PU such as perforation and bleeding have remained fairly constant. The purpose of this study was to identify the risk factors that predict morbidity and mortality in patients with perforated PU. Methods: The records of 269 patients who were operated on for perforated PU were reviewed retrospectively. The following factors were analyzed in terms of morbidity and mortality: age >65 years; gender; associated medical illness; chronic ingestion of non-steroidal anti-inflammatory drugs, aspirin, corticosteroids or immunosuppressants; alcohol ingestion and smoking habits; American Society of Anesthesiologist (ASA) status; season; delayed operation; site of ulcer perforation; and shock on admission and type of operation. Results: There were 30 female (11.16%) and 239 male (88.84%) patients. Seventy-one (26.4%) patients had associated diseases. Simple closure was performed in 257 (95.5%) patients; 12 patients (4.5%) underwent definitive operations. A total of 108 postoperative complications were present in 65 (24.2%) patients. Twenty-three patients died (8.55%). Multivariate analysis showed that only age, ASA score, treatment delay, presence of shock and definitive operation were independent predictors of mortality. Significant risk factors that led to morbidity were ASA status, time of surgery, season, presence of shock and type of surgery. There was a significant difference concerning morbidity and mortality between simple closure of the perforation and definitive surgery. Conclusions: Age, delayed surgery, presence of shock, ASA risk and definitive surgery are factors significantly associated with fatal outcomes in patients undergoing emergency surgery for perforated PU. Therefore, proper resuscitation from shock, improving ASA grade, decreasing delay and reserving definitive surgery for selected patients is needed to improve overall results.

The management of duodenal traumas remains controversial. The experience of Ankara Numune Training and Research Hospital Emergency Surgery Department with duodenal injuries during a 10-year period was analyzed to identify trends in operative management and sources of duodenum-related morbidity and mortality.Between 1994 and 2003, 1799 patients with blunt abdominal trauma were operated on and the incidence of duodenal trauma was 2.8% (50 patients). The injuries were penetrating in 31 (62%) patients and blunt in 19 (38%). Primary repair (PR) of injury was performed in 24 (48%) patients, primary repair and tube duodenostomy (PRTd) in 8 (16%) patients, complex repair (CR) in 11 (22%) patients, and exploration only without a duodenal procedure in 5 (10%) patients. Two of the patients died during laparotomy. The mortality rate was 12% and the incidence of duodenum-related morbidity was 12%. The overall morbidity rate was 40% (20 patients). The most commonly injured portion of the duodenum was DII (58%), and the most frequent cause of duodenum-related and overall morbidity in our series was Grade III duodenal injury.Our experience suggests that the use of primary repair in grade III injury may be associated with higher duodenum-related morbidity. Our recommendation is to use complex repair for grade III duodenal injuries.

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.

Breast carcinoma is a frequent disease that affects the female population. As for other malignant diseases, several studies have been carried out in an attempt to identify its etiology, yet the etiological agent has not been clearly defined. The etiological relationship between thyroid disease and breast cancer is still being investigated. However, most of the studies in this field are conflicting and discussions on this relationship still continue.Our prospective open study was conducted on 136 consecutive patients operated for breast carcinoma. As a control group, 68 individuals with normal breast examination, who did not have any known malignancy and/or thyroid disease, living in the same geographical region and with matching socio-cultural and economical status, were included in the study. We aimed to identify the occurrence and frequency of thyroid pathologies in both groups to compare the clinical and the laboratory features of thyroid disease and breast carcinoma in an attempt to contribute to the studies investigating the relationship between these two entities.We found thyroid pathology in 77.9% of breast cancer patients while this was 47.1% in the control group. Breast cancer patients had higher levels of free-T3 and more frequent diffuse and nodular enlargement of thyroid gland in ultrasonography when compared to the control group. Furthermore, in the presence of thyroid disease, breast cancer patients had statistically significant increases in the number of metastatic lymph nodes, vascular invasion, and tumor size.In conclusion, the frequency of thyroid pathology is higher in breast cancer patients compared to controls indicating a relationship between breast carcinoma and thyroid pathology. Our study shows that the presence of thyroid pathology in breast cancer patients can be influential on the spread of cancer and adversely affect its prognosis. We thought further studies are needed to confirm these findings and to explain the reason for co-occurrence of breast cancer and thyroid disease and furthermore to investigate the prognosis and survival of breast cancer patients in the presence of thyroid pathology.

Background/Purpose. In this prospective open clinical study, we investigated the problems that might arise during the obliteration of the residual cavity in hepatic hydatidosis. These problems might be related to the duration of the obliteration period and to the effects of omentoplasty on the residual cavity. Methods. We operated on 54 hepatic hydatidosis patients with cystodrainage and omentoplasty. We followed these patients for a period of 8 years after the operation. We used ultrasonography (US) to evaluate the obliteration of the cystic cavity; evaluations were made by serological tests as well (hemagglutination test, IHA, and IgE radioallergosorbent test, RAST). Results. Most of the reductions in the size of the cystic cavity were observed within the first 30 days following the operation (69.7%). At the end of the first postoperative year, cystic cavity obliteration was not complete in 34 patients, and 5 of these cases had positive indirect IHA and IgE RAST tests for Echinococcus granulosus. These patients were treated with extension of albendazol therapy. In 2 of these 5 patients, obliteration of the cystic cavity was complete within 12 months; their serological tests became negative at 15 and 21 months, respectively. In the remaining 3 whose serological tests were still positive at the end of the first year, obliteration of the cystic cavity was complete by 27, 33, and 45 months respectively. Of these 3 patients, the tests became negative at 30 and 52 months for the first 2 patients; the last patient is still serologically positive although we have not determined any findings related to the recurrence of the cyst. Conclusions. Omentoplasty is the preferred method in the surgical treatment of hepatic hydatidosis. However, we should keep the following facts in mind while following these patients with US: the technique can be insufficient, the obliteration of the residual cavity takes time and can be misdiagnosed as a recurrence, and ultrasonographic appearances can mimic some other diseases whether they are benign or malignant. Moreover, follow-up studies should be complemented with the serological tests. Thus, all these steps will minimize a misdiagnosis and unnecessary reoperations for hepatic hydatidosis.