Prognostic significance of miR-34 rs4938723 T > C polymorphism in triple negative breast cancer patients.

OBJECTIVES: The aim of this was the assessment of the prognostic role of the rs4938723 C > T polymorphism of the miR-34 in triple negative breast cancer patients. METHODS: Therefore formalin fixed paraffin embedded tissue samples from 114 triple negative breast cancer patients and blood samples from 124 healthy donors were genotyped and subsequently extensive statistical analysis was performed in order to investigate the clinical value of this polymorphism in triple negative breast cancer. RESULTS: Our statistical analysis disclosed that the majority of patients harboring ductal breast carcinoma (69.4%) have the TC or CC genotypes (P = .020). Moreover the survival of the patients was significantly correlated with the occurrence of the TC or CC alleles (P < .001). Regarding the correlation of miR-34 polymorphisms with patients' survival we found that women with TC or CC single nucleotide polymorphisms were characterized by shorter disease free survival intervals (P = .05). Furthermore triple negative breast cancer patients with TC/CC genotype exhibited shorter overall survival intervals as disclosed by Kaplan Meier analysis (P < .001) and Cox regression analysis (HR = 3.2, %95 CI = 2.0-5.5, P = .008). Stratified Kaplan-Meier analysis showed that the women harboring the TC or CC genotype along with the ductal histology had significantly shorter survival (P < .001). This result was also confirmed by Univariate Cox regression analysis, which showed that women ductal breast cancer and TC or CC genotype are of worse prognosis (HR = 2.35, %95 CI = 2.1-4.65, P = .003). CONCLUSIONS: In conclusion, we found that the TC and CC alleles are associated with unfavorable prognosis in triple negative breast cancer patients.

Discrepancies of current recommendations in breast cancer follow-up: a systematic review.

INTRODUCTION: Management and optimal follow-up of early breast cancer survivors remain up to this day a challenge due to the lack of well-established guidelines. Multiple medical societies, organizations and working groups have provided recommendations for follow-up but there is no uniform, globally approved algorithm to guide clinical practice. METHODS: A systematic review was performed to identify and evaluate discrepancies between available guidelines for the follow-up of breast cancer survivors. RESULTS: Differences in the follow-up schedule, laboratory and imaging investigations were noted. In the clinical practice setting, the situation is complicated further by clinicians who often request unnecessary tests not currently incorporated in any of the existing guidelines. CONCLUSIONS: Follow-up of patients with early breast cancer needs to become standardized and prospective clinical trials focusing on optimal follow-up are more than mandatory.

Low protein expression of MET in ER-positive and HER2-positive breast cancer.

AIM: The mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that plays a key role in cell survival, growth, angiogenesis and metastasis. Because its expression is frequently altered in tumors, MET is currently under investigation as a potential target for anticancer therapy. The purpose of the present study was to determine the prognostic value of tumor MET expression levels in patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-positive breast cancer, in order to strengthen the rationale for targeted therapy using MET inhibitors in this breast cancer subpopulation. MATERIALS AND METHODS: We determined the expression of MET in formalin-fixed paraffin-embedded surgical specimens of ER- and HER2-positive breast cancer by immunohistochemistry. RESULTS: Comparisons of MET expression with clinical parameters, including survival of the patients, were performed with MET expression as a dichotomized variable classified as high or low. Out of 78 tumors, 3 (3.8%) showed high MET expression. The analysis examining the association between MET and survival did not yield any statistically significant result regarding overall survival or disease-free survival. CONCLUSION: ER- and HER2-positive breast carcinomas do not exhibit high MET expression. This null finding, the first to be reported in the literature, is of great importance, since it indicates that this sub-group population is not proper candidate for clinical trials with MET inhibitors.

Breast cancer in women aged 25 years and younger.

OBJECTIVE: To evaluate breast cancer characteristics in women aged 25 years and younger. METHODS: This was a retrospective, nested, within-cases matched study. The study design was based on a two-phase protocol. In the first phase, stage, grade, histologic subtype, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status were compared between 28 patients (aged 25 years and younger) and 685 older premenopausal women (aged older than 25 years) with breast cancer. The second phase aimed to determine whether young patients exhibited worse prognosis when compared with older premenopausal women. RESULTS: Young patients presented at a more advanced stage (P=.012) and exhibited a higher grade (P=.018). No significant differences were noted regarding histologic subtype, estrogen receptor, and progesterone receptor status. Genetic testing for BRCA1 and BRCA2 mutations was performed in 12 of 28 young patients and mutations were found in 25% of them. Moreover, young women presented poorer overall survival (hazard ratio [HR] 4.30, 95% confidence interval [CI] 1.09-17.03) than their older counterparts, matched by histologic subtype, stage, and grade; a similar pattern was noted regarding relapse-free survival (HR 8.28, 95% CI 2.24-30.60). CONCLUSION: Breast cancer diagnosis in women aged 25 years and younger is uncommon; however, these patients present at a more advanced stage, with a higher grade, and exhibit poorer survival.

Does pregnancy-associated breast cancer imply a worse prognosis? A matched case-case study.

BACKGROUND: Significant controversy exists in the literature regarding the role of pregnancy in the prognosis of breast cancer. We designed a matched case-case study, matching pregnancy-associated breast cancer (PABC) cases with breast cancer cases for stage, age, and year of diagnosis. PATIENTS AND METHODS: 39 consecutive cases of PABC were matched with 39 premenopausal cases of breast cancer. Univariate and multivariate survival analyses followed by adjustment for stage, grade, estrogen receptor status, and age at diagnosis, were performed. RESULTS: Regarding overall survival (OS), univariate analysis pointed to longer OS in non-PABC cases vs. PABC cases. Accordingly, a more advanced stage predicted shorter survival. In the multivariate analysis, the independent aggravating effect mediated by pregnancy persisted. Interestingly, a post hoc nested analysis within PABC cases indicated that the 3rd trimester pointed to shorter OS. The aforementioned results on OS were also replicated during the examination of relapse-free survival. CONCLUSION: Implementing a matched case-case design, the present study points to pregnancy as a poor prognostic factor for breast cancer.

Detection of RUNX2 gene expression in cumulus cells in women undergoing controlled ovarian stimulation.

BACKGROUND: RUNX2 is a transcription factor, whose expression has been recently identified in the mouse ovary. Regulation of RUNX2 expression and its function in the human ovary have not been determined yet. The aim of the present study is the investigation of the possible correlation between RUNX2 gene expression in cumulus cells and controlled ovarian stimulation and pregnancy outcomes after ART treatment. METHODS: A total of 41 patients undergoing ICSI treatment for male factor infertility were enrolled into a specific ART program, during which cumulus cells were collected. The expression of RUNX2 gene in cumulus cells was examined by real-time PCR. RESULTS: Concerning RUNX2 gene expression, 12 out of 41 women were detected with RUNX2 expression, with ratios ranging from 0.84 to 1.00, while 28 out of 41 women had no expression (ratio = 0). Only 1 woman presented a weak RUNX2 gene expression (ratio = 0.52). From 8 women that proceeded to pregnancy, 7 of them did not express RUNX2 gene in cumulus cells, while one was the woman with weak gene expression that also achieved pregnancy. The group of women without RUNX2 expression presented higher number of follicles (p = 0.013), higher number of retrieved oocytes (p = 0.016), higher basal LH serum levels (p = 0.016) and higher peak estradiol levels (p = 0.013), while the number of fertilized oocytes differed marginally between the two groups (p = 0.089). Moreover, RUNX2 expression was negatively associated with LH levels (OR = 0.22, p = 0.021) and E2 levels (OR = 0.25, p = 0.026). CONCLUSIONS: Consequently, based on the preliminary findings of the present pilot study a potential inhibitory mechanism of RUNX2 gene is observed in the ovary when high mRNA levels are detected, suggesting that RUNX2 could possibly be used as a candidate genetic marker in the monitoring of the outcome of an ART treatment.

LH receptor gene expression in cumulus cells in women entering an ART program.

PURPOSE: Luteinizing hormone (LH) exerts its actions through its receptor (LHR), which is mainly expressed in theca cells and to a lesser extent in oocytes, granulosa and cumulus cells. The aim of the present study was the investigation of a possible correlation between LHR gene and LHR splice variants expression in cumulus cells and ovarian response as well as ART outcome. METHODS: Forty patients undergoing ICSI treatment for male factor infertility underwent a long luteal GnRH-agonist downregulation protocol with a fixed 5-day rLH pre-treatment prior to rFSH stimulation and samples of cumulus cells were collected on the day of egg collection. RNA extraction and cDNA preparation was followed by LHR gene expression investigation through real-time PCR. Furthermore, cumulus cells were investigated for the detection of LHR splice variants using reverse transcription PCR. RESULTS: Concerning LHR expression in cumulus cells, a statistically significant negative association was observed with the duration of ovarian stimulation (odds ratio = 0.23, p = 0.012). Interestingly, 6 over 7 women who fell pregnant expressed at least two specific types of LHR splice variants (735 bp, 621 bp), while only 1 out of 19 women that did not express any splice variant achieved a pregnancy. CONCLUSIONS: Consequently, the present study provide a step towards a new role of LHR gene expression profiling as a biomarker in the prediction of ovarian response at least in terms of duration of stimulation and also a tentative role of LHR splice variants expression in the prediction of pregnancy success.

Variable effects of maternal and paternal-fetal contribution to the risk for preeclampsia combining GSTP1, eNOS, and LPL gene polymorphisms.

OBJECTIVE: To evaluate the maternal, paternal, and fetal genotype contribution to preeclampsia. STUDY DESIGN, MATERIALS, AND METHODS: We combined the analysis of polymorphisms of the GSTP1, eNOS, and LPL genes - affecting biotransformation enzymes and endothelial function - in a cohort of 167 preeclamptic and normal control trios (mother, father, and child) comprising a total of 501 samples in the Greek population, never analyzed before by this approach. RESULTS: For the frequency of the GSTP1 Ile(105)/Val(105), the eNOS Glu298Asp and the LPL-93 polymorphisms, statistically significant differences were found between the two groups. However, the transmission rates of the parental alleles to neonates studied by the transmission disequilibrium test, disclosed no increased rate of transmission to preeclampsia children for the variant alleles of Val(105) GSTP1, 298Asp eNOS, and -93G LPL. CONCLUSIONS: These novel data, suggest that interaction of all three types of genotypes (mother, father and neonate), reveals no effects on the development of preeclampsia, but provide the impetus for further studies to decipher the individual contribution of each genetic parameter of preeclampsia.

Low salivary testosterone levels in patients with breast cancer.

BACKGROUND: Correlation between circulating sex steroid levels and breast cancer has been controversial, with measurement of free, or bioavailable hormone rarely available. Salivary hormone levels represent the bioavailable fraction. To further elucidate the role of endogenous hormones in breast cancer, we aimed to assess correlation between salivary sex steroid levels and breast cancer prevalence. METHODS: Salivary hormone levels of testosterone (T), Estradiol (E2), Progesterone (P), Estriol (E3), Estrone (E1), DHEAS and Cortisol (C) were measured by Enzyme Immunoassay (EIA) in 357 women with histologically verified breast cancer and 184 age-matched control women. RESULTS: Salivary T and DHEAS levels were significantly lower in breast cancer cases vs. controls (27.2+13.9 vs. 32.2+17.5 pg/ml, p < 0.001 for T and 5.3+4.3 vs. 6.4+4.5 ng/ml, p = 0.007 for DHEAS). E2 and E1 levels were elevated and E3 levels were lowered in cases vs. controls. CONCLUSIONS: Salivary T levels, representing the bioavailable hormone, are significantly lower in women with breast cancer compared to age-matched control women. These findings support the protective role of bioavailable testosterone in counteracting the proliferative effects of estrogens on mammary tissue.

Gitelman syndrome-associated severe hypokalemia and hypomagnesemia: case report and review of the literature.

We report a case of a woman with Gitelman syndrome who presented to our hospital mainly due to hyperemesis. Following her admission, intravenous potassium and magnesium supplementation was commenced to counter the observed hypokalemia and hypomagnesemia. Hyperemesis receded and although serum potassium remained low, she became asymptomatic. Oral potassium and magnesium supplementation was administered throughout pregnancy and biweekly ion level measurements were scheduled. Despite the intensive replacement, ion levels remained constantly low. She delivered at 38 weeks with an elective caesarean section because of a breech presentation, a healthy female baby weighing 3350 g. Neonatal electrolyte profile was normal.

Placental pathology in women with gestational diabetes.

BACKGROUND: The aim of this study was to investigate pathologic differences of the placenta in pregnancies complicated by gestational diabetes compared to non-diabetic pregnancies. METHODS: Forty singleton pregnancies complicated by gestational diabetes were recruited and compared to 40 consecutive normal pregnancies. A pathologist, blinded to all clinical data, reviewed all histological samples of the placentas. The histological assessment was carried out with regard to the following aspects: fetal vessel thrombosis, villous immaturity, chorangiosis, presence of nucleated fetal red blood cells (NFRBCs), ischemia, infarction, presence of hydropic or avascular villi, lymphohistiocytic villitis and villous fibrinoid necrosis. RESULTS: The presence of degenerative lesions such as fibrinoid necrosis and vascular lesions like chorangiosis was apparent, mainly in the diabetes group. Villous immaturity and the presence of NFRBC as an indication of chronic fetal hypoxia were significantly increased in the placentas of women with diabetes compared with the control group. Fetal/placental weight ratio was significantly lower in the diabetic group. CONCLUSION: Histological abnormalities were observed more frequently in the diabetic placentas compared to the controls. These findings support the hypothesis that impaired placental function is one of the main reasons for the increased frequency of fetal complications in diabetic pregnancies.

Increasing the noninvasive management of rhesus isoimmunization.

OBJECTIVE: To determine the clinical outcome of isoimmunized pregnancies managed by middle cerebral artery peak systolic velocity (MCA-PSV) in an intention-to-treat study. METHOD: Rhesus isoimmunized pregnancies were managed with serial ultrasound and Doppler studies at 7-day intervals up to 34 weeks of gestation, between 2001 and 2005. Invasive diagnostic and therapeutic procedures were carried out when MCA-PSV was indicative of moderate or severe anemia. RESULTS: The overall sensitivity in detecting moderate to severe fetal anemia at less than 34 weeks was 100% (95% confidence interval, 54.1-100.0 L). Twenty-two cases were managed with MCA-PSV. Twelve cases needed fetal blood sampling and 6 cases needed intrauterine transfusion. Cordocentesis revealed a hematocrit of more than 26% in 6 fetuses. CONCLUSION: Management by MCA-PSV Doppler at weekly intervals is a highly sensitive method for detecting fetal anemia. It reduces the number of fetal blood samples needed and significantly lowers interventional procedures.

Management of pregnancy in adolescence complicated by acute lymphoblastic leukemia.

The management of the common acute lymphoblastic leukemia in pregnancy has been controversial. We report a case of a 16-year-old primigravida with acute lymphoblastic leukemia, first presented in pregnancy, which was treated with aggressive chemotherapy protocols. Full remission of the disease was achieved. The neonate was born at 32 weeks following a cesarean section. The woman remains in complete remission, continuing maintenance chemotherapy, 18 months following diagnosis. The offspring did not show any abnormality in physical examinations or laboratory tests and keeps growing normally 18 months after birth.